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Shared Genetic Loci Between Schizophrenia and White Blood Cell Counts Suggest Genetically Determined Systemic Immune Abnormalities. Schizophrenia bulletin BACKGROUND:Immune mechanisms are indicated in schizophrenia (SCZ). Recent genome-wide association studies (GWAS) have identified genetic variants associated with SCZ and immune-related phenotypes. Here, we use cutting edge statistical tools to identify shared genetic variants between SCZ and white blood cell (WBC) counts and further understand the role of the immune system in SCZ. STUDY DESIGN:GWAS results from SCZ (patients, n = 53 386; controls, n = 77 258) and WBC counts (n = 56 3085) were analyzed. We applied linkage disequilibrium score regression, the conditional false discovery rate method and the bivariate causal mixture model for analyses of genetic associations and overlap, and 2 sample Mendelian randomization to estimate causal effects. STUDY RESULTS:The polygenicity for SCZ was 7.5 times higher than for WBC count and constituted 32%-59% of WBC count genetic loci. While there was a significant but weak positive genetic correlation between SCZ and lymphocytes (rg = 0.05), the conditional false discovery rate method identified 383 shared genetic loci (53% concordant effect directions), with shared variants encompassing all investigated WBC subtypes: lymphocytes, n = 215 (56% concordant); neutrophils, n = 158 (49% concordant); monocytes, n = 146 (47% concordant); eosinophils, n = 135 (56% concordant); and basophils, n = 64 (53% concordant). A few causal effects were suggested, but consensus was lacking across different Mendelian randomization methods. Functional analyses indicated cellular functioning and regulation of translation as overlapping mechanisms. CONCLUSIONS:Our results suggest that genetic factors involved in WBC counts are associated with the risk of SCZ, indicating a role of immune mechanisms in subgroups of SCZ with potential for stratification of patients for immune targeted treatment. 10.1093/schbul/sbad082
Lipoprotein(a) Concentration and Risks of Cardiovascular Disease and Diabetes. Gudbjartsson Daniel F,Thorgeirsson Gudmundur,Sulem Patrick,Helgadottir Anna,Gylfason Arnaldur,Saemundsdottir Jona,Bjornsson Eythor,Norddahl Gudmundur L,Jonasdottir Aslaug,Jonasdottir Adalbjorg,Eggertsson Hannes P,Gretarsdottir Solveig,Thorleifsson Gudmar,Indridason Olafur S,Palsson Runolfur,Jonasson Fridbert,Jonsdottir Ingileif,Eyjolfsson Gudmundur I,Sigurdardottir Olof,Olafsson Isleifur,Danielsen Ragnar,Matthiasson Stefan E,Kristmundsdottir Snaedis,Halldorsson Bjarni V,Hreidarsson Astradur B,Valdimarsson Einar M,Gudnason Thorarinn,Benediktsson Rafn,Steinthorsdottir Valgerdur,Thorsteinsdottir Unnur,Holm Hilma,Stefansson Kari Journal of the American College of Cardiology BACKGROUND:Lipoprotein(a) [Lp(a)] is a causal risk factor for cardiovascular diseases that has no established therapy. The attribute of Lp(a) that affects cardiovascular risk is not established. Low levels of Lp(a) have been associated with type 2 diabetes (T2D). OBJECTIVES:This study investigated whether cardiovascular risk is conferred by Lp(a) molar concentration or apolipoprotein(a) [apo(a)] size, and whether the relationship between Lp(a) and T2D risk is causal. METHODS:This was a case-control study of 143,087 Icelanders with genetic information, including 17,715 with coronary artery disease (CAD) and 8,734 with T2D. This study used measured and genetically imputed Lp(a) molar concentration, kringle IV type 2 (KIV-2) repeats (which determine apo(a) size), and a splice variant in LPA associated with small apo(a) but low Lp(a) molar concentration to disentangle the relationship between Lp(a) and cardiovascular risk. Loss-of-function homozygotes and other subjects genetically predicted to have low Lp(a) levels were evaluated to assess the relationship between Lp(a) and T2D. RESULTS:Lp(a) molar concentration was associated dose-dependently with CAD risk, peripheral artery disease, aortic valve stenosis, heart failure, and lifespan. Lp(a) molar concentration fully explained the Lp(a) association with CAD, and there was no residual association with apo(a) size. Homozygous carriers of loss-of-function mutations had little or no Lp(a) and increased the risk of T2D. CONCLUSIONS:Molar concentration is the attribute of Lp(a) that affects risk of cardiovascular diseases. Low Lp(a) concentration (bottom 10%) increases T2D risk. Pharmacologic reduction of Lp(a) concentration in the 20% of individuals with the greatest concentration down to the population median is predicted to decrease CAD risk without increasing T2D risk. 10.1016/j.jacc.2019.10.019
Estimation of the Required Lipoprotein(a)-Lowering Therapeutic Effect Size for Reduction in Coronary Heart Disease Outcomes: A Mendelian Randomization Analysis. Lamina Claudia,Kronenberg Florian, JAMA cardiology Importance:Genetic and epidemiologic data suggest that lipoprotein(a) (Lp[a]) is one of the strongest genetically determined risk factors for coronary heart disease (CHD). Specific therapies to lower Lp(a) are on the horizon, but the required reduction of Lp(a) to translate into clinically relevant lowering of CHD outcomes is a matter of debate. Objective:To estimate the required Lp(a)-lowering effect size that may be associated with a reduction of CHD outcomes compared with the effect size of low-density lipoprotein cholesterol (LDL-C)-lowering therapies. Design, Setting, and Participants:Genetic epidemiologic study using a mendelian randomization analysis to estimate the required Lp(a)-lowering effect size for a clinically meaningful effect on outcomes. We used the effect estimates for Lp(a) from a genome-wide association study (GWAS) and meta-analysis on Lp(a) published in 2017 of 5 different primarily population-based studies of European ancestry. All Lp(a) measurements were performed in 1 laboratory. Genetic estimates for 27 single-nucleotide polymorphisms on Lp(a) concentrations were used. Odds ratios for these 27 single-nucleotide polymorphisms associated with CHD risk were retrieved from a subsample of the CHD Exome+ consortium. Exposures:Genetic LPA score, plasma Lp(a) concentrations, and observations of statin therapies on CHD outcomes. Main Outcomes and Measures:Coronary heart disease. Results:The study included 13 781 individuals from the Lp(a)-GWAS-Consortium from 5 primarily population-based studies and 20 793 CHD cases and 27 540 controls from a subsample of the CHD Exome+ consortium. Four of the studies were similar in age distribution (means between 51 and 59 years), and 1 cohort was younger; mean age, 32 years. The frequency of women was similar between 51% and 55%. We estimated that the required reduction in Lp(a) effect size would be 65.7 mg/dL (95% CI, 46.3-88.3) to reach the same potential effect on clinical outcomes that can be reached by lowering LDL-C by 38.67 mg/dL (to convert to millimoles per liter, multiply by 0.0259). Conclusions and Relevance:This mendelian randomization analysis estimated a required Lp(a)-lowering effect size of 65.7 mg/dL to reach the same effect as a 38.67-mg/dL lowering of LDL-C. However, this estimate is determined by the observed effect estimates of single-nucleotide polymorphisms on Lp(a) concentrations and is therefore influenced by the standardization of the Lp(a) assay used. As a consequence, calculations of the required Lp(a)-lowering potential of a drug to be clinically effective might have been overestimated in the past. 10.1001/jamacardio.2019.1041
Differential effects of PCSK9 variants on risk of coronary disease and ischaemic stroke. European heart journal Aims:PCSK9 genetic variants that have large effects on low-density lipoprotein cholesterol (LDL-C) and coronary heart disease (CHD) have prompted the development of therapeutic PCSK9-inhibition. However, there is limited evidence that PCSK9 variants are associated with ischaemic stroke (IS). Methods and results:Associations of the loss-of-function PCSK9 genetic variant (rs11591147; R46L), and five additional PCSK9 variants, with IS and IS subtypes (cardioembolic, large vessel, and small vessel) were estimated in a meta-analysis involving 10 307 IS cases and 19 326 controls of European ancestry. They were then compared with the associations of these variants with LDL-C levels (in up to 172 970 individuals) and CHD (in up to 60 801 CHD cases and 123 504 controls). The rs11591147 T allele was associated with 0.5 mmol/L lower LDL-C level (P = 9 × 10-143) and 23% lower CHD risk [odds ratio (OR): 0.77, 95% confidence interval (CI): 0.69-0.87, P = 7 × 10-6]. However, it was not associated with risk of IS (OR: 1.04, 95% CI: 0.84-1.28, P = 0.74) or IS subtypes. Information from additional PCSK9 variants also indicated consistently weaker effects on IS than on CHD. Conclusion:PCSK9 genetic variants that confer life-long lower PCSK9 and LDL-C levels appear to have significantly weaker, if any, associations with risk of IS than with risk of CHD. By contrast, similar proportional reductions in risks of IS and CHD have been observed in randomized trials of therapeutic PCSK9-inhibition. These findings have implications for our understanding of when Mendelian randomization can be relied upon to predict the effects of therapeutic interventions. 10.1093/eurheartj/ehx373
Apolipoprotein(a) isoform size, lipoprotein(a) concentration, and coronary artery disease: a mendelian randomisation analysis. The lancet. Diabetes & endocrinology BACKGROUND:The lipoprotein(a) pathway is a causal factor in coronary heart disease. We used a genetic approach to distinguish the relevance of two distinct components of this pathway, apolipoprotein(a) isoform size and circulating lipoprotein(a) concentration, to coronary heart disease. METHODS:In this mendelian randomisation study, we measured lipoprotein(a) concentration and determined apolipoprotein(a) isoform size with a genetic method (kringle IV type 2 [KIV2] repeats in the LPA gene) and a serum-based electrophoretic assay in patients and controls (frequency matched for age and sex) from the Pakistan Risk of Myocardial Infarction Study (PROMIS). We calculated odds ratios (ORs) for myocardial infarction per 1-SD difference in either LPA KIV2 repeats or lipoprotein(a) concentration. In a genome-wide analysis of up to 17 503 participants in PROMIS, we identified genetic variants associated with either apolipoprotein(a) isoform size or lipoprotein(a) concentration. Using a mendelian randomisation study design and genetic data on 60 801 patients with coronary heart disease and 123 504 controls from the CARDIoGRAMplusC4D consortium, we calculated ORs for myocardial infarction with variants that produced similar differences in either apolipoprotein(a) isoform size in serum or lipoprotein(a) concentration. Finally, we compared phenotypic versus genotypic ORs to estimate whether apolipoprotein(a) isoform size, lipoprotein(a) concentration, or both were causally associated with coronary heart disease. FINDINGS:The PROMIS cohort included 9015 patients with acute myocardial infarction and 8629 matched controls. In participants for whom KIV2 repeat and lipoprotein(a) data were available, the OR for myocardial infarction was 0·93 (95% CI 0·90-0·97; p<0·0001) per 1-SD increment in LPA KIV2 repeats after adjustment for lipoprotein(a) concentration and conventional lipid concentrations. The OR for myocardial infarction was 1·10 (1·05-1·14; p<0·0001) per 1-SD increment in lipoprotein(a) concentration, after adjustment for LPA KIV2 repeats and conventional lipids. Genome-wide analysis identified rs2457564 as a variant associated with smaller apolipoprotein(a) isoform size, but not lipoprotein(a) concentration, and rs3777392 as a variant associated with lipoprotein(a) concentration, but not apolipoprotein(a) isoform size. In 60 801 patients with coronary heart disease and 123 504 controls, OR for myocardial infarction was 0·96 (0·94-0·98; p<0·0001) per 1-SD increment in apolipoprotein(a) protein isoform size in serum due to rs2457564, which was directionally concordant with the OR observed in PROMIS for a similar change. The OR for myocardial infarction was 1·27 (1·07-1·50; p=0·007) per 1-SD increment in lipoprotein(a) concentration due to rs3777392, which was directionally concordant with the OR observed for a similar change in PROMIS. INTERPRETATION:Human genetic data suggest that both smaller apolipoprotein(a) isoform size and increased lipoprotein(a) concentration are independent and causal risk factors for coronary heart disease. Lipoprotein(a)-lowering interventions could be preferentially effective in reducing the risk of coronary heart disease in individuals with smaller apolipoprotein(a) isoforms. FUNDING:British Heart Foundation, US National Institutes of Health, Fogarty International Center, Wellcome Trust, UK Medical Research Council, UK National Institute for Health Research, and Pfizer. 10.1016/S2213-8587(17)30088-8
Childhood BMI and Adult Type 2 Diabetes, Coronary Artery Diseases, Chronic Kidney Disease, and Cardiometabolic Traits: A Mendelian Randomization Analysis. Geng Tingting,Smith Caren E,Li Changwei,Huang Tao Diabetes care OBJECTIVE:To test the causal effect of childhood BMI on adult cardiometabolic diseases using a Mendelian randomization analysis. RESEARCH DESIGN AND METHODS:We used 15 single nucleotide polymorphisms as instrumental variables for childhood BMI to test the causal effect of childhood BMI on cardiometabolic diseases using summary-level data from consortia. RESULTS:We found that a 1-SD increase in childhood BMI (kg/m) was associated with an 83% increase in risk of type 2 diabetes (odds ratio [OR] 1.83 [95% CI 1.46, 2.30]; = 2.5 × 10) and a 28% increase in risk of coronary artery disease (CAD) (OR 1.28 [95% CI 1.17, 1.39]; = 2.1 × 10) at the Bonferroni-adjusted level of significance ( < 0.017) in adults. In addition, a 1-SD increase in childhood BMI was associated with a 0.587-SD increase in adulthood BMI (kg/m), a 0.062-SD increase in hip circumference (cm), a 0.602-SD increase in waist circumference (cm), a 0.111 pmol/L increase in log fasting insulin, a 0.068 increase in log-transformed HOMA of ß-cell function (%), a 0.126 increase in log-transformed HOMA of insulin resistance (%), and a 0.109-SD increase in triglyceride (mg/dL) but a 0.138-SD decrease in HDL (mg/dL) in adults at the Bonferroni-adjusted level of significance ( < 0.0026). CONCLUSIONS:A genetic predisposition to higher childhood BMI was associated with increased risk of type 2 diabetes and CAD in adult life. These results provide evidence supportive of a causal association between childhood BMI and these outcomes. 10.2337/dc17-2141
The Impact of Glycated Hemoglobin (HbA) on Cardiovascular Disease Risk: A Mendelian Randomization Study Using UK Biobank. Au Yeung Shiu Lun,Luo Shan,Schooling C Mary Diabetes care OBJECTIVE:Glycated hemoglobin (HbA) is positively associated with cardiovascular disease (CVD), although evidence is primarily observational. Mendelian randomization studies have only examined its relation with subtypes of CVD. We examined the relation of HbA with CVD and its subtypes in the UK Biobank using Mendelian randomization. RESEARCH DESIGN AND METHODS:We used 38 genetic variants strongly and independently related to HbA ( = 123,665) applied to the UK Biobank ( = 392,038). We used inverse variance weighting (IVW) to obtain the associations of HbA with CVD, coronary artery disease (CAD), and stroke (overall and stroke subtypes). Sensitivity analyses included Mendelian randomization (MR)-Egger, a weighted median, and exclusion of potentially invalid single nucleotide polymorphisms (SNPs). We also applied the same genetic instruments to CARDIoGRAMplusC4D (Coronary ARtery DIsease Genome wide Replication and Meta-analysis [CARDIoGRAM] plus The Coronary Artery Disease [C4D] Genetics) 1000 Genomes-based genome-wide association study ( = 184,305) as a validation for CAD. RESULTS:In the UK Biobank, HbA was not associated with CVD using IVW (odds ratio [OR] 1.11 per %, 95% CI 0.83-1.48). However, HbA was associated with increased CAD risk (OR 1.50 per %, 95% CI 1.08-2.11) with directionally consistent results from MR-Egger and weighted median. The positive association with CAD was more pronounced when we excluded potentially invalid SNPs (OR 2.24 per %, 95% CI 1.55-3.25). The positive association was replicated in CARDIoGRAM (OR 1.52 per %, 95% CI 1.03-2.26). The association of HbA with stroke and its subtypes was less clear given the low number of cases. CONCLUSIONS:HbA likely causes CAD. The underlying mechanisms remain to be elucidated. 10.2337/dc18-0289
Association of Genetically Predicted Lipid Levels With the Extent of Coronary Atherosclerosis in Icelandic Adults. Björnsson Eythór,Thorleifsson Guðmar,Helgadóttir Anna,Guðnason Thórarinn,Guðbjartsson Tómas,Andersen Karl,Grétarsdóttir Sólveig,Ólafsson Ísleifur,Tragante Vinicius,Ólafsson Ólafur Hreiðar,Jónsdóttir Birna,Eyjólfsson Guðmundur I,Sigurðardóttir Ólöf,Thorgeirsson Guðmundur,Guðbjartsson Daníel F,Thorsteinsdóttir Unnur,Hólm Hilma,Stefánsson Kári JAMA cardiology Importance:Genetic studies have evaluated the influence of blood lipid levels on the risk of coronary artery disease (CAD), but less is known about how they are associated with the extent of coronary atherosclerosis. Objective:To estimate the contributions of genetically predicted blood lipid levels on the extent of coronary atherosclerosis. Design, Setting, and Participants:This genetic study included Icelandic adults who had undergone coronary angiography or assessment of coronary artery calcium using cardiac computed tomography. The study incorporates data collected from January 1987 to December 2017 in Iceland in the Swedish Coronary Angiography and Angioplasty Registry and 2 registries of individuals who had undergone percutaneous coronary interventions and coronary artery bypass grafting. For each participant, genetic scores were calculated for levels of non-high-density lipoprotein cholesterol (non-HDL-C), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides, based on reported effect sizes of 345 independent, lipid-associated variants. The genetic scores' predictive ability for lipid levels was assessed in more than 87 000 Icelandic adults. A mendelian randomization approach was used to estimate the contribution of each lipid trait. Exposures:Genetic scores for levels of non-HDL-C, LDL-C, HDL-C, and triglycerides. Main Outcomes and Measures:The extent of angiographic CAD and coronary artery calcium quantity. Results:A total of 12 460 adults (mean [SD] age, 65.1 [10.7] years; 8383 men [67.3%]) underwent coronary angiography, and 4837 had coronary artery calcium assessed by computed tomography. A genetically predicted increase in non-HDL-C levels by 1 SD (38 mg/dL [to convert to millimoles per liter, multiply by 0.0259]) was associated with greater odds of obstructive CAD (odds ratio [OR], 1.83 [95% CI, 1.63-2.07]; P = 2.8 × 10-23). Among patients with obstructive CAD, there were significant associations with multivessel disease (OR, 1.26 [95% CI, 1.11-1.44]; P = 4.1 × 10-4) and 3-vessel disease (OR, 1.47 [95% CI, 1.26-1.72]; P = 9.2 × 10-7). There were also significant associations with the presence of coronary artery calcium (OR, 2.04 [95% CI, 1.70-2.44]; P = 5.3 × 10-15) and loge-transformed coronary artery calcium (effect, 0.70 [95% CI, 0.53-0.87]; P = 1.0 × 10-15). Genetically predicted levels of non-HDL-C remained associated with obstructive CAD and coronary artery calcium extent even after accounting for the association with LDL-C. Genetically predicted levels of HDL-C and triglycerides were associated individually with the extent of coronary atherosclerosis, but not after accounting for the association with non-HDL cholesterol. Conclusions and Relevance:In this study, genetically predicted levels of non-HDL-C were associated with the extent of coronary atherosclerosis as estimated by 2 different methods. The association was stronger than for genetically predicted levels of LDL-C. These findings further support the notion that non-HDL-C may be a better marker of the overall burden of atherogenic lipoproteins than LDL-C. 10.1001/jamacardio.2019.2946
Mendelian Randomization Study of ACLY and Cardiovascular Disease. The New England journal of medicine 10.1056/NEJMc1908496
Mendelian Randomization Study of ACLY and Cardiovascular Disease. The New England journal of medicine 10.1056/NEJMc1908496
Plasma lipids and risk of aortic valve stenosis: a Mendelian randomization study. European heart journal AIMS:Aortic valve stenosis is commonly considered a degenerative disorder with no recommended preventive intervention, with only valve replacement surgery or catheter intervention as treatment options. We sought to assess the causal association between exposure to lipid levels and risk of aortic stenosis. METHODS AND RESULTS:Causality of association was assessed using two-sample Mendelian randomization framework through different statistical methods. We retrieved summary estimations of 157 genetic variants that have been shown to be associated with plasma lipid levels in the Global Lipids Genetics Consortium that included 188 577 participants, mostly European ancestry, and genetic association with aortic stenosis as the main outcome from a total of 432 173 participants in the UK Biobank. Secondary negative control outcomes included aortic regurgitation and mitral regurgitation. The odds ratio for developing aortic stenosis per unit increase in lipid parameter was 1.52 [95% confidence interval (CI) 1.22-1.90; per 0.98 mmol/L] for low density lipoprotein (LDL)-cholesterol, 1.03 (95% CI 0.80-1.31; per 0.41 mmol/L) for high density lipoprotein (HDL)-cholesterol, and 1.38 (95% CI 0.92-2.07; per 1 mmol/L) for triglycerides. There was no evidence of a causal association between any of the lipid parameters and aortic or mitral regurgitation. CONCLUSION:Lifelong exposure to high LDL-cholesterol increases the risk of symptomatic aortic stenosis, suggesting that LDL-lowering treatment may be effective in its prevention. 10.1093/eurheartj/ehaa070
Genome-wide Association Analysis in Humans Links Nucleotide Metabolism to Leukocyte Telomere Length. American journal of human genetics Leukocyte telomere length (LTL) is a heritable biomarker of genomic aging. In this study, we perform a genome-wide meta-analysis of LTL by pooling densely genotyped and imputed association results across large-scale European-descent studies including up to 78,592 individuals. We identify 49 genomic regions at a false dicovery rate (FDR) < 0.05 threshold and prioritize genes at 31, with five highlighting nucleotide metabolism as an important regulator of LTL. We report six genome-wide significant loci in or near SENP7, MOB1B, CARMIL1, PRRC2A, TERF2, and RFWD3, and our results support recently identified PARP1, POT1, ATM, and MPHOSPH6 loci. Phenome-wide analyses in >350,000 UK Biobank participants suggest that genetically shorter telomere length increases the risk of hypothyroidism and decreases the risk of thyroid cancer, lymphoma, and a range of proliferative conditions. Our results replicate previously reported associations with increased risk of coronary artery disease and lower risk for multiple cancer types. Our findings substantially expand current knowledge on genes that regulate LTL and their impact on human health and disease. 10.1016/j.ajhg.2020.02.006
Causal associations of blood lipids with risk of ischemic stroke and intracerebral hemorrhage in Chinese adults. Nature medicine Stroke is the second leading cause of death worldwide and accounts for >2 million deaths annually in China. Ischemic stroke (IS) and intracerebral hemorrhage (ICH) account for an equal number of deaths in China, despite a fourfold greater incidence of IS. Stroke incidence and ICH proportion are higher in China than in Western populations, despite having a lower mean low-density lipoprotein cholesterol (LDL-C) concentration. Observational studies reported weaker positive associations of LDL-C with IS than with coronary heart disease (CHD), but LDL-C-lowering trials demonstrated similar risk reductions for IS and CHD. Mendelian randomization studies of LDL-C and IS have reported conflicting results, and concerns about the excess risks of ICH associated with lowering LDL-C may have prevented the more widespread use of statins in China. We examined the associations of biochemically measured lipids with stroke in a nested case-control study in the China Kadoorie Biobank (CKB) and compared the risks for both stroke types associated with equivalent differences in LDL-C in Mendelian randomization analyses. The results demonstrated positive associations of LDL-C with IS and equally strong inverse associations with ICH, which were confirmed by genetic analyses and LDL-C-lowering trials. Lowering LDL-C is still likely to have net benefit for the prevention of overall stroke and cardiovascular disease in China. 10.1038/s41591-019-0366-x
Midlife vascular risk factors and risk of incident dementia: Longitudinal cohort and Mendelian randomization analyses in the UK Biobank. Malik Rainer,Georgakis Marios K,Neitzel Julia,Rannikmäe Kristiina,Ewers Michael,Seshadri Sudha,Sudlow Cathie L M,Dichgans Martin Alzheimer's & dementia : the journal of the Alzheimer's Association INTRODUCTION:Midlife clustering of vascular risk factors has been associated with late-life dementia, but causal effects of individual biological and lifestyle factors remain largely unknown. METHODS:Among 229,976 individuals (mean follow-up 9 years), we explored whether midlife cardiovascular health measured by Life's Simple 7 (LS7) is associated with incident all-cause dementia and whether the individual components of the score are causally associated with dementia. RESULTS:Adherence to the biological metrics of LS7 (blood pressure, cholesterol, glycemic status) was associated with lower incident dementia risk (hazard ratio = 0.93 per 1-point increase, 95% confidence interval [CI; 0.89-0.96]). In contrast, there was no association between the composite LS7 score and the lifestyle subscore (smoking, body mass index, diet, physical activity) and incident dementia. In Mendelian randomization analyses, genetically elevated blood pressure was associated with higher risk of dementia (odds ratio = 1.31 per one-standard deviation increase, 95% CI [1.05-1.60]). DISCUSSION:These findings underscore the importance of blood pressure control in midlife to mitigate dementia risk. 10.1002/alz.12320
Associations of Adiposity, Circulating Protein Biomarkers, and Risk of Major Vascular Diseases. Pang Yuanjie,Kartsonaki Christiana,Lv Jun,Fairhurst-Hunter Zammy,Millwood Iona Y,Yu Canqing,Guo Yu,Chen Yiping,Bian Zheng,Yang Ling,Chen Junshi,Clarke Robert,Walters Robin G,Holmes Michael V,Li Liming,Chen Zhengming JAMA cardiology Importance:Obesity is associated with a higher risk of cardiovascular disease (CVD), but little is known about the role that circulating protein biomarkers play in this association. Objective:To examine the observational and genetic associations of adiposity with circulating protein biomarkers and the observational associations of proteins with incident CVD. Design, Setting, and Participants:This subcohort study included 628 participants from the prospective China Kadoorie Biobank who did not have a history of cancer at baseline. The Olink platform measured 92 protein markers in baseline plasma samples. Data were collected from June 2004 to January 2016 and analyzed from January 2019 to June 2020. Exposures:Measured body mass index (BMI) obtained during the baseline survey and genetically instrumented BMI derived using 571 externally weighted single-nucleotide variants. Main Outcomes and Measures:Cross-sectional associations of adiposity with biomarkers were examined using linear regression. Associations of biomarkers with CVD risk were assessed using Cox regression among those without prior cancer or CVD at baseline. Mendelian randomization was conducted to derive genetically estimated associations of BMI with biomarkers. Findings:In observational analyses of 628 individuals (mean [SD] age, 52.2 [10.5] years; 385 women [61.3%]), BMI (mean [SD], 23.9 [3.6]) was positively associated with 27 proteins (per 1-SD higher BMI; eg, interleukin-6: 0.21 [95% CI, 0.12-0.29] SD; interleukin-18: 0.13 [95% CI, 0.05-0.21] SD; monocyte chemoattractant protein-1: 0.12 [95% CI, 0.04-0.20] SD; hepatocyte growth factor: 0.31 [95% CI, 0.24-0.39] SD), and inversely with 3 proteins (Fas ligand: -0.11 [95% CI, -0.19 to -0.03] SD; TNF-related weak inducer of apoptosis, -0.14 [95% CI, -0.23 to -0.06] SD; and carbonic anhydrase 9: (-0.14 [95% CI, -0.22 to -0.05] SD), with similar associations identified for other adiposity traits (eg, waist circumference [r = 0.96]). In mendelian randomization, the associations of genetically elevated BMI with specific proteins were directionally consistent with the observational associations. In meta-analyses of genetically elevated BMI with 8 proteins, combining present estimates with previous studies, the most robust associations were shown for interleukin-6 (per 1-SD higher BMI; 0.21 [95% CI, 0.13-0.29] SD), interleukin-18 (0.16 [95% CI, 0.06-0.26] SD), monocyte chemoattractant protein-1 (0.21 [95% CI, 0.11-0.30] SD), monocyte chemotactic protein-3 (0.12 [95% CI, 0.03-0.21] SD), TNF-related apoptosis-inducing ligand (0.23 [95% CI, 0.13-0.32] SD), and hepatocyte growth factor (0.14 [95% CI, 0.06-0.22] SD). Of the 30 BMI-associated biomarkers, 10 (including interleukin-6, interleukin-18, and hepatocyte growth factor) were nominally associated with incident CVD. Conclusions and Relevance:Mendelian randomization shows adiposity to be associated with a range of protein biomarkers, with some biomarkers also showing association with CVD risk. Future studies are warranted to validate these findings and assess whether proteins may be mediators between adiposity and CVD. 10.1001/jamacardio.2020.6041
Non-linear Mendelian randomization analyses support a role for vitamin D deficiency in cardiovascular disease risk. European heart journal AIMS:Low vitamin D status is associated with a higher risk for cardiovascular diseases (CVDs). Although most existing linear Mendelian randomization (MR) studies reported a null effect of vitamin D on CVD risk, a non-linear effect cannot be excluded. Our aim was to apply the non-linear MR design to investigate the association of serum 25-hydroxyvitamin D [25(OH)D] concentration with CVD risk. METHODS AND RESULTS:The non-linear MR analysis was conducted in the UK Biobank with 44 519 CVD cases and 251 269 controls. Blood pressure (BP) and cardiac-imaging-derived phenotypes were included as secondary outcomes. Serum 25(OH)D concentration was instrumented using 35 confirmed genome-wide significant variants.We also estimated the potential reduction in CVD incidence attributable to correction of low vitamin D status. There was a L-shaped association between genetically predicted serum 25(OH)D and CVD risk (Pnon-linear = 0.007), where CVD risk initially decreased steeply with increasing concentrations and levelled off at around 50 nmol/L. A similar association was seen for systolic (Pnon-linear = 0.03) and diastolic (Pnon-linear = 0.07) BP. No evidence of association was seen for cardiac-imaging phenotypes (P = 0.05 for all). Correction of serum 25(OH)D level below 50 nmol/L was predicted to result in a 4.4% reduction in CVD incidence (95% confidence interval: 1.8- 7.3%). CONCLUSION:Vitamin D deficiency can increase the risk of CVD. Burden of CVD could be reduced by population-wide correction of low vitamin D status. 10.1093/eurheartj/ehab809
Mendelian Randomization Study of and Cardiovascular Disease. The New England journal of medicine BACKGROUND:ATP citrate lyase is an enzyme in the cholesterol-biosynthesis pathway upstream of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR), the target of statins. Whether the genetic inhibition of ATP citrate lyase is associated with deleterious outcomes and whether it has the same effect, per unit decrease in the low-density lipoprotein (LDL) cholesterol level, as the genetic inhibition of HMGCR is unclear. METHODS:We constructed genetic scores composed of independently inherited variants in the genes encoding ATP citrate lyase () and HMGCR to create instruments that mimic the effect of ATP citrate lyase inhibitors and HMGCR inhibitors (statins), respectively. We then compared the associations of these genetic scores with plasma lipid levels, lipoprotein levels, and the risk of cardiovascular events and cancer. RESULTS:A total of 654,783 participants, including 105,429 participants who had major cardiovascular events, were included in the study. The and scores were associated with similar patterns of changes in plasma lipid and lipoprotein levels and with similar effects on the risk of cardiovascular events per decrease of 10 mg per deciliter in the LDL cholesterol level: odds ratio for cardiovascular events, 0.823 (95% confidence interval [CI], 0.78 to 0.87; P = 4.0×10) for the score and 0.836 (95% CI, 0.81 to 0.87; P = 3.9×10) for the score. Neither lifelong genetic inhibition of ATP citrate lyase nor lifelong genetic inhibition of HMGCR was associated with an increased risk of cancer. CONCLUSIONS:Genetic variants that mimic the effect of ATP citrate lyase inhibitors and statins appeared to lower plasma LDL cholesterol levels by the same mechanism of action and were associated with similar effects on the risk of cardiovascular disease per unit decrease in the LDL cholesterol level. (Funded by Esperion Therapeutics and others.). 10.1056/NEJMoa1806747
Sleep Duration and Myocardial Infarction. Journal of the American College of Cardiology BACKGROUND:Observational studies suggest associations between extremes of sleep duration and myocardial infarction (MI), but the causal contribution of sleep to MI and its potential to mitigate genetic predisposition to coronary disease is unclear. OBJECTIVES:This study sought to investigate associations between sleep duration and incident MI, accounting for joint effects with other sleep traits and genetic risk of coronary artery disease, and to assess causality using Mendelian randomization (MR). METHODS:In 461,347 UK Biobank (UKB) participants free of relevant cardiovascular disease, the authors estimated multivariable adjusted hazard ratios (HR) for MI (5,128 incident cases) across habitual self-reported short (<6 h) and long (>9 h) sleep duration, and examined joint effects with sleep disturbance traits and a coronary artery disease genetic risk score. The authors conducted 2-sample MR for short (24 single nucleotide polymorphisms) and continuous (71 single nucleotide polymorphisms) sleep duration with MI (n = 43,676 cases/128,199 controls), and replicated results in UKB (n = 12,111/325,421). RESULTS:Compared with sleeping 6 to 9 h/night, short sleepers had a 20% higher multivariable-adjusted risk of incident MI (HR: 1.20; 95% confidence interval [CI]: 1.07 to 1.33), and long sleepers had a 34% higher risk (HR: 1.34; 95% CI: 1.13 to 1.58); associations were independent of other sleep traits. Healthy sleep duration mitigated MI risk even among individuals with high genetic liability (HR: 0.82; 95% CI: 0.68 to 0.998). MR was consistent with a causal effect of short sleep duration on MI in CARDIoGRAMplusC4D (Coronary ARtery DIsease Genome wide Replication and Meta-analysis plus Coronary Artery Disease Genetics Consortium) (HR: 1.19; 95% CI: 1.09 to 1.29) and UKB (HR: 1.21; 95% CI: 1.08 to 1.37). CONCLUSIONS:Prospective observational and MR analyses support short sleep duration as a potentially causal risk factor for MI. Investigation of sleep extension to prevent MI may be warranted. 10.1016/j.jacc.2019.07.022
Apolipoprotein B Particles and Cardiovascular Disease: A Narrative Review. Sniderman Allan D,Thanassoulis George,Glavinovic Tamara,Navar Ann Marie,Pencina Michael,Catapano Alberico,Ference Brian A JAMA cardiology Importance:The conventional model of atherosclerosis presumes that the mass of cholesterol within very low-density lipoprotein particles, low-density lipoprotein particles, chylomicron, and lipoprotein (a) particles in plasma is the principal determinant of the mass of cholesterol that will be deposited within the arterial wall and will drive atherogenesis. However, each of these particles contains one molecule of apolipoprotein B (apoB) and there is now substantial evidence that apoB more accurately measures the atherogenic risk owing to the apoB lipoproteins than does low-density lipoprotein cholesterol or non-high-density lipoprotein cholesterol. Observations:Cholesterol can only enter the arterial wall within apoB particles. However, the mass of cholesterol per apoB particle is variable. Therefore, the mass of cholesterol that will be deposited within the arterial wall is determined by the number of apoB particles that are trapped within the arterial wall. The number of apoB particles that enter the arterial wall is determined primarily by the number of apoB particles within the arterial lumen. However, once within the arterial wall, smaller cholesterol-depleted apoB particles have a greater tendency to be trapped than larger cholesterol-enriched apoB particles because they bind more avidly to the glycosaminoglycans within the subintimal space of the arterial wall. Thus, a cholesterol-enriched particle would deposit more cholesterol than a cholesterol-depleted apoB particle whereas more, smaller apoB particles that enter the arterial wall will be trapped than larger apoB particles. The net result is, with the exceptions of the abnormal chylomicron remnants in type III hyperlipoproteinemia and lipoprotein (a), all apoB particles are equally atherogenic. Conclusions and Relevance:Apolipoprotein B unifies, amplifies, and simplifies the information from the conventional lipid markers as to the atherogenic risk attributable to the apoB lipoproteins. 10.1001/jamacardio.2019.3780
Association between adiposity and cardiovascular outcomes: an umbrella review and meta-analysis of observational and Mendelian randomization studies. European heart journal AIMS:The aim of this study was to investigate the causal relationship and evidence of an association between increased adiposity and the risk of incident cardiovascular disease (CVD) events or mortality. METHODS AND RESULTS:Observational (informing association) and Mendelian randomization (MR) (informing causality) studies were assessed to gather mutually complementary insights and elucidate perplexing epidemiological relationships. Systematic reviews and meta-analyses of observational and MR studies that were published until January 2021 and evaluated the association between obesity-related indices and CVD risk were searched. Twelve systematic reviews with 53 meta-analyses results (including over 501 cohort studies) and 12 MR studies were included in the analysis. A body mass index (BMI) increase was associated with higher risks of coronary heart disease, heart failure, atrial fibrillation, all-cause stroke, haemorrhagic stroke, ischaemic stroke, hypertension, aortic valve stenosis, pulmonary embolism, and venous thrombo-embolism. The MR study results demonstrated a causal effect of obesity on all indices but stroke. The CVD risk increase for every 5 kg/m2 increase in BMI varied from 10% [relative risk (RR) 1.10; 95% confidence interval (CI) 1.01-1.21; certainty of evidence, low] for haemorrhagic stroke to 49% (RR 1.49; 95% CI 1.40-1.60; certainty of evidence, high) for hypertension. The all-cause and CVD-specific mortality risks increased with adiposity in cohorts, but the MR studies demonstrated no causal effect of adiposity on all-cause mortality. CONCLUSION:High adiposity is associated with increased CVD risk despite divergent evidence gradients. Adiposity was a causal risk factor for CVD except all-cause mortality and stroke. Half (49%; 26/53) of the associations were supported by high-level evidence. The associations were consistent between sexes and across global regions. This study provides guidance on how to integrate evidence from observational (association) and genetics-driven (causation) studies accumulated to date, to enable a more reliable interpretation of epidemiological relationships. 10.1093/eurheartj/ehab454
High Blood Pressure and Risk of Dementia: A Two-Sample Mendelian Randomization Study in the UK Biobank. Sproviero William,Winchester Laura,Newby Danielle,Fernandes Marco,Shi Liu,Goodday Sarah M,Prats-Uribe Albert,Alhambra Daniel P,Buckley Noel J,Nevado-Holgado Alejo J Biological psychiatry BACKGROUND:Findings from randomized controlled trials have yielded conflicting results on the association between blood pressure (BP) and dementia traits. We tested the hypothesis that a causal relationship exists between systolic BP (SBP) and/or diastolic BP (DBP) and risk of Alzheimer's disease (AD). METHODS:We performed a generalized summary Mendelian randomization (GSMR) analysis using summary statistics of a genome-wide association study meta-analysis of 299,024 individuals of SBP or DBP as exposure variables against three different outcomes: 1) AD diagnosis (International Genomics of Alzheimer's Project), 2) maternal family history of AD (UK Biobank), and 3) paternal family history of AD (UK Biobank). Finally, a combined meta-analysis of 368,440 individuals that included these three summary statistics was used as final outcome. RESULTS:GSMR applied to the International Genomics of Alzheimer's Project dataset revealed a significant effect of high SBP lowering the risk of AD (β = -0.19, p = .04). GSMR applied to the maternal family history of AD UK Biobank dataset (SBP [β = -0.12, p = .02], DBP [β = -0.10, p = .05]) and to the paternal family history of AD UK Biobank dataset (SBP [β = -0.16, p = .02], DBP [β = -0.24, p = 7.4 × 10]) showed the same effect. A subsequent combined meta-analysis confirmed the overall significant effect for the other SBP analyses (β = -0.14, p = .03). The DBP analysis in the combined meta-analysis also confirmed a DBP effect on AD (β = -0.14, p = .03). CONCLUSIONS:A causal effect exists between high BP and a reduced late-life risk of AD. The results were obtained through careful consideration of confounding factors and the application of complementary MR methods on independent cohorts. 10.1016/j.biopsych.2020.12.015
Genetics of 35 blood and urine biomarkers in the UK Biobank. Nature genetics Clinical laboratory tests are a critical component of the continuum of care. We evaluate the genetic basis of 35 blood and urine laboratory measurements in the UK Biobank (n = 363,228 individuals). We identify 1,857 loci associated with at least one trait, containing 3,374 fine-mapped associations and additional sets of large-effect (>0.1 s.d.) protein-altering, human leukocyte antigen (HLA) and copy number variant (CNV) associations. Through Mendelian randomization (MR) analysis, we discover 51 causal relationships, including previously known agonistic effects of urate on gout and cystatin C on stroke. Finally, we develop polygenic risk scores (PRSs) for each biomarker and build 'multi-PRS' models for diseases using 35 PRSs simultaneously, which improved chronic kidney disease, type 2 diabetes, gout and alcoholic cirrhosis genetic risk stratification in an independent dataset (FinnGen; n = 135,500) relative to single-disease PRSs. Together, our results delineate the genetic basis of biomarkers and their causal influences on diseases and improve genetic risk stratification for common diseases. 10.1038/s41588-020-00757-z
Coffee Consumption and Incident Tachyarrhythmias: Reported Behavior, Mendelian Randomization, and Their Interactions. JAMA internal medicine Importance:The notion that caffeine increases the risk of cardiac arrhythmias is common. However, evidence that the consumption of caffeinated products increases the risk of arrhythmias remains poorly substantiated. Objective:To assess the association between consumption of common caffeinated products and the risk of arrhythmias. Design, Setting, and Participants:This prospective cohort study analyzed longitudinal data from the UK Biobank between January 1, 2006, and December 31, 2018. After exclusion criteria were applied, 386 258 individuals were available for analyses. Exposures:Daily coffee intake and genetic polymorphisms that affect caffeine metabolism. Main Outcomes and Measures:Any cardiac arrhythmia, including atrial fibrillation or flutter, supraventricular tachycardia, ventricular tachycardia, premature atrial complexes, and premature ventricular complexes. Results:A total of 386 258 individuals (mean [SD] age, 56 [8] years; 52.3% female) were assessed. During a mean (SD) follow-up of 4.5 (3.1) years, 16 979 participants developed an incident arrhythmia. After adjustment for demographic characteristics, comorbid conditions, and lifestyle habits, each additional cup of habitual coffee consumed was associated with a 3% lower risk of incident arrhythmia (hazard ratio [HR], 0.97; 95% CI, 0.96-0.98; P < .001). In analyses of each arrhythmia alone, statistically significant associations exhibiting a similar magnitude were observed for atrial fibrillation and/or flutter (HR, 0.97; 95% CI, 0.96-0.98; P < .001) and supraventricular tachycardia (HR, 0.96; 95% CI, 0.94-0.99; P = .002). Two distinct interaction analyses, one using a caffeine metabolism-related polygenic score of 7 genetic polymorphisms and another restricted to CYP1A2 rs762551 alone, did not reveal any evidence of effect modification. A mendelian randomization study that used these same genetic variants revealed no significant association between underlying propensities to differing caffeine metabolism and the risk of incident arrhythmia. Conclusions and Relevance:In this prospective cohort study, greater amounts of habitual coffee consumption were associated with a lower risk of arrhythmia, with no evidence that genetically mediated caffeine metabolism affected that association. Mendelian randomization failed to provide evidence that caffeine consumption was associated with arrhythmias. 10.1001/jamainternmed.2021.3616
Advancing the use of genome-wide association studies for drug repurposing. Nature reviews. Genetics Genome-wide association studies (GWAS) have revealed important biological insights into complex diseases, which are broadly expected to lead to the identification of new drug targets and opportunities for treatment. Drug development, however, remains hampered by the time taken and costs expended to achieve regulatory approval, leading many clinicians and researchers to consider alternative paths to more immediate clinical outcomes. In this Review, we explore approaches that leverage common variant genetics to identify opportunities for repurposing existing drugs, also known as drug repositioning. These approaches include the identification of compounds by linking individual loci to genes and pathways that can be pharmacologically modulated, transcriptome-wide association studies, gene-set association, causal inference by Mendelian randomization, and polygenic scoring. 10.1038/s41576-021-00387-z
Frequent LPA KIV-2 Variants Lower Lipoprotein(a) Concentrations and Protect Against Coronary Artery Disease. Journal of the American College of Cardiology BACKGROUND:Lipoprotein(a) (Lp(a)) concentrations are a major independent risk factor for coronary artery disease (CAD) and are mainly determined by variation in LPA. Up to 70% of the LPA coding sequence is located in the hypervariable kringle IV type 2 (KIV-2) region. It is hardly accessible by conventional technologies, but may contain functional variants. OBJECTIVES:This study sought to investigate the new, very frequent splicing variant KIV-2 4733G>A on Lp(a) and CAD. METHODS:We genotyped 4733G>A in the GCKD (German Chronic Kidney Disease) study (n = 4,673) by allele-specific polymerase chain reaction, performed minigene assays, identified proxy single nucleotide polymorphisms and used them to characterize its effect on CAD by survival analysis in UK Biobank (n = 440,234). Frequencies in ethnic groups were assessed in the 1000 Genomes Project. RESULTS:The 4733G>A variant (38.2% carrier frequency) was found in most isoform sizes. It reduces allelic expression without abolishing protein production, lowers Lp(a) by 13.6 mg/dL (95% CI: 12.5-14.7; P < 0.0001) and is the strongest variance-explaining factor after the smaller isoform. Splicing of minigenes was modified. Compound heterozygosity (4.6% of the population) for 4733G>A and 4925G>A, another KIV-2 splicing mutation, reduces Lp(a) by 31.8 mg/dL and most importantly narrows the interquartile range by 9-fold (from 42.1 to 4.6 mg/dL) when compared to the wild type. In UK Biobank 4733G>A alone and compound heterozygosity with 4925G>A reduced HR for CAD by 9% (95% CI: 7%-11%) and 12% (95% CI: 7%-16%) (both P < 0.001). Frequencies in ethnicities differ notably. CONCLUSIONS:Functional variants in the previously inaccessible LPA KIV-2 region cooperate in determining Lp(a) variance and CAD risk. Even a moderate but lifelong genetic Lp(a) reduction translates to a noticeable CAD risk reduction. 10.1016/j.jacc.2021.05.037
Epigenetic Age and the Risk of Incident Atrial Fibrillation. Circulation BACKGROUND:The most prominent risk factor for atrial fibrillation (AF) is chronological age; however, underlying mechanisms are unexplained. Algorithms using epigenetic modifications to the human genome effectively predict chronological age. Chronological and epigenetic predicted ages may diverge in a phenomenon referred to as epigenetic age acceleration (EAA), which may reflect accelerated biological aging. We sought to evaluate for associations between epigenetic age measures and incident AF. METHODS:Measures for 4 epigenetic clocks (Horvath, Hannum, DNA methylation [DNAm] PhenoAge, and DNAm GrimAge) and an epigenetic predictor of PAI-1 (plasminogen activator inhibitor-1) levels (ie, DNAm PAI-1) were determined for study participants from 3 population-based cohort studies. Cox models evaluated for associations with incident AF and results were combined via random-effects meta-analyses. Two-sample summary-level Mendelian randomization analyses evaluated for associations between genetic instruments of the EAA measures and AF. RESULTS:Among 5600 participants (mean age, 65.5 years; female, 60.1%; Black, 50.7%), there were 905 incident AF cases during a mean follow-up of 12.9 years. Unadjusted analyses revealed all 4 epigenetic clocks and the DNAm PAI-1 predictor were associated with statistically significant higher hazards of incident AF, though the magnitudes of their point estimates were smaller relative to the associations observed for chronological age. The pooled EAA estimates for each epigenetic measure, with the exception of Horvath EAA, were associated with incident AF in models adjusted for chronological age, race, sex, and smoking variables. After multivariable adjustment for additional known AF risk factors that could also potentially function as mediators, pooled EAA measures for 2 clocks remained statistically significant. Five-year increases in EAA measures for DNAm GrimAge and DNAm PhenoAge were associated with 19% (adjusted hazard ratio [HR], 1.19 [95% CI, 1.09-1.31]; <0.01) and 15% (adjusted HR, 1.15 [95% CI, 1.05-1.25]; <0.01) higher hazards of incident AF, respectively. Mendelian randomization analyses for the 5 EAA measures did not reveal statistically significant associations with AF. CONCLUSIONS:Our study identified adjusted associations between EAA measures and incident AF, suggesting that biological aging plays an important role independent of chronological age, though a potential underlying causal relationship remains unclear. These aging processes may be modifiable and not constrained by the immutable factor of time. 10.1161/CIRCULATIONAHA.121.056456
Therapeutic Targets for Heart Failure Identified Using Proteomics and Mendelian Randomization. Circulation BACKGROUND:Heart failure (HF) is a highly prevalent disorder for which disease mechanisms are incompletely understood. The discovery of disease-associated proteins with causal genetic evidence provides an opportunity to identify new therapeutic targets. METHODS:We investigated the observational and causal associations of 90 cardiovascular proteins, which were measured using affinity-based proteomic assays. First, we estimated the associations of 90 cardiovascular proteins with incident heart failure by means of a fixed-effect meta-analysis of 4 population-based studies, composed of a total of 3019 participants with 732 HF events. The causal effects of HF-associated proteins were then investigated by Mendelian randomization, using -protein quantitative loci genetic instruments identified from genomewide association studies in more than 30 000 individuals. To improve the precision of causal estimates, we implemented an Mendelian randomization model that accounted for linkage disequilibrium between instruments and tested the robustness of causal estimates through a multiverse sensitivity analysis that included up to 120 combinations of instrument selection parameters and Mendelian randomization models per protein. The druggability of candidate proteins was surveyed, and mechanism of action and potential on-target side effects were explored with cross-trait Mendelian randomization analysis. RESULTS:Forty-four of ninety proteins were positively associated with risk of incident HF (<6.0×10). Among these, 8 proteins had evidence of a causal association with HF that was robust to multiverse sensitivity analysis: higher CSF-1 (macrophage colony-stimulating factor 1), Gal-3 (galectin-3) and KIM-1 (kidney injury molecule 1) were positively associated with risk of HF, whereas higher ADM (adrenomedullin), CHI3L1 (chitinase-3-like protein 1), CTSL1 (cathepsin L1), FGF-23 (fibroblast growth factor 23), and MMP-12 (matrix metalloproteinase-12) were protective. Therapeutics targeting ADM and Gal-3 are currently under evaluation in clinical trials, and all the remaining proteins were considered druggable, except KIM-1. CONCLUSIONS:We identified 44 circulating proteins that were associated with incident HF, of which 8 showed evidence of a causal relationship and 7 were druggable, including adrenomedullin, which represents a particularly promising drug target. Our approach demonstrates a tractable roadmap for the triangulation of population genomic and proteomic data for the prioritization of therapeutic targets for complex human diseases. 10.1161/CIRCULATIONAHA.121.056663
Elevated Lipoprotein(a) and Risk of Atrial Fibrillation: An Observational and Mendelian Randomization Study. Journal of the American College of Cardiology BACKGROUND:Atrial fibrillation (AF) is a cardiac arrhythmia associated with an elevated risk of stroke, heart failure, and mortality. However, preventative therapies are needed with ancillary benefits on its cardiovascular comorbidities. Lipoprotein(a) (Lp[a]) is a recognized risk factor for atherosclerotic cardiovascular disease (ASCVD), which itself increases AF risk, but it remains unknown whether Lp(a) is a causal mediator of AF independent of ASCVD. OBJECTIVES:This study investigated the role of Lp(a) in AF and whether it is independent of ASCVD. METHODS:Measured and genetically predicted Lp(a) levels were tested for association with 20,432 cases of incident AF in the UK Biobank (N = 435,579). Mendelian randomization analyses were performed by using summary-level data for AF from publicly available genome-wide association studies (N = 1,145,375). RESULTS:In the UK Biobank, each 50 nmol/L (23 mg/dL) increase in Lp(a) was associated with an increased risk of incident AF using measured Lp(a) (HR: 1.03; 95% CI: 1.02-1.04 ; P = 1.65 × 10) and genetically predicted Lp(a) (OR: 1.03; 95% CI: 1.02-1.05; P = 1.33 × 10). Mendelian randomization analyses using independent data replicated the effect (OR: 1.04 per 50 nmol/L Lp[a] increase; 95% CI: 1.03-1.05 per 50 nmol/L Lp[a] increase; P = 9.23 × 10). There was no evidence of risk-conferring effect from low-density lipoprotein cholesterol or triglycerides, and only 39% (95% CI: 27%-73%) of Lp(a) risk was mediated through ASCVD, suggesting that Lp(a) partly influences AF independent of its known effects on ASCVD. CONCLUSIONS:Our findings implicate Lp(a) as a potential causal mediator in the development of AF which show that the effects of Lp(a) extend across myocardial tissues. Ongoing clinical trials for Lp(a)-lowering therapies should evaluate effects on AF prevention. 10.1016/j.jacc.2022.02.018
Lipoprotein(a) and Incident Atrial Fibrillation: Leveraging Nature's Randomization to Identify Novel Causal Associations. Journal of the American College of Cardiology 10.1016/j.jacc.2022.02.026
The aging epigenome. eLife A new approach helps to assess the impact of accelerated epigenetic aging on the risk of cancer. 10.7554/eLife.78693
Effects of Coronary Artery Disease-Associated Variants on Vascular Smooth Muscle Cells. Circulation BACKGROUND:Genome-wide association studies have identified many genetic loci that are robustly associated with coronary artery disease (CAD). However, the underlying biological mechanisms are still unknown for most of these loci, hindering the progress to medical translation. Evidence suggests that the genetic influence on CAD susceptibility may act partly through vascular smooth muscle cells (VSMCs). METHODS:We undertook genotyping, RNA sequencing, and cell behavior assays on a large bank of VSMCs (n>1499). Expression quantitative trait locus and splicing quantitative trait locus analyses were performed to identify genes with an expression that was influenced by CAD-associated variants. To identify candidate causal genes for CAD, we ascertained colocalizations of VSMC expression quantitative trait locus signals with CAD association signals by performing causal variants identification in associated regions analysis and the summary data-based mendelian randomization test. Druggability analysis was then performed on the candidate causal genes. CAD risk variants were tested for associations with VSMC proliferation, migration, and apoptosis. Collective effects of multiple CAD-associated variants on VSMC behavior were estimated by polygenic scores. RESULTS:Approximately 60% of the known CAD-associated variants showed statistically significant expression quantitative trait locus or splicing quantitative trait locus effects in VSMCs. Colocalization analyses identified 84 genes with expression quantitative trait locus signals that significantly colocalized with CAD association signals, identifying them as candidate causal genes. Druggability analysis indicated that 38 of the candidate causal genes were druggable, and 13 had evidence of drug-gene interactions. Of the CAD-associated variants tested, 139 showed suggestive associations with VSMC proliferation, migration, or apoptosis. A polygenic score model explained up to 5.94% of variation in several VSMC behavior parameters, consistent with polygenic influences on VSMC behavior. CONCLUSIONS:This comprehensive analysis shows that a large percentage of CAD loci can modulate gene expression in VSMCs and influence VSMC behavior. Several candidate causal genes identified are likely to be druggable and thus represent potential therapeutic targets. 10.1161/CIRCULATIONAHA.121.058389
Association Between Brain Structure and Alcohol Use Behaviors in Adults: A Mendelian Randomization and Multiomics Study. JAMA psychiatry Importance:Past studies have identified associations between brain macrostructure and alcohol use behaviors. However, identifying directional associations between these phenotypes is difficult due to the limitations of observational studies. Objective:To use mendelian randomization (MR) to identify directional associations between brain structure and alcohol use and elucidate the transcriptomic and cellular underpinnings of identified associations. Design, Setting, and Participants:The main source data comprised summary statistics from population-based and case-control genome-wide association studies (GWAS) of neuroimaging, behavioral, and clinical phenotypes (N = 763 874). Using these data, bidirectional and multivariable MR was performed analyzing associations between brain macrostructure and alcohol use. Downstream transcriptome-wide association studies (TWAS) and cell-type enrichment analyses investigated the biology underlying identified associations. The study approach was data driven and did not test any a priori hypotheses. Data were analyzed August 2021 to May 2022. Main Outcomes and Measures:Brain structure phenotypes (global cortical thickness [GCT] and global cortical surface area [GCSA] in 33 709 individuals and left-right subcortical volumes in 19 629 individuals) and alcohol use behaviors (alcoholic drinks per week [DPW] in 537 349 individuals, binge drinking frequency in 143 685 individuals, and alcohol use disorder in 8845 individuals vs 20 657 control individuals [total of 29 502]). Results:The main bidirectional MR analyses were performed in samples totaling 763 874 individuals, among whom more than 94% were of European ancestry, 52% to 54% were female, and the mean cohort ages were 40 to 63 years. Negative associations were identified between genetically predicted GCT and binge drinking (β, -2.52; 95% CI, -4.13 to -0.91) and DPW (β, -0.88; 95% CI, -1.37 to -0.40) at a false discovery rate (FDR) of 0.05. These associations remained significant in multivariable MR models that accounted for neuropsychiatric phenotypes, substance use, trauma, and neurodegeneration. TWAS of GCT and alcohol use behaviors identified 5 genes at the 17q21.31 locus oppositely associated with GCT and binge drinking or DPW (FDR = 0.05). Cell-type enrichment analyses implicated glutamatergic cortical neurons in alcohol use behaviors. Conclusions and Relevance:The findings in this study show that the associations between GCT and alcohol use may reflect a predispositional influence of GCT and that 17q21.31 genes and glutamatergic cortical neurons may play a role in this association. While replication studies are needed, these findings should enhance the understanding of associations between brain structure and alcohol use. 10.1001/jamapsychiatry.2022.2196
Increased soluble urokinase plasminogen activator levels modulate monocyte function to promote atherosclerosis. The Journal of clinical investigation People with kidney disease are disproportionately affected by atherosclerosis for unclear reasons. Soluble urokinase plasminogen activator receptor (suPAR) is an immune-derived mediator of kidney disease, levels of which are strongly associated with cardiovascular outcomes. We assessed suPAR's pathogenic involvement in atherosclerosis using epidemiologic, genetic, and experimental approaches. We found serum suPAR levels to be predictive of coronary artery calcification and cardiovascular events in 5,406 participants without known coronary disease. In a genome-wide association meta-analysis including over 25,000 individuals, we identified a missense variant in the plasminogen activator, urokinase receptor (PLAUR) gene (rs4760), confirmed experimentally to lead to higher suPAR levels. Mendelian randomization analysis in the UK Biobank using rs4760 indicated a causal association between genetically predicted suPAR levels and atherosclerotic phenotypes. In an experimental model of atherosclerosis, proprotein convertase subtilisin/kexin-9 (Pcsk9) transfection in mice overexpressing suPAR (suPARTg) led to substantially increased atherosclerotic plaques with necrotic cores and macrophage infiltration compared with those in WT mice, despite similar cholesterol levels. Prior to induction of atherosclerosis, aortas of suPARTg mice excreted higher levels of CCL2 and had higher monocyte counts compared with WT aortas. Aortic and circulating suPARTg monocytes exhibited a proinflammatory profile and enhanced chemotaxis. These findings characterize suPAR as a pathogenic factor for atherosclerosis acting at least partially through modulation of monocyte function. 10.1172/JCI158788
Influence of the microbiome, diet and genetics on inter-individual variation in the human plasma metabolome. Nature medicine The levels of the thousands of metabolites in the human plasma metabolome are strongly influenced by an individual's genetics and the composition of their diet and gut microbiome. Here, by assessing 1,183 plasma metabolites in 1,368 extensively phenotyped individuals from the Lifelines DEEP and Genome of the Netherlands cohorts, we quantified the proportion of inter-individual variation in the plasma metabolome explained by different factors, characterizing 610, 85 and 38 metabolites as dominantly associated with diet, the gut microbiome and genetics, respectively. Moreover, a diet quality score derived from metabolite levels was significantly associated with diet quality, as assessed by a detailed food frequency questionnaire. Through Mendelian randomization and mediation analyses, we revealed putative causal relationships between diet, the gut microbiome and metabolites. For example, Mendelian randomization analyses support a potential causal effect of Eubacterium rectale in decreasing plasma levels of hydrogen sulfite-a toxin that affects cardiovascular function. Lastly, based on analysis of the plasma metabolome of 311 individuals at two time points separated by 4 years, we observed a positive correlation between the stability of metabolite levels and the amount of variance in the levels of that metabolite that could be explained in our analysis. Altogether, characterization of factors that explain inter-individual variation in the plasma metabolome can help design approaches for modulating diet or the gut microbiome to shape a healthy metabolome. 10.1038/s41591-022-02014-8
Mild-to-Moderate Kidney Dysfunction and Cardiovascular Disease: Observational and Mendelian Randomization Analyses. Circulation BACKGROUND:End-stage renal disease is associated with a high risk of cardiovascular events. It is unknown, however, whether mild-to-moderate kidney dysfunction is causally related to coronary heart disease (CHD) and stroke. METHODS:Observational analyses were conducted using individual-level data from 4 population data sources (Emerging Risk Factors Collaboration, EPIC-CVD [European Prospective Investigation into Cancer and Nutrition-Cardiovascular Disease Study], Million Veteran Program, and UK Biobank), comprising 648 135 participants with no history of cardiovascular disease or diabetes at baseline, yielding 42 858 and 15 693 incident CHD and stroke events, respectively, during 6.8 million person-years of follow-up. Using a genetic risk score of 218 variants for estimated glomerular filtration rate (eGFR), we conducted Mendelian randomization analyses involving 413 718 participants (25 917 CHD and 8622 strokes) in EPIC-CVD, Million Veteran Program, and UK Biobank. RESULTS:There were U-shaped observational associations of creatinine-based eGFR with CHD and stroke, with higher risk in participants with eGFR values <60 or >105 mL·min·1.73 m, compared with those with eGFR between 60 and 105 mL·min·1.73 m. Mendelian randomization analyses for CHD showed an association among participants with eGFR <60 mL·min·1.73 m, with a 14% (95% CI, 3%-27%) higher CHD risk per 5 mL·min·1.73 m lower genetically predicted eGFR, but not for those with eGFR >105 mL·min·1.73 m. Results were not materially different after adjustment for factors associated with the eGFR genetic risk score, such as lipoprotein(a), triglycerides, hemoglobin A1c, and blood pressure. Mendelian randomization results for stroke were nonsignificant but broadly similar to those for CHD. CONCLUSIONS:In people without manifest cardiovascular disease or diabetes, mild-to-moderate kidney dysfunction is causally related to risk of CHD, highlighting the potential value of preventive approaches that preserve and modulate kidney function. 10.1161/CIRCULATIONAHA.122.060700
Smoking, alcohol consumption, and 24 gastrointestinal diseases: Mendelian randomization analysis. eLife Background:Whether the positive associations of smoking and alcohol consumption with gastrointestinal diseases are causal is uncertain. We conducted this Mendelian randomization (MR) to comprehensively examine associations of smoking and alcohol consumption with common gastrointestinal diseases. Methods:Genetic variants associated with smoking initiation and alcohol consumption at the genome-wide significance level were selected as instrumental variables. Genetic associations with 24 gastrointestinal diseases were obtained from the UK Biobank, FinnGen study, and other large consortia. Univariable and multivariable MR analyses were conducted to estimate the overall and independent MR associations after mutual adjustment for genetic liability to smoking and alcohol consumption. Results:Genetic predisposition to smoking initiation was associated with increased risk of 20 of 24 gastrointestinal diseases, including 7 upper gastrointestinal diseases (gastroesophageal reflux, esophageal cancer, gastric ulcer, duodenal ulcer, acute gastritis, chronic gastritis, and gastric cancer), 4 lower gastrointestinal diseases (irritable bowel syndrome, diverticular disease, Crohn's disease, and ulcerative colitis), 8 hepatobiliary and pancreatic diseases (non-alcoholic fatty liver disease, alcoholic liver disease, cirrhosis, liver cancer, cholecystitis, cholelithiasis, and acute and chronic pancreatitis), and acute appendicitis. Fifteen out of 20 associations persisted after adjusting for genetically predicted alcohol consumption. Genetically predicted higher alcohol consumption was associated with increased risk of duodenal ulcer, alcoholic liver disease, cirrhosis, and chronic pancreatitis; however, the association for duodenal ulcer did not remain statistically significant after adjustment for genetic predisposition to smoking initiation. Conclusions:This study provides MR evidence supporting causal associations of smoking with a broad range of gastrointestinal diseases, whereas alcohol consumption was associated with only a few gastrointestinal diseases. Funding:The Natural Science Fund for Distinguished Young Scholars of Zhejiang Province; National Natural Science Foundation of China; Key Project of Research and Development Plan of Hunan Province; the Swedish Heart Lung Foundation; the Swedish Research Council; the Swedish Cancer Society. 10.7554/eLife.84051
Causal relationships between blood lipids and depression phenotypes: a Mendelian randomisation analysis. So Hon-Cheong,Chau Carlos Kwan-Long,Cheng Yu-Ying,Sham Pak C Psychological medicine BACKGROUND:The etiology of depression remains poorly understood. Changes in blood lipid levels were reported to be associated with depression and suicide, however study findings were mixed. METHODS:We performed a two-sample Mendelian randomisation (MR) analysis to investigate the causal relationship between blood lipids and depression phenotypes, based on large-scale GWAS summary statistics (N = 188 577/480 359 for lipid/depression traits respectively). Five depression-related phenotypes were included, namely major depression (MD; from PGC), depressive symptoms (DS; from SSGAC), longest duration and number of episodes of low mood, and history of deliberate self-harm (DSH)/suicide (from UK Biobank). MR was conducted with inverse-variance weighted (MR-IVW), Egger and Generalised Summary-data-based MR (GSMR) methods. RESULTS:There was consistent evidence that triglyceride (TG) is causally associated with DS (MR-IVW β for one-s.d. increase in TG = 0.0346, 95% CI 0.0114-0.0578), supported by MR-IVW and GSMR and multiple r2 clumping thresholds. We also observed relatively consistent associations of TG with DSH/suicide (MR-Egger OR = 2.514, CI 1.579-4.003). There was moderate evidence for positive associations of TG with MD and the number of episodes of low mood. For HDL-c, we observed moderate evidence for causal associations with DS and MD. LDL-c and TC did not show robust causal relationships with depression phenotypes, except for weak evidence that LDL-c is inversely related to DSH/suicide. We did not detect significant associations when depression phenotypes were treated as exposures. CONCLUSIONS:This study provides evidence to a causal relationship between TG, and to a lesser extent, altered cholesterol levels with depression phenotypes. Further studies on its mechanistic basis and the effects of lipid-lowering therapies are warranted. 10.1017/S0033291720000951
Circulating Lipoprotein Lipids, Apolipoproteins and Ischemic Stroke. Yuan Shuai,Tang Bowen,Zheng Jie,Larsson Susanna C Annals of neurology OBJECTIVE:We conducted a Mendelian randomization (MR) study to disentangle the comparative effects of lipids and apolipoproteins on ischemic stroke. METHODS:Single-nucleotide polymorphisms associated with low- and high-density lipoprotein (LDL and HDL) cholesterol, triglycerides, and apolipoprotein A-I and B (apoA-I and apoB) at the level of genomewide significance (p < 5 × 10 ) in the UK Biobank were used as instrumental variables. Summary-level data for ischemic stroke and its subtypes were obtained from the MEGASTROKE consortium with 514,791 individuals (60,341 ischemic stroke cases, and 454,450 non-cases). RESULTS:Increased levels of apoB, LDL cholesterol, and triglycerides were associated with higher risk of any ischemic stroke, large artery stroke, and small vessel stroke in the main and sensitivity univariable MR analyses. In multivariable MR analysis including apoB, LDL cholesterol, and triglycerides in the same model, apoB retained a robust effect (p < 0.05), whereas the estimate for LDL cholesterol was reversed, and that for triglycerides largely attenuated. Decreased levels of apoA-I and HDL cholesterol were robustly associated with increased risk of any ischemic stroke, large artery stroke, and small vessel stroke in all univariable MR analyses, but the association for apoA-I was attenuated to the null after mutual adjustment. INTERPRETATION:The present MR study reveals that apoB is the predominant trait that accounts for the etiological basis of apoB, LDL cholesterol, and triglycerides in relation to ischemic stroke, in particular large artery and small vessel stroke. Whether HDL cholesterol exerts a protective effect on ischemic stroke independent of apoA-I needs further investigation. ANN NEUROL 2020;88:1229-1236. 10.1002/ana.25916
The causal effects of serum lipids and apolipoproteins on kidney function: multivariable and bidirectional Mendelian-randomization analyses. International journal of epidemiology BACKGROUND:The causal nature of the observed associations between serum lipids and apolipoproteins and kidney function are unclear. METHODS:Using two-sample and multivariable Mendelian randomization (MR), we examined the causal effects of serum lipids and apolipoproteins on kidney function, indicated by the glomerular-filtration rate estimated using creatinine (eGFRcrea) or cystatin C (eGFRcys) and the urinary albumin-to-creatinine ratio (UACR). We obtained lipid- and apolipoprotein-associated genetic variants from the Global Lipids Genetics Consortium (n = 331 368) and UK Biobank (n = 441 016), respectively, and kidney-function markers from the Trøndelag Health Study (HUNT; n = 69 736) and UK Biobank (n = 464 207). The reverse causal direction was examined using variants associated with kidney-function markers selected from recent genome-wide association studies. RESULTS:There were no strong associations between genetically predicted lipid and apolipoprotein levels with kidney-function markers. Some, but inconsistent, evidence suggested a weak association of higher genetically predicted atherogenic lipid levels [indicated by low-density lipoprotein cholesterol (LDL-C), triglycerides and apolipoprotein B] with increased eGFR and UACR. For high-density lipoprotein cholesterol (HDL-C), results differed between eGFRcrea and eGFRcys, but neither analysis suggested substantial effects. We found no clear evidence of a reverse causal effect of eGFR on lipid or apolipoprotein traits, but higher UACR was associated with higher LDL-C, triglyceride and apolipoprotein B levels. CONCLUSION:Our MR estimates suggest that serum lipid and apolipoprotein levels do not cause substantial changes in kidney function. A possible weak effect of higher atherogenic lipids on increased eGFR and UACR warrants further investigation. Processes leading to higher UACR may lead to more atherogenic lipid levels. 10.1093/ije/dyab014
Evaluating the relationship between circulating lipoprotein lipids and apolipoproteins with risk of coronary heart disease: A multivariable Mendelian randomisation analysis. PLoS medicine BACKGROUND:Circulating lipoprotein lipids cause coronary heart disease (CHD). However, the precise way in which one or more lipoprotein lipid-related entities account for this relationship remains unclear. Using genetic instruments for lipoprotein lipid traits implemented through multivariable Mendelian randomisation (MR), we sought to compare their causal roles in the aetiology of CHD. METHODS AND FINDINGS:We conducted a genome-wide association study (GWAS) of circulating non-fasted lipoprotein lipid traits in the UK Biobank (UKBB) for low-density lipoprotein (LDL) cholesterol, triglycerides, and apolipoprotein B to identify lipid-associated single nucleotide polymorphisms (SNPs). Using data from CARDIoGRAMplusC4D for CHD (consisting of 60,801 cases and 123,504 controls), we performed univariable and multivariable MR analyses. Similar GWAS and MR analyses were conducted for high-density lipoprotein (HDL) cholesterol and apolipoprotein A-I. The GWAS of lipids and apolipoproteins in the UKBB included between 393,193 and 441,016 individuals in whom the mean age was 56.9 y (range 39-73 y) and of whom 54.2% were women. The mean (standard deviation) lipid concentrations were LDL cholesterol 3.57 (0.87) mmol/L and HDL cholesterol 1.45 (0.38) mmol/L, and the median triglycerides was 1.50 (IQR = 1.11) mmol/L. The mean (standard deviation) values for apolipoproteins B and A-I were 1.03 (0.24) g/L and 1.54 (0.27) g/L, respectively. The GWAS identified multiple independent SNPs associated at P < 5 × 10-8 for LDL cholesterol (220), apolipoprotein B (n = 255), triglycerides (440), HDL cholesterol (534), and apolipoprotein A-I (440). Between 56%-93% of SNPs identified for each lipid trait had not been previously reported in large-scale GWASs. Almost half (46%) of these SNPs were associated at P < 5 × 10-8 with more than one lipid-related trait. Assessed individually using MR, LDL cholesterol (odds ratio [OR] 1.66 per 1-standard-deviation-higher trait; 95% CI: 1.49-1.86; P < 0.001), triglycerides (OR 1.34; 95% CI: 1.25-1.44; P < 0.001) and apolipoprotein B (OR 1.73; 95% CI: 1.56-1.91; P < 0.001) had effect estimates consistent with a higher risk of CHD. In multivariable MR, only apolipoprotein B (OR 1.92; 95% CI: 1.31-2.81; P < 0.001) retained a robust effect, with the estimate for LDL cholesterol (OR 0.85; 95% CI: 0.57-1.27; P = 0.44) reversing and that of triglycerides (OR 1.12; 95% CI: 1.02-1.23; P = 0.01) becoming weaker. Individual MR analyses showed a 1-standard-deviation-higher HDL cholesterol (OR 0.80; 95% CI: 0.75-0.86; P < 0.001) and apolipoprotein A-I (OR 0.83; 95% CI: 0.77-0.89; P < 0.001) to lower the risk of CHD, but these effect estimates attenuated substantially to the null on accounting for apolipoprotein B. A limitation is that, owing to the nature of lipoprotein metabolism, measures related to the composition of lipoprotein particles are highly correlated, creating a challenge in making exclusive interpretations on causation of individual components. CONCLUSIONS:These findings suggest that apolipoprotein B is the predominant trait that accounts for the aetiological relationship of lipoprotein lipids with risk of CHD. 10.1371/journal.pmed.1003062
Plasma HDL cholesterol and risk of myocardial infarction: a mendelian randomisation study. Voight Benjamin F,Peloso Gina M,Orho-Melander Marju,Frikke-Schmidt Ruth,Barbalic Maja,Jensen Majken K,Hindy George,Hólm Hilma,Ding Eric L,Johnson Toby,Schunkert Heribert,Samani Nilesh J,Clarke Robert,Hopewell Jemma C,Thompson John F,Li Mingyao,Thorleifsson Gudmar,Newton-Cheh Christopher,Musunuru Kiran,Pirruccello James P,Saleheen Danish,Chen Li,Stewart Alexandre F R,Schillert Arne,Thorsteinsdottir Unnur,Thorgeirsson Gudmundur,Anand Sonia,Engert James C,Morgan Thomas,Spertus John,Stoll Monika,Berger Klaus,Martinelli Nicola,Girelli Domenico,McKeown Pascal P,Patterson Christopher C,Epstein Stephen E,Devaney Joseph,Burnett Mary-Susan,Mooser Vincent,Ripatti Samuli,Surakka Ida,Nieminen Markku S,Sinisalo Juha,Lokki Marja-Liisa,Perola Markus,Havulinna Aki,de Faire Ulf,Gigante Bruna,Ingelsson Erik,Zeller Tanja,Wild Philipp,de Bakker Paul I W,Klungel Olaf H,Maitland-van der Zee Anke-Hilse,Peters Bas J M,de Boer Anthonius,Grobbee Diederick E,Kamphuisen Pieter W,Deneer Vera H M,Elbers Clara C,Onland-Moret N Charlotte,Hofker Marten H,Wijmenga Cisca,Verschuren W M Monique,Boer Jolanda M A,van der Schouw Yvonne T,Rasheed Asif,Frossard Philippe,Demissie Serkalem,Willer Cristen,Do Ron,Ordovas Jose M,Abecasis Gonçalo R,Boehnke Michael,Mohlke Karen L,Daly Mark J,Guiducci Candace,Burtt Noël P,Surti Aarti,Gonzalez Elena,Purcell Shaun,Gabriel Stacey,Marrugat Jaume,Peden John,Erdmann Jeanette,Diemert Patrick,Willenborg Christina,König Inke R,Fischer Marcus,Hengstenberg Christian,Ziegler Andreas,Buysschaert Ian,Lambrechts Diether,Van de Werf Frans,Fox Keith A,El Mokhtari Nour Eddine,Rubin Diana,Schrezenmeir Jürgen,Schreiber Stefan,Schäfer Arne,Danesh John,Blankenberg Stefan,Roberts Robert,McPherson Ruth,Watkins Hugh,Hall Alistair S,Overvad Kim,Rimm Eric,Boerwinkle Eric,Tybjaerg-Hansen Anne,Cupples L Adrienne,Reilly Muredach P,Melander Olle,Mannucci Pier M,Ardissino Diego,Siscovick David,Elosua Roberto,Stefansson Kari,O'Donnell Christopher J,Salomaa Veikko,Rader Daniel J,Peltonen Leena,Schwartz Stephen M,Altshuler David,Kathiresan Sekar Lancet (London, England) BACKGROUND:High plasma HDL cholesterol is associated with reduced risk of myocardial infarction, but whether this association is causal is unclear. Exploiting the fact that genotypes are randomly assigned at meiosis, are independent of non-genetic confounding, and are unmodified by disease processes, mendelian randomisation can be used to test the hypothesis that the association of a plasma biomarker with disease is causal. METHODS:We performed two mendelian randomisation analyses. First, we used as an instrument a single nucleotide polymorphism (SNP) in the endothelial lipase gene (LIPG Asn396Ser) and tested this SNP in 20 studies (20,913 myocardial infarction cases, 95,407 controls). Second, we used as an instrument a genetic score consisting of 14 common SNPs that exclusively associate with HDL cholesterol and tested this score in up to 12,482 cases of myocardial infarction and 41,331 controls. As a positive control, we also tested a genetic score of 13 common SNPs exclusively associated with LDL cholesterol. FINDINGS:Carriers of the LIPG 396Ser allele (2·6% frequency) had higher HDL cholesterol (0·14 mmol/L higher, p=8×10(-13)) but similar levels of other lipid and non-lipid risk factors for myocardial infarction compared with non-carriers. This difference in HDL cholesterol is expected to decrease risk of myocardial infarction by 13% (odds ratio [OR] 0·87, 95% CI 0·84-0·91). However, we noted that the 396Ser allele was not associated with risk of myocardial infarction (OR 0·99, 95% CI 0·88-1·11, p=0·85). From observational epidemiology, an increase of 1 SD in HDL cholesterol was associated with reduced risk of myocardial infarction (OR 0·62, 95% CI 0·58-0·66). However, a 1 SD increase in HDL cholesterol due to genetic score was not associated with risk of myocardial infarction (OR 0·93, 95% CI 0·68-1·26, p=0·63). For LDL cholesterol, the estimate from observational epidemiology (a 1 SD increase in LDL cholesterol associated with OR 1·54, 95% CI 1·45-1·63) was concordant with that from genetic score (OR 2·13, 95% CI 1·69-2·69, p=2×10(-10)). INTERPRETATION:Some genetic mechanisms that raise plasma HDL cholesterol do not seem to lower risk of myocardial infarction. These data challenge the concept that raising of plasma HDL cholesterol will uniformly translate into reductions in risk of myocardial infarction. FUNDING:US National Institutes of Health, The Wellcome Trust, European Union, British Heart Foundation, and the German Federal Ministry of Education and Research. 10.1016/S0140-6736(12)60312-2
Mendelian randomization in cardiometabolic disease: challenges in evaluating causality. Holmes Michael V,Ala-Korpela Mika,Smith George Davey Nature reviews. Cardiology Mendelian randomization (MR) is a burgeoning field that involves the use of genetic variants to assess causal relationships between exposures and outcomes. MR studies can be straightforward; for example, genetic variants within or near the encoding locus that is associated with protein concentrations can help to assess their causal role in disease. However, a more complex relationship between the genetic variants and an exposure can make findings from MR more difficult to interpret. In this Review, we describe some of these challenges in interpreting MR analyses, including those from studies using genetic variants to assess causality of multiple traits (such as branched-chain amino acids and risk of diabetes mellitus); studies describing pleiotropic variants (for example, C-reactive protein and its contribution to coronary heart disease); and those investigating variants that disrupt normal function of an exposure (for example, HDL cholesterol or IL-6 and coronary heart disease). Furthermore, MR studies on variants that encode enzymes responsible for the metabolism of an exposure (such as alcohol) are discussed, in addition to those assessing the effects of variants on time-dependent exposures (extracellular superoxide dismutase), cumulative exposures (LDL cholesterol), and overlapping exposures (triglycerides and non-HDL cholesterol). We elaborate on the molecular features of each relationship, and provide explanations for the likely causal associations. In doing so, we hope to contribute towards more reliable evaluations of MR findings. 10.1038/nrcardio.2017.78
Evaluating the relationship between alcohol consumption, tobacco use, and cardiovascular disease: A multivariable Mendelian randomization study. PLoS medicine BACKGROUND:Alcohol consumption and smoking, 2 major risk factors for cardiovascular disease (CVD), often occur together. The objective of this study is to use a wide range of CVD risk factors and outcomes to evaluate potential total and direct causal roles of alcohol and tobacco use on CVD risk factors and events. METHODS AND FINDINGS:Using large publicly available genome-wide association studies (GWASs) (results from more than 1.2 million combined study participants) of predominantly European ancestry, we conducted 2-sample single-variable Mendelian randomization (SVMR) and multivariable Mendelian randomization (MVMR) to simultaneously assess the independent impact of alcohol consumption and smoking on a wide range of CVD risk factors and outcomes. Multiple sensitivity analyses, including complementary Mendelian randomization (MR) methods, and secondary alcohol consumption and smoking datasets were used. SVMR showed genetic predisposition for alcohol consumption to be associated with CVD risk factors, including high-density lipoprotein cholesterol (HDL-C) (beta 0.40, 95% confidence interval (CI), 0.04-0.47, P value = 1.72 × 10-28), triglycerides (TRG) (beta -0.23, 95% CI, -0.30, -0.15, P value = 4.69 × 10-10), automated systolic blood pressure (BP) measurement (beta 0.11, 95% CI, 0.03-0.18, P value = 4.72 × 10-3), and automated diastolic BP measurement (beta 0.09, 95% CI, 0.03-0.16, P value = 5.24 × 10-3). Conversely, genetically predicted smoking was associated with increased TRG (beta 0.097, 95% CI, 0.014-0.027, P value = 6.59 × 10-12). Alcohol consumption was also associated with increased myocardial infarction (MI) and coronary heart disease (CHD) risks (MI odds ratio (OR) = 1.24, 95% CI, 1.03-1.50, P value = 0.02; CHD OR = 1.21, 95% CI, 1.01-1.45, P value = 0.04); however, its impact was attenuated in MVMR adjusting for smoking. Conversely, alcohol maintained an association with coronary atherosclerosis (OR 1.02, 95% CI, 1.01-1.03, P value = 5.56 × 10-4). In comparison, after adjusting for alcohol consumption, smoking retained its association with several CVD outcomes including MI (OR = 1.84, 95% CI, 1.43, 2.37, P value = 2.0 × 10-6), CHD (OR = 1.64, 95% CI, 1.28-2.09, P value = 8.07 × 10-5), heart failure (HF) (OR = 1.61, 95% CI, 1.32-1.95, P value = 1.9 × 10-6), and large artery atherosclerosis (OR = 2.4, 95% CI, 1.41-4.07, P value = 0.003). Notably, using the FinnGen cohort data, we were able to replicate the association between smoking and several CVD outcomes including MI (OR = 1.77, 95% CI, 1.10-2.84, P value = 0.02), HF (OR = 1.67, 95% CI, 1.14-2.46, P value = 0.008), and peripheral artery disease (PAD) (OR = 2.35, 95% CI, 1.38-4.01, P value = 0.002). The main limitations of this study include possible bias from unmeasured confounders, inability of summary-level MR to investigate a potentially nonlinear relationship between alcohol consumption and CVD risk, and the generalizability of the UK Biobank (UKB) to other populations. CONCLUSIONS:Evaluating the widest range of CVD risk factors and outcomes of any alcohol consumption or smoking MR study to date, we failed to find a cardioprotective impact of genetically predicted alcohol consumption on CVD outcomes. However, alcohol was associated with and increased HDL-C, decreased TRG, and increased BP, which may indicate pathways through impact CVD risk, warranting further study. We found smoking to be a risk factor for many CVDs even after adjusting for alcohol. While future studies incorporating alcohol consumption patterns are necessary, our data suggest causal inference between alcohol, smoking, and CVD risk, further supporting that lifestyle modifications might be able to reduce overall CVD risk. 10.1371/journal.pmed.1003410
Prioritizing putative influential genes in cardiovascular disease susceptibility by applying tissue-specific Mendelian randomization. Genome medicine BACKGROUND:The extent to which changes in gene expression can influence cardiovascular disease risk across different tissue types has not yet been systematically explored. We have developed an analysis pipeline that integrates tissue-specific gene expression, Mendelian randomization and multiple-trait colocalization to develop functional mechanistic insight into the causal pathway from a genetic variant to a complex trait. METHODS:We undertook an expression quantitative trait loci-wide association study to uncover genetic variants associated with both nearby gene expression and cardiovascular traits. Fine-mapping was performed to prioritize possible causal variants for detected associations. Two-sample Mendelian randomization (MR) was then applied using findings from genome-wide association studies (GWAS) to investigate whether changes in gene expression within certain tissue types may influence cardiovascular trait variation. We subsequently used Bayesian multiple-trait colocalization to further interrogate the findings and also gain insight into whether DNA methylation, as well as gene expression, may play a role in disease susceptibility. Finally, we applied our analysis pipeline genome-wide using summary statistics from large-scale GWAS. RESULTS:Eight genetic loci were associated with changes in gene expression and measures of cardiovascular function. Our MR analysis provided evidence of tissue-specific effects at multiple loci, of which the effects at the ADCY3 and FADS1 loci for body mass index and cholesterol, respectively, were particularly insightful. Multiple-trait colocalization uncovered evidence which suggested that changes in DNA methylation at the promoter region upstream of FADS1/TMEM258 may also affect cardiovascular trait variation along with gene expression. Furthermore, colocalization analyses uncovered evidence of tissue specificity between gene expression in liver tissue and cholesterol levels. Applying our pipeline genome-wide using summary statistics from GWAS uncovered 233 association signals at loci which represent promising candidates for further evaluation. CONCLUSIONS:Disease susceptibility can be influenced by differential changes in tissue-specific gene expression and DNA methylation. The approach undertaken in our study can be used to elucidate mechanisms in disease, as well as helping prioritize putative causal genes at associated loci where multiple nearby genes may be co-regulated. Future studies which continue to uncover quantitative trait loci for molecular traits across various tissue and cell types will further improve our capability to understand and prevent disease. 10.1186/s13073-019-0613-2
Vitamin D Supplementation and Cardiovascular Disease Risk. Zittermann Armin,Pilz Stefan JAMA cardiology 10.1001/jamacardio.2017.2935
Brothers in Arms: ABCA1- and ABCG1-Mediated Cholesterol Efflux as Promising Targets in Cardiovascular Disease Treatment. Frambach Sanne J C M,de Haas Ria,Smeitink Jan A M,Rongen Gerard A,Russel Frans G M,Schirris Tom J J Pharmacological reviews Atherosclerosis is a leading cause of cardiovascular disease worldwide, and hypercholesterolemia is a major risk factor. Preventive treatments mainly focus on the effective reduction of low-density lipoprotein cholesterol, but their therapeutic value is limited by the inability to completely normalize atherosclerotic risk, probably due to the disease complexity and multifactorial pathogenesis. Consequently, high-density lipoprotein cholesterol gained much interest, as it appeared to be cardioprotective due to its major role in reverse cholesterol transport (RCT). RCT facilitates removal of cholesterol from peripheral tissues, including atherosclerotic plaques, and its subsequent hepatic clearance into bile. Therefore, RCT is expected to limit plaque formation and progression. Cellular cholesterol efflux is initiated and propagated by the ATP-binding cassette (ABC) transporters ABCA1 and ABCG1. Their expression and function are expected to be rate-limiting for cholesterol efflux, which makes them interesting targets to stimulate RCT and lower atherosclerotic risk. This systematic review discusses the molecular mechanisms relevant for RCT and ABCA1 and ABCG1 function, followed by a critical overview of potential pharmacological strategies with small molecules to enhance cellular cholesterol efflux and RCT. These strategies include regulation of ABCA1 and ABCG1 expression, degradation, and mRNA stability. Various small molecules have been demonstrated to increase RCT, but the underlying mechanisms are often not completely understood and are rather unspecific, potentially causing adverse effects. Better understanding of these mechanisms could enable the development of safer drugs to increase RCT and provide more insight into its relation with atherosclerotic risk. SIGNIFICANCE STATEMENT: Hypercholesterolemia is an important risk factor of atherosclerosis, which is a leading pathological mechanism underlying cardiovascular disease. Cholesterol is removed from atherosclerotic plaques and subsequently cleared by the liver into bile. This transport is mediated by high-density lipoprotein particles, to which cholesterol is transferred via ATP-binding cassette transporters ABCA1 and ABCG1. Small-molecule pharmacological strategies stimulating these transporters may provide promising options for cardiovascular disease treatment. 10.1124/pr.119.017897
Anti-inflammatory therapeutics for the treatment of atherosclerosis. Charo Israel F,Taub Rebecca Nature reviews. Drug discovery Atherosclerosis is the primary cause of heart disease and stroke and is thus the underlying pathology of the leading causes of death in the western world. Although risk can be reduced by lowering lipid levels, the equally important contribution of inflammation to the development of cardiovascular disease is not adequately addressed by existing therapies. Here, we summarize the evidence supporting a role for inflammation in the pathogenesis of atherosclerosis, discuss agents that are currently in the clinic and provide a perspective on the challenges faced in the development of drugs that target vascular inflammation. 10.1038/nrd3444
Cardiometabolic outcomes and mortality in medically treated primary aldosteronism: a retrospective cohort study. The lancet. Diabetes & endocrinology BACKGROUND:Mineralocorticoid receptor (MR) antagonists are the recommended medical therapy for primary aldosteronism. Whether this recommendation effectively reduces cardiometabolic risk is not well understood. We aimed to investigate the risk of incident cardiovascular events in patients with primary aldosteronism treated with MR antagonists compared with patients with essential hypertension. METHODS:We did a cohort study using patients from a research registry from Brigham and Women's Hospital, Massachusetts General Hospital, and their affiliated partner hospitals. We identified patients with primary aldosteronism using International Classification of Disease, 9th and 10th Revision codes, who were assessed between the years 1991-2016 and were at least 18 years of age. We excluded patients who underwent surgical adrenalectomy, had a previous cardiovascular event, were not treated with MR antagonists, or had no follow-up visits after study entry. From the same registry, we identified a population with essential hypertension that was frequency matched by decade of age at study entry. We extracted patient cohort data and collated it into a de-identified database. The primary outcome was an incident cardiovascular event, defined as a composite of incident myocardial infarction or coronary revascularisation, hospital admission with congestive heart failure, or stroke, which was assessed using adjusted Cox regression models. Secondary outcomes were the individual components of the composite cardiovascular outcome, as well as incident atrial fibrillation, incident diabetes, and death. FINDINGS:We identified 602 eligible patients with primary aldosteronism treated with MR antagonists and 41 853 age-matched patients with essential hypertension from the registry. The two groups of patients had comparable cardiovascular risk profiles and blood pressure throughout the study. The incidence of cardiovascular events was higher in patients with primary aldosteronism on MR antagonists than in patients with essential hypertension (56·3 [95% CI 48·8-64·7] vs 26·6 [26·1-27·2] events per 1000 person-years, adjusted hazard ratio 1·91 [95% CI 1·63-2·25]; adjusted 10-year cumulative incidence difference 14·1 [95% CI 10·1-18·0] excess events per 100 people). Patients with primary aldosteronism also had higher adjusted risks for incident mortality (hazard ratio [HR] 1·34 [95% CI 1·06-1·71]), diabetes (1·26 [1·01-1·57]), and atrial fibrillation (1·93 [1·54-2·42]). Compared with essential hypertension, the excess risk for cardiovascular events and mortality was limited to patients with primary aldosteronism whose renin activity remained suppressed (<1 μg/L per h) on MR antagonists (adjusted HR [2·83 [95% CI 2·11-3·80], and 1·79 [1·14-2·80], respectively) whereas patients who were treated with higher MR antagonist doses and had unsuppressed renin (≥1 μg/L per h) had no significant excess risk. INTERPRETATION:The current practice of MR antagonist therapy in primary aldosteronism is associated with significantly higher risk for incident cardiometabolic events and death, independent of blood pressure control, than for patients with essential hypertension. Titration of MR antagonist therapy to raise renin might mitigate this excess risk. FUNDING:US National Institutes of Health. 10.1016/S2213-8587(17)30367-4
Intake and metabolism of omega-3 and omega-6 polyunsaturated fatty acids: nutritional implications for cardiometabolic diseases. Schulze Matthias B,Minihane Anne Marie,Saleh Rasha Noureldin M,Risérus Ulf The lancet. Diabetes & endocrinology Prospective observational studies support the use of long-chain omega-3 polyunsaturated fatty acids (PUFAs) in the primary prevention of atherosclerotic cardiovascular disease; however, randomised controlled trials, have often reported neutral findings. There is a long history of debate about the potential harmful effects of a high intake of omega-6 PUFAs, although this idea is not supported by prospective observational studies or randomised controlled trials. Health effects of PUFAs might be influenced by Δ-5 and Δ-6 desaturases, the key enzymes in the metabolism of PUFAs. The activity of these enzymes and modulation by variants in encoding genes (FADS1-2-3 gene cluster) are linked to several cardiometabolic traits. This Review will further consider non-genetic determinants of desaturase activity, which have the potential to modify the availability of PUFAs to tissues. Finally, we discuss the consequences of altered desaturase activity in the context of PUFA intake, that is, gene-diet interactions and their clinical and public health implications. 10.1016/S2213-8587(20)30148-0
Effect of Monthly High-Dose Vitamin D Supplementation on Cardiovascular Disease in the Vitamin D Assessment Study : A Randomized Clinical Trial. Scragg Robert,Stewart Alistair W,Waayer Debbie,Lawes Carlene M M,Toop Les,Sluyter John,Murphy Judy,Khaw Kay-Tee,Camargo Carlos A JAMA cardiology Importance:Cohort studies have reported increased incidence of cardiovascular disease (CVD) among individuals with low vitamin D status. To date, randomized clinical trials of vitamin D supplementation have not found an effect, possibly because of using too low a dose of vitamin D. Objective:To examine whether monthly high-dose vitamin D supplementation prevents CVD in the general population. Design, Setting, and Participants:The Vitamin D Assessment Study is a randomized, double-blind, placebo-controlled trial that recruited participants mostly from family practices in Auckland, New Zealand, from April 5, 2011, through November 6, 2012, with follow-up until July 2015. Participants were community-resident adults aged 50 to 84 years. Of 47 905 adults invited from family practices and 163 from community groups, 5110 participants were randomized to receive vitamin D3 (n = 2558) or placebo (n = 2552). Two participants retracted consent, and all others (n = 5108) were included in the primary analysis. Interventions:Oral vitamin D3 in an initial dose of 200 000 IU, followed a month later by monthly doses of 100 000 IU, or placebo for a median of 3.3 years (range, 2.5-4.2 years). Main Outcomes and Measures:The primary outcome was the number of participants with incident CVD and death, including a prespecified subgroup analysis in participants with vitamin D deficiency (baseline deseasonalized 25-hydroxyvitamin D [25(OH)D] levels <20 ng/mL). Secondary outcomes were myocardial infarction, angina, heart failure, hypertension, arrhythmias, arteriosclerosis, stroke, and venous thrombosis. Results:Of the 5108 participants included in the analysis, the mean (SD) age was 65.9 (8.3) years, 2969 (58.1%) were male, and 4253 (83.3%) were of European or other ethnicity, with the remainder being Polynesian or South Asian. Mean (SD) baseline deseasonalized 25(OH)D concentration was 26.5 (9.0) ng/mL, with 1270 participants (24.9%) being vitamin D deficient. In a random sample of 438 participants, the mean follow-up 25(OH)D level was greater than 20 ng/mL higher in the vitamin D group than in the placebo group. The primary outcome of CVD occurred in 303 participants (11.8%) in the vitamin D group and 293 participants (11.5%) in the placebo group, yielding an adjusted hazard ratio of 1.02 (95% CI, 0.87-1.20). Similar results were seen for participants with baseline vitamin D deficiency and for secondary outcomes. Conclusions and Relevance:Monthly high-dose vitamin D supplementation does not prevent CVD. This result does not support the use of monthly vitamin D supplementation for this purpose. The effects of daily or weekly dosing require further study. Trial Registration:clinicaltrials.gov Identifier: ACTRN12611000402943. 10.1001/jamacardio.2017.0175
Estimated glomerular filtration rate and albuminuria for prediction of cardiovascular outcomes: a collaborative meta-analysis of individual participant data. Matsushita Kunihiro,Coresh Josef,Sang Yingying,Chalmers John,Fox Caroline,Guallar Eliseo,Jafar Tazeen,Jassal Simerjot K,Landman Gijs W D,Muntner Paul,Roderick Paul,Sairenchi Toshimi,Schöttker Ben,Shankar Anoop,Shlipak Michael,Tonelli Marcello,Townend Jonathan,van Zuilen Arjan,Yamagishi Kazumasa,Yamashita Kentaro,Gansevoort Ron,Sarnak Mark,Warnock David G,Woodward Mark,Ärnlöv Johan, The lancet. Diabetes & endocrinology BACKGROUND:The usefulness of estimated glomerular filtration rate (eGFR) and albuminuria for prediction of cardiovascular outcomes is controversial. We aimed to assess the addition of creatinine-based eGFR and albuminuria to traditional risk factors for prediction of cardiovascular risk with a meta-analytic approach. METHODS:We meta-analysed individual-level data for 637 315 individuals without a history of cardiovascular disease from 24 cohorts (median follow-up 4·2-19·0 years) included in the Chronic Kidney Disease Prognosis Consortium. We assessed C statistic difference and reclassification improvement for cardiovascular mortality and fatal and non-fatal cases of coronary heart disease, stroke, and heart failure in a 5 year timeframe, contrasting prediction models for traditional risk factors with and without creatinine-based eGFR, albuminuria (either albumin-to-creatinine ratio [ACR] or semi-quantitative dipstick proteinuria), or both. FINDINGS:The addition of eGFR and ACR significantly improved the discrimination of cardiovascular outcomes beyond traditional risk factors in general populations, but the improvement was greater with ACR than with eGFR, and more evident for cardiovascular mortality (C statistic difference 0·0139 [95% CI 0·0105-0·0174] for ACR and 0·0065 [0·0042-0·0088] for eGFR) and heart failure (0·0196 [0·0108-0·0284] and 0·0109 [0·0059-0·0159]) than for coronary disease (0·0048 [0·0029-0·0067] and 0·0036 [0·0019-0·0054]) and stroke (0·0105 [0·0058-0·0151] and 0·0036 [0·0004-0·0069]). Dipstick proteinuria showed smaller improvement than ACR. The discrimination improvement with eGFR or ACR was especially evident in individuals with diabetes or hypertension, but remained significant with ACR for cardiovascular mortality and heart failure in those without either of these disorders. In individuals with chronic kidney disease, the combination of eGFR and ACR for risk discrimination outperformed most single traditional predictors; the C statistic for cardiovascular mortality fell by 0·0227 (0·0158-0·0296) after omission of eGFR and ACR compared with less than 0·007 for any single modifiable traditional predictor. INTERPRETATION:Creatinine-based eGFR and albuminuria should be taken into account for cardiovascular prediction, especially when these measures are already assessed for clinical purpose or if cardiovascular mortality and heart failure are outcomes of interest. ACR could have particularly broad implications for cardiovascular prediction. In populations with chronic kidney disease, the simultaneous assessment of eGFR and ACR could facilitate improved classification of cardiovascular risk, supporting current guidelines for chronic kidney disease. Our results lend some support to also incorporating eGFR and ACR into assessments of cardiovascular risk in the general population. FUNDING:US National Kidney Foundation, National Institute of Diabetes and Digestive and Kidney Diseases. 10.1016/S2213-8587(15)00040-6
Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation Physiological reviews Nitric oxide (NO) is a small free radical with critical signaling roles in physiology and pathophysiology. The generation of sufficient NO levels to regulate the resistance of the blood vessels and hence the maintenance of adequate blood flow is critical to the healthy performance of the vasculature. A novel paradigm indicates that classical NO synthesis by dedicated NO synthases is supplemented by nitrite reduction pathways under hypoxia. At the same time, reactive oxygen species (ROS), which include superoxide and hydrogen peroxide, are produced in the vascular system for signaling purposes, as effectors of the immune response, or as byproducts of cellular metabolism. NO and ROS can be generated by distinct enzymes or by the same enzyme through alternate reduction and oxidation processes. The latter oxidoreductase systems include NO synthases, molybdopterin enzymes, and hemoglobins, which can form superoxide by reduction of molecular oxygen or NO by reduction of inorganic nitrite. Enzymatic uncoupling, changes in oxygen tension, and the concentration of coenzymes and reductants can modulate the NO/ROS production from these oxidoreductases and determine the redox balance in health and disease. The dysregulation of the mechanisms involved in the generation of NO and ROS is an important cause of cardiovascular disease and target for therapy. In this review we will present the biology of NO and ROS in the cardiovascular system, with special emphasis on their routes of formation and regulation, as well as the therapeutic challenges and opportunities for the management of NO and ROS in cardiovascular disease. 10.1152/physrev.00036.2017
Cytokines in atherosclerosis: pathogenic and regulatory pathways. Tedgui Alain,Mallat Ziad Physiological reviews Atherosclerosis is a chronic disease of the arterial wall where both innate and adaptive immunoinflammatory mechanisms are involved. Inflammation is central at all stages of atherosclerosis. It is implicated in the formation of early fatty streaks, when the endothelium is activated and expresses chemokines and adhesion molecules leading to monocyte/lymphocyte recruitment and infiltration into the subendothelium. It also acts at the onset of adverse clinical vascular events, when activated cells within the plaque secrete matrix proteases that degrade extracellular matrix proteins and weaken the fibrous cap, leading to rupture and thrombus formation. Cells involved in the atherosclerotic process secrete and are activated by soluble factors, known as cytokines. Important recent advances in the comprehension of the mechanisms of atherosclerosis provided evidence that the immunoinflammatory response in atherosclerosis is modulated by regulatory pathways, in which the two anti-inflammatory cytokines interleukin-10 and transforming growth factor-beta play a critical role. The purpose of this review is to bring together the current information concerning the role of cytokines in the development, progression, and complications of atherosclerosis. Specific emphasis is placed on the contribution of pro- and anti-inflammatory cytokines to pathogenic (innate and adaptive) and regulatory immunity in the context of atherosclerosis. Based on our current knowledge of the role of cytokines in atherosclerosis, we propose some novel therapeutic strategies to combat this disease. In addition, we discuss the potential of circulating cytokine levels as biomarkers of coronary artery disease. 10.1152/physrev.00024.2005
Cardiovascular events and target organ damage in primary aldosteronism compared with essential hypertension: a systematic review and meta-analysis. Monticone Silvia,D'Ascenzo Fabrizio,Moretti Claudio,Williams Tracy Ann,Veglio Franco,Gaita Fiorenzo,Mulatero Paolo The lancet. Diabetes & endocrinology BACKGROUND:There is conflicting evidence, relying on heterogeneous studies, as to whether aldosterone excess is responsible for an increased risk of cardiovascular and cerebrovascular complications in patients with primary aldosteronism. We aimed to assess the association between primary aldosteronism and adverse cardiac and cerebrovascular events, target organ damage, diabetes, and metabolic syndrome, compared with the association of essential hypertension and these cardiovascular and end organ events, by integrating results of previous studies. METHODS:We did a meta-analysis of prospective and retrospective observational studies that compared patients with primary aldosteronism and essential hypertension, to analyse the association between primary aldosteronism and stroke, coronary artery disease (as co-primary endpoints), atrial fibrillation and heart failure, target organ damage, metabolic syndrome, and diabetes (as secondary endpoints). We searched MEDLINE and Cochrane Library for articles published up to Feb 28, 2017, with no start date restriction. Eligible studies compared patients with primary aldosteronism with patients with essential hypertension (as a control group) and reported on the clinical events or endpoints of interest. We also compared primary aldosteronism subtypes, aldosterone-producing adenoma, and bilateral adrenal hyperplasia. FINDINGS:We identified 31 studies including 3838 patients with primary aldosteronism and 9284 patients with essential hypertension. After a median of 8·8 years (IQR 6·2-10·7) from the diagnosis of hypertension, compared with patients with essential hypertension, patients with primary aldosteronism had an increased risk of stroke (odds ratio [OR] 2·58, 95% CI 1·93-3·45), coronary artery disease (1·77, 1·10-2·83), atrial fibrillation (3·52, 2·06-5·99), and heart failure (2·05, 1·11-3·78). These results were consistent for patients with aldosterone-producing adenoma and bilateral adrenal hyperplasia, with no difference between these subgroups. Similarly, primary aldosteronism increased the risk of diabetes (OR 1·33, 95% CI 1·01-1·74), metabolic syndrome (1·53, 1·22-1·91), and left ventricular hypertrophy (2·29, 1·65-3·17). INTERPRETATION:Diagnosing primary aldosteronism in the early stages of disease, with early initiation of specific treatment, is important because affected patients display an increased cardiovascular risk compared with patients with essential hypertension. FUNDING:None. 10.1016/S2213-8587(17)30319-4
Hypoxia-inducible factor 1 and cardiovascular disease. Semenza Gregg L Annual review of physiology Cardiac function is required for blood circulation and systemic oxygen delivery. However, the heart has intrinsic oxygen demands that must be met to maintain effective contractility. Hypoxia-inducible factor 1 (HIF-1) is a transcription factor that functions as a master regulator of oxygen homeostasis in all metazoan species. HIF-1 controls oxygen delivery, by regulating angiogenesis and vascular remodeling, and oxygen utilization, by regulating glucose metabolism and redox homeostasis. Analysis of animal models suggests that by activation of these homeostatic mechanisms, HIF-1 plays a critical protective role in the pathophysiology of ischemic heart disease and pressure-overload heart failure. 10.1146/annurev-physiol-021113-170322
Bempedoic Acid and Cardiovascular Outcomes in Statin-Intolerant Patients. The New England journal of medicine BACKGROUND:Bempedoic acid, an ATP citrate lyase inhibitor, reduces low-density lipoprotein (LDL) cholesterol levels and is associated with a low incidence of muscle-related adverse events; its effects on cardiovascular outcomes remain uncertain. METHODS:We conducted a double-blind, randomized, placebo-controlled trial involving patients who were unable or unwilling to take statins owing to unacceptable adverse effects ("statin-intolerant" patients) and had, or were at high risk for, cardiovascular disease. The patients were assigned to receive oral bempedoic acid, 180 mg daily, or placebo. The primary end point was a four-component composite of major adverse cardiovascular events, defined as death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or coronary revascularization. RESULTS:A total of 13,970 patients underwent randomization; 6992 were assigned to the bempedoic acid group and 6978 to the placebo group. The median duration of follow-up was 40.6 months. The mean LDL cholesterol level at baseline was 139.0 mg per deciliter in both groups, and after 6 months, the reduction in the level was greater with bempedoic acid than with placebo by 29.2 mg per deciliter; the observed difference in the percent reductions was 21.1 percentage points in favor of bempedoic acid. The incidence of a primary end-point event was significantly lower with bempedoic acid than with placebo (819 patients [11.7%] vs. 927 [13.3%]; hazard ratio, 0.87; 95% confidence interval [CI], 0.79 to 0.96; P = 0.004), as were the incidences of a composite of death from cardiovascular causes, nonfatal stroke, or nonfatal myocardial infarction (575 [8.2%] vs. 663 [9.5%]; hazard ratio, 0.85; 95% CI, 0.76 to 0.96; P = 0.006); fatal or nonfatal myocardial infarction (261 [3.7%] vs. 334 [4.8%]; hazard ratio, 0.77; 95% CI, 0.66 to 0.91; P = 0.002); and coronary revascularization (435 [6.2%] vs. 529 [7.6%]; hazard ratio, 0.81; 95% CI, 0.72 to 0.92; P = 0.001). Bempedoic acid had no significant effects on fatal or nonfatal stroke, death from cardiovascular causes, and death from any cause. The incidences of gout and cholelithiasis were higher with bempedoic acid than with placebo (3.1% vs. 2.1% and 2.2% vs. 1.2%, respectively), as were the incidences of small increases in serum creatinine, uric acid, and hepatic-enzyme levels. CONCLUSIONS:Among statin-intolerant patients, treatment with bempedoic acid was associated with a lower risk of major adverse cardiovascular events (death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or coronary revascularization). (Funded by Esperion Therapeutics; CLEAR Outcomes ClinicalTrials.gov number, NCT02993406.). 10.1056/NEJMoa2215024
Circulating ketone bodies and cardiovascular outcomes: the MESA study. European heart journal AIMS:Ketone bodies (KB) are an important alternative metabolic fuel source for the myocardium. Experimental and human investigations suggest that KB may have protective effects in patients with heart failure. This study aimed to examine the association between KB and cardiovascular outcomes and mortality in an ethnically diverse population free from cardiovascular disease (CVD). METHODS AND RESULTS:This analysis included 6796 participants (mean age 62 ± 10 years, 53% women) from the Multi-Ethnic Study of Atherosclerosis. Total KB was measured by nuclear magnetic resonance spectroscopy. Multivariable-adjusted Cox proportional hazard models were used to examine the association of total KB with cardiovascular outcomes. At a mean follow-up of 13.6 years, after adjusting for traditional CVD risk factors, increasing total KB was associated with a higher rate of hard CVD, defined as a composite of myocardial infarction, resuscitated cardiac arrest, stroke, and cardiovascular death, and all CVD (additionally included adjudicated angina) [hazard ratio, HR (95% confidence interval, CI): 1.54 (1.12-2.12) and 1.37 (1.04-1.80) per 10-fold increase in total KB, respectively]. Participants also experienced an 87% (95% CI: 1.17-2.97) increased rate of CVD mortality and an 81% (1.45-2.23) increased rate of all-cause mortality per 10-fold increase in total KB. Moreover, a higher rate of incident heart failure was observed with increasing total KB [1.68 (1.07-2.65), per 10-fold increase in total KB]. CONCLUSION:The study found that elevated endogenous KB in a healthy community-based population is associated with a higher rate of CVD and mortality. Ketone bodies could serve as a potential biomarker for cardiovascular risk assessment. 10.1093/eurheartj/ehad087
The Long-Awaited Revascularization Guidelines Are Out: What's In Them? Grubb Kendra J,Kirtane Ajay J Circulation 10.1161/CIRCULATIONAHA.121.057930
Atrial Fibrillation and Dementia: A Report From the AF-SCREEN International Collaboration. Circulation Growing evidence suggests a consistent association between atrial fibrillation (AF) and cognitive impairment and dementia that is independent of clinical stroke. This report from the AF-SCREEN International Collaboration summarizes the evidence linking AF to cognitive impairment and dementia. It provides guidance on the investigation and management of dementia in patients with AF on the basis of best available evidence. The document also addresses suspected pathophysiologic mechanisms and identifies knowledge gaps for future research. Whereas AF and dementia share numerous risk factors, the association appears to be independent of these variables. Nevertheless, the evidence remains inconclusive regarding a direct causal effect. Several pathophysiologic mechanisms have been proposed, some of which are potentially amenable to early intervention, including cerebral microinfarction, AF-related cerebral hypoperfusion, inflammation, microhemorrhage, brain atrophy, and systemic atherosclerotic vascular disease. The mitigating role of oral anticoagulation in specific subgroups (eg, low stroke risk, short duration or silent AF, after successful AF ablation, or atrial cardiopathy) and the effect of rhythm versus rate control strategies remain unknown. Likewise, screening for AF (in cognitively normal or cognitively impaired patients) and screening for cognitive impairment in patients with AF are debated. The pathophysiology of dementia and therapeutic strategies to reduce cognitive impairment warrant further investigation in individuals with AF. Cognition should be evaluated in future AF studies and integrated with patient-specific outcome priorities and patient preferences. Further large-scale prospective studies and randomized trials are needed to establish whether AF is a risk factor for cognitive impairment, to investigate strategies to prevent dementia, and to determine whether screening for unknown AF followed by targeted therapy might prevent or reduce cognitive impairment and dementia. 10.1161/CIRCULATIONAHA.121.055018
Roles of Mineralocorticoid Receptors in Cardiovascular and Cardiorenal Diseases. Barrera-Chimal Jonatan,Bonnard Benjamin,Jaisser Frederic Annual review of physiology Mineralocorticoid receptor (MR) activation in the heart and vessels leads to pathological effects, such as excessive extracellular matrix accumulation, oxidative stress, and sustained inflammation. In these organs, the MR is expressed in cardiomyocytes, fibroblasts, endothelial cells, smooth muscle cells, and inflammatory cells. We review the accumulating experimental and clinical evidence that pharmacological MR antagonism has a positive impact on a battery of cardiac and vascular pathological states, including heart failure, myocardial infarction, arrhythmic diseases, atherosclerosis, vascular stiffness, and cardiac and vascular injury linked to metabolic comorbidities and chronic kidney disease. Moreover, we present perspectives on optimization of the use of MR antagonists in patients more likely to respond to such therapy and review the evidence suggesting that novel nonsteroidal MR antagonists offer an improved safety profile while retaining their cardiovascular protective effects. Finally, we highlight future therapeutic applications of MR antagonists in cardiovascular injury. 10.1146/annurev-physiol-060821-013950
Heart-brain interactions in cardiac and brain diseases: why sex matters. European heart journal Cardiovascular disease and brain disorders, such as depression and cognitive dysfunction, are highly prevalent conditions and are among the leading causes limiting patient's quality of life. A growing body of evidence has shown an intimate crosstalk between the heart and the brain, resulting from a complex network of several physiological and neurohumoral circuits. From a pathophysiological perspective, both organs share common risk factors, such as hypertension, diabetes, smoking or dyslipidaemia, and are similarly affected by systemic inflammation, atherosclerosis, and dysfunction of the neuroendocrine system. In addition, there is an increasing awareness that physiological interactions between the two organs play important roles in potentiating disease and that sex- and gender-related differences modify those interactions between the heart and the brain over the entire lifespan. The present review summarizes contemporary evidence of the effect of sex on heart-brain interactions and how these influence pathogenesis, clinical manifestation, and treatment responses of specific heart and brain diseases. 10.1093/eurheartj/ehac061
Inflammation, Aging, and Cardiovascular Disease: JACC Review Topic of the Week. Journal of the American College of Cardiology Aging and inflammation both contribute pivotally to cardiovascular (CV) and cerebrovascular disease, the leading causes of death and disability worldwide. The concept of inflamm-aging recognizes that low-grade inflammatory pathways observed in the elderly contribute to CV risk. Understanding the mechanisms that link inflammation and aging could reveal new therapeutic targets and offer options to cope with the growing aging population worldwide. This review reports recent scientific advances in the pathways through which inflamm-aging mediates age-dependent decline in CV function and disease onset and considers critically the translational potential of such concepts into everyday clinical practice. 10.1016/j.jacc.2021.12.017
Reactive Oxygen Species Scavenging Nanomedicine for the Treatment of Ischemic Heart Disease. Advanced materials (Deerfield Beach, Fla.) Ischemic heart disease (IHD) is the leading cause of disability and mortality worldwide. Reactive oxygen species (ROS) have been shown to play key roles in the progression of diabetes, hypertension, and hypercholesterolemia, which are independent risk factors that lead to atherosclerosis and the development of IHD. Engineered biomaterial-based nanomedicines are under extensive investigation and exploration, serving as smart and multifunctional nanocarriers for synergistic therapeutic effect. Capitalizing on cell/molecule-targeting drug delivery, nanomedicines present enhanced specificity and safety with favorable pharmacokinetics and pharmacodynamics. Herein, the roles of ROS in both IHD and its risk factors are discussed, highlighting cardiovascular medications that have antioxidant properties, and summarizing the advantages, properties, and recent achievements of nanomedicines that have ROS scavenging capacity for the treatment of diabetes, hypertension, hypercholesterolemia, atherosclerosis, ischemia/reperfusion, and myocardial infarction. Finally, the current challenges of nanomedicines for ROS-scavenging treatment of IHD and possible future directions are discussed from a clinical perspective. 10.1002/adma.202202169
Targeting the CCL2-CCR2 axis for atheroprotection. European heart journal Decades of research have established atherosclerosis as an inflammatory disease. Only recently though, clinical trials provided proof-of-concept evidence for the efficacy of anti-inflammatory strategies with respect to cardiovascular events, thus offering a new paradigm for lowering residual vascular risk. Efforts to target the inflammasome-interleukin-1β-interleukin-6 pathway have been highly successful, but inter-individual variations in drug response, a lack of reduction in all-cause mortality, and a higher rate of infections also highlight the need for a second generation of anti-inflammatory agents targeting atherosclerosis-specific immune mechanisms while minimizing systemic side effects. CC-motif chemokine ligand 2/monocyte-chemoattractant protein-1 (CCL2/MCP-1) orchestrates inflammatory monocyte trafficking between the bone marrow, circulation, and atherosclerotic plaques by binding to its cognate receptor CCR2. Adding to a strong body of data from experimental atherosclerosis models, a coherent series of recent large-scale genetic and observational epidemiological studies along with data from human atherosclerotic plaques highlight the relevance and therapeutic potential of the CCL2-CCR2 axis in human atherosclerosis. Here, we summarize experimental and human data pinpointing the CCL2-CCR2 pathway as an emerging drug target in cardiovascular disease. Furthermore, we contextualize previous efforts to interfere with this pathway, scrutinize approaches of ligand targeting vs. receptor targeting, and discuss possible pathway-intrinsic opportunities and challenges related to pharmacological targeting of the CCL2-CCR2 axis in human atherosclerotic disease. 10.1093/eurheartj/ehac094
Lipoprotein(a) and its Significance in Cardiovascular Disease: A Review. JAMA cardiology Importance:Lipoprotein(a) (Lp[a]) is a low-density lipoprotein (LDL) cholesterol-like particle bound to apolipoprotein(a). This novel marker of cardiovascular disease acts through induction of vascular inflammation, atherogenesis, calcification, and thrombosis. While an absolute risk threshold remains to be universally accepted, an estimated 20% to 25% of the global population have Lp(a) levels of 50 mg/dL or higher, a level noted by the European Atherosclerosis Society to confer increased cardiovascular risk. Observations:Compelling evidence from pathophysiological, observational, and genetic studies suggest a potentially causal association between high Lp(a) levels, atherosclerotic cardiovascular disease, and calcific aortic valve stenosis. Additional evidence has demonstrated that elevated Lp(a) levels are associated with a residual cardiovascular risk despite traditional risk factor optimization, including LDL cholesterol reduction. These findings have led to the formulation of the Lp(a) hypothesis, namely that Lp(a) lowering leads to cardiovascular risk reduction, intensifying the search for Lp(a)-reducing therapies. The ineffectiveness of lifestyle modification, statins, and ezetimibe to lower Lp(a); the modest Lp(a) reduction with proprotein convertase subtilisin/kexin type 9 inhibitors; the adverse effect profile and unclear cardiovascular benefit of pharmacotherapies such as niacin and mipomersen; and the impracticality of regular lipoprotein apheresis represent major challenges to currently available therapies. Nevertheless, emerging nucleic acid-based therapies, such as the antisense oligonucleotide pelacarsen and the small interfering RNA olpasiran, are generating interest because of their potent Lp(a)-lowering effects. Assessment of new-onset diabetes in patients achieving very low Lp(a) levels will be important in future trials. Conclusions and Relevance:Epidemiologic and genetic studies suggest a potentially causal association between elevated Lp(a) levels, atherosclerotic cardiovascular disease, and aortic valve stenosis. Emerging nucleic acid-based therapies have potent Lp(a)-lowering effects and appear safe; phase 3 trials will establish whether they improve cardiovascular outcomes. 10.1001/jamacardio.2022.0987
Sodium Glucose Cotransporter-2 Inhibition for Acute Myocardial Infarction: JACC Review Topic of the Week. Journal of the American College of Cardiology Sodium glucose cotransporter-2 (SGLT2) inhibitors improve cardiorenal outcomes in patients with type 2 diabetes mellitus, chronic kidney disease, and chronic heart failure. SGLT2 inhibitors also reduce the risk of cardiovascular mortality and hospitalization for heart failure among patients with type 2 diabetes mellitus and a remote history of myocardial infarction (MI). As a result of the growing body of evidence in diverse disease states, and the hypothesized mechanisms of action, it is reasonable to consider the potential of SGLT2 inhibition to improve outcomes in patients with acute MI as well if initiated early after presentation. Whether these therapies are efficacious and safe to use early in the course of acute coronary heart disease remains relatively unexplored. Here, we describe the contemporary data and continuing evidence gap for considering the use of SGLT2 inhibitors early following an acute MI to reduce cardiovascular morbidity and mortality. 10.1016/j.jacc.2022.03.353
Polygenic Risk Scores for Cardiovascular Disease: A Scientific Statement From the American Heart Association. Circulation Cardiovascular disease is the leading contributor to years lost due to disability or premature death among adults. Current efforts focus on risk prediction and risk factor mitigation' which have been recognized for the past half-century. However, despite advances, risk prediction remains imprecise with persistently high rates of incident cardiovascular disease. Genetic characterization has been proposed as an approach to enable earlier and potentially tailored prevention. Rare mendelian pathogenic variants predisposing to cardiometabolic conditions have long been known to contribute to disease risk in some families. However, twin and familial aggregation studies imply that diverse cardiovascular conditions are heritable in the general population. Significant technological and methodological advances since the Human Genome Project are facilitating population-based comprehensive genetic profiling at decreasing costs. Genome-wide association studies from such endeavors continue to elucidate causal mechanisms for cardiovascular diseases. Systematic cataloging for cardiovascular risk alleles also enabled the development of polygenic risk scores. Genetic profiling is becoming widespread in large-scale research, including in health care-associated biobanks, randomized controlled trials, and direct-to-consumer profiling in tens of millions of people. Thus, individuals and their physicians are increasingly presented with polygenic risk scores for cardiovascular conditions in clinical encounters. In this scientific statement, we review the contemporary science, clinical considerations, and future challenges for polygenic risk scores for cardiovascular diseases. We selected 5 cardiometabolic diseases (coronary artery disease, hypercholesterolemia, type 2 diabetes, atrial fibrillation, and venous thromboembolic disease) and response to drug therapy and offer provisional guidance to health care professionals, researchers, policymakers, and patients. 10.1161/CIR.0000000000001077
Coronary In-Stent Restenosis: JACC State-of-the-Art Review. Journal of the American College of Cardiology The introduction and subsequent iterations of drug-eluting stent technologies have substantially improved the efficacy and safety of percutaneous coronary interventions. However, the incidence of in-stent restenosis (ISR) and the resultant need for repeated revascularization still occur at a rate of 1%-2% per year. Given that millions of drug-eluting stents are implanted each year around the globe, ISR can be considered as a pathologic entity of public health significance. The mechanisms of ISR are multifactorial. Since the first description of the angiographic patterns of ISR, the advent of intracoronary imaging has further elucidated the mechanisms and patterns of ISR. The armamentarium and treatment strategies of ISR have also evolved over time. Currently, an individualized approach using intracoronary imaging to characterize the underlying substrate of ISR is recommended. In this paper, we comprehensively reviewed the incidence, mechanisms, and imaging characterization of ISR and propose a contemporary treatment algorithm. 10.1016/j.jacc.2022.05.017
Cellular senescence and cardiovascular diseases: moving to the "heart" of the problem. Physiological reviews Cardiovascular diseases (CVDs) constitute the prime cause of global mortality, with an immense impact on patient quality of life and disability. Clinical evidence has revealed a strong connection between cellular senescence and worse cardiac outcomes in the majority of CVDs concerning both ischemic and nonischemic cardiomyopathies. Cellular senescence is characterized by cell cycle arrest accompanied by alterations in several metabolic pathways, resulting in morphological and functional changes. Metabolic rewiring of senescent cells results in marked paracrine activity, through a unique secretome, often exerting deleterious effects on neighboring cells. Here, we recapitulate the hallmarks and key molecular pathways involved in cellular senescence in the cardiac context and summarize the different roles of senescence in the majority of CVDs. In the last few years, the possibility of eliminating senescent cells in various pathological conditions has been increasingly explored, giving rise to the field of senotherapeutics. Therefore, we additionally attempt to clarify the current state of this field with a focus on cardiac senescence and discuss the potential of implementing senolytics as a treatment option in heart disease. 10.1152/physrev.00007.2022
Cardiac Phenotypes in Secondary Hypertension: JACC State-of-the-Art Review. Journal of the American College of Cardiology Several forms of secondary hypertension carry a high risk of cardiac morbidity and mortality. Evaluation of cardiac phenotypes in secondary hypertension provides a unique opportunity to study underlying hormonal and biochemical mechanisms affecting the heart. We review the characteristics of cardiac dysfunction in different forms of secondary hypertension and clarify the mechanisms behind the higher prevalence of heart damage in these patients than in those with primary hypertension. Attention to the specific clinical/biochemical phenotypes of these conditions may assist clinicians to screen for and confirm secondary forms of hypertension. Thereby, early signs of heart damage can be recognized and monitored, allowing individualized treatment to delay or prevent evolution toward more advanced disease. 10.1016/j.jacc.2022.08.714
Neutrophils in aging and aging-related pathologies. Immunological reviews Over the past millennia, life expectancy has drastically increased. While a mere 25 years during Bronze and Iron ages, life expectancy in many European countries and in Japan is currently above 80 years. Such an increase in life expectancy is a result of improved diet, life style, and medical care. Yet, increased life span and aging also represent the most important non-modifiable risk factors for several pathologies including cardiovascular disease, neurodegenerative diseases, and cancer. In recent years, neutrophils have been implicated in all of these pathologies. Hence, this review provides an overview of how aging impacts neutrophil production and function and conversely how neutrophils drive aging-associated pathologies. Finally, we provide a perspective on how processes of neutrophil-driven pathologies in the context of aging can be targeted therapeutically. 10.1111/imr.13153
Polygenic risk scores for the prediction of cardiometabolic disease. European heart journal Cardiometabolic diseases contribute more to global morbidity and mortality than any other group of disorders. Polygenic risk scores (PRSs), the weighted summation of individually small-effect genetic variants, represent an advance in our ability to predict the development and complications of cardiometabolic diseases. This article reviews the evidence supporting the use of PRS in seven common cardiometabolic diseases: coronary artery disease (CAD), stroke, hypertension, heart failure and cardiomyopathies, obesity, atrial fibrillation (AF), and type 2 diabetes mellitus (T2DM). Data suggest that PRS for CAD, AF, and T2DM consistently improves prediction when incorporated into existing clinical risk tools. In other areas such as ischaemic stroke and hypertension, clinical application appears premature but emerging evidence suggests that the study of larger and more diverse populations coupled with more granular phenotyping will propel the translation of PRS into practical clinical prediction tools. 10.1093/eurheartj/ehac648
Management of Acute Coronary Syndrome in the Older Adult Population: A Scientific Statement From the American Heart Association. Circulation Diagnostic and therapeutic advances during the past decades have substantially improved health outcomes for patients with acute coronary syndrome. Both age-related physiological changes and accumulated cardiovascular risk factors increase the susceptibility to acute coronary syndrome over a lifetime. Compared with younger patients, outcomes for acute coronary syndrome in the large and growing demographic of older adults are relatively worse. Increased atherosclerotic plaque burden and complexity of anatomic disease, compounded by age-related cardiovascular and noncardiovascular comorbid conditions, contribute to the worse prognosis observed in older individuals. Geriatric syndromes, including frailty, multimorbidity, impaired cognitive and physical function, polypharmacy, and other complexities of care, can undermine the therapeutic efficacy of guidelines-based treatments and the resiliency of older adults to survive and recover, as well. In this American Heart Association scientific statement, we (1) review age-related physiological changes that predispose to acute coronary syndrome and management complexity; (2) describe the influence of commonly encountered geriatric syndromes on cardiovascular disease outcomes; and (3) recommend age-appropriate and guideline-concordant revascularization and acute coronary syndrome management strategies, including transitions of care, the use of cardiac rehabilitation, palliative care services, and holistic approaches. The primacy of individualized risk assessment and patient-centered care decision-making is highlighted throughout. 10.1161/CIR.0000000000001112
GLP-1 Receptor Agonists for the Reduction of Atherosclerotic Cardiovascular Risk in Patients With Type 2 Diabetes. Circulation Patients with type 2 diabetes are at high risk for development of cardiovascular disease, including myocardial infarction, stroke, heart failure, and cardiovascular death. Multiple large cardiovascular outcome trials with novel glucose-lowering agents, namely SGLT2i (SGLT2 inhibitors) and GLP-1 RA (GLP-1 receptor agonists), have demonstrated robust and significant reductions of major adverse cardiovascular events and additional cardiovascular outcomes, such as hospitalizations for heart failure. This evidence has changed the landscape for treatment of patients with type 2 diabetes. Both diabetes and cardiology guidelines and professional societies have responded to this paradigm shift by including strong recommendations to use SGLT2i and/or GLP-1 RA, with evidence-based benefits to reduce cardiovascular risk in high-risk individuals with type 2 diabetes, independent of the need for additional glucose control. GLP-1 RA were initially developed as glucose-lowering drugs because activation of the GLP-1 receptor by these agents leads to a reduction in blood glucose and an improvement in postprandial glucose metabolism. By stimulating GLP-1R in hypothalamic neurons, GLP-1 RA additionally induce satiety and lead to weight loss. Data from cardiovascular outcome trials demonstrated a robust and consistent reduction in atherothrombotic events, particularly in patients with established atherosclerotic cardiovascular disease. Despite the consistent evidence of atherosclerotic cardiovascular disease benefit from these trials, the number of patients receiving these drugs remains low. This overview summarizes the experimental and clinical evidence of cardiovascular risk reduction offered by GLP-1 RA, and provides practical information on how these drugs should be implemented in the treatment of type 2 diabetes in the cardiology community. 10.1161/CIRCULATIONAHA.122.059595
Genome-wide association studies of cardiovascular disease. Physiological reviews Genome-wide association studies (GWAS) aim to identify common genetic variants that are associated with traits and diseases. Since 2005, more than 5,000 GWAS have been published for almost as many traits. These studies have offered insights into the loci and genes underlying phenotypic traits, have highlighted genetic correlations across traits and diseases, and are beginning to demonstrate clinical utility by identifying individuals at increased risk for common diseases. GWAS have been widely utilized across cardiovascular diseases and associated phenotypic traits, with insights facilitated by multicenter registry studies and large biobank data sets. In this review, we describe how GWAS have informed the genetic architecture of cardiovascular diseases and the insights they have provided into disease pathophysiology, using archetypal conditions for both common and rare diseases. We also describe how biobank data sets can complement disease-specific studies, particularly for rarer cardiovascular diseases, and how findings from GWAS have the potential to impact on clinical care. Finally, we discuss the outstanding challenges facing research in this field and how they can be addressed. 10.1152/physrev.00024.2022
Circulating cardiac biomarkers, structural brain changes, and dementia: Emerging insights and perspectives. Alzheimer's & dementia : the journal of the Alzheimer's Association Diseases of the heart and brain are strongly linked to each other, and cardiac dysfunction is associated with cognitive decline and dementia. This link between cardiovascular disease and dementia offers opportunities for dementia prevention through prevention and treatment of cardiovascular risk factors and heart disease. Increasing evidence suggests the clinical utility of cardiac biomarkers as risk markers for structural brain changes and cognitive impairment. We propose the hypothesis that structural brain changes are the link between impaired cardiac function, as captured by blood-based cardiac biomarkers, and cognitive impairment. This review provides an overview of the literature and illustrates emerging insights into the association of markers of hemodynamic stress (natriuretic peptides) and markers of myocardial injury (cardiac troponins) with imaging findings of brain damage and cognitive impairment or dementia. Based on these findings, we discuss potential pathophysiological mechanisms underlying the association of cardiac biomarkers with structural brain changes and dementia. We suggest testable hypotheses and a research plan to close the gaps in understanding the mechanisms linking vascular damage and neurodegeneration, and to pave the way for targeted effective interventions for dementia prevention. From a clinical perspective, cardiac biomarkers open the window for early identification of patients at risk of dementia, who represent a target population for preventive interventions targeting modifiable cardiovascular risk factors to avert cognitive decline and dementia. 10.1002/alz.12926
Pericoronary Adipose Tissue as a Marker of Cardiovascular Risk: JACC Review Topic of the Week. Journal of the American College of Cardiology Vascular inflammation is a key driver in atherosclerotic progression and plaque rupture. Recent evidence has shown that coronary computed tomography provides a noninvasive method of quantifying coronary inflammation by mapping changes in pericoronary adipose tissue (PCAT) radiodensity, which are associated with cardiovascular diseases. However, there are significant knowledge gaps in the performance and measurement of PCAT that complicate its interpretation. In this review the authors aim to summarize the role of PCAT in cardiac imaging and explore the clinical implications and applicability as a novel biomarker of cardiovascular risk, as well as to discuss its limitations and potential pitfalls. 10.1016/j.jacc.2022.12.021
Associations between plasma fatty acid concentrations and schizophrenia: a two-sample Mendelian randomisation study. The lancet. Psychiatry BACKGROUND:Although studies suggest that concentrations of omega-3 and omega-6 fatty acids are lower in individuals with schizophrenia, evidence for beneficial effects of fatty acid supplementation is scarce. Therefore, in this study, we aimed to determine whether omega-3 and omega-6 fatty acid concentrations are causally related to schizophrenia. METHODS:We did a two-sample Mendelian randomisation study, using deidentified summary-level data that were publicly available. Exposure-outcome relationships were evaluated using the inverse variance weighted two-sample Mendelian randomisation method using results from genome-wide association studies (GWASs) of fatty acid concentrations and schizophrenia. GWAS results were available for European (fatty acids) and European and Asian (schizophrenia) ancestry samples. Overall age and gender information were not calculable from the summary-level GWAS results. Weighted median, weighted mode, and Mendelian randomisation Egger regression methods were used as sensitivity analyses. To address underlying mechanisms, further analyses were done using single instruments within the FADS gene cluster and ELOVL2 gene locus. FADS gene cluster and ELOVL2 gene causal effects on schizophrenia were calculated by dividing the single nucleotide polymorphism (SNP)-schizophrenia effect estimate by the SNP-fatty acid effect estimate with standard errors derived using the first term from a delta method expansion for the ratio estimate. Multivariable Mendelian randomisation was used to estimate direct effects of omega-3 fatty acids on schizophrenia, independent of omega-6 fatty acids, lipoproteins (ie, HDL and LDL), and triglycerides. FINDINGS:Mendelian randomisation analyses indicated that long-chain omega-3 and long-chain omega-6 fatty acid concentrations were associated with a lower risk of schizophrenia (eg, inverse variance weighted odds ratio [OR] 0·83 [95% CI 0·75-0·92] for docosahexaenoic acid). By contrast, there was weak evidence that short-chain omega-3 and short-chain omega-6 fatty acids were associated with an increased risk of schizophrenia (eg, inverse variance weighted OR 1·07 [95% CI 0·98-1·18] for α-linolenic acid). Effects were consistent across the sensitivity analyses and the FADS single-SNP analyses, suggesting that long-chain omega-3 and long-chain omega-6 fatty acid concentrations were associated with lower risk of schizophrenia (eg, OR 0·74 [95% CI 0·58-0·96] for docosahexaenoic acid) whereas short-chain omega-3 and short-chain omega-6 fatty acid concentrations were associated with an increased risk of schizophrenia (eg, OR 1·08 [95% CI 1·02-1·15] for α-linolenic acid). By contrast, estimates from the ELOVL2 single-SNP analyses were more imprecise and compatible with both risk-increasing and protective effects for each of the fatty acid measures. Multivariable Mendelian randomisation indicated that the protective effect of docosahexaenoic acid on schizophrenia persisted after conditioning on other lipids, although evidence was slightly weaker (multivariable inverse variance weighted OR 0·84 [95% CI 0·71-1·01]). INTERPRETATION:Our results are compatible with the protective effects of long-chain omega-3 and long-chain omega-6 fatty acids on schizophrenia, suggesting that people with schizophrenia might have difficulty converting short-chain polyunsaturated fatty acids to long-chain polyunsaturated fatty acids. Further studies are required to determine whether long-chain polyunsaturated fatty acid supplementation or diet enrichment might help prevent onset of schizophrenia. FUNDING:National Institute for Health Research Biomedical Research Centre at University Hospitals Bristol and Weston NHS Foundation Trust and the University of Bristol. 10.1016/S2215-0366(21)00286-8
Mendelian randomization highlights causal association between genetically increased C-reactive protein levels and reduced Alzheimer's disease risk. Alzheimer's & dementia : the journal of the Alzheimer's Association 10.1002/alz.12687
Mendelian Randomization Study of PCSK9 and HMG-CoA Reductase Inhibition and Cognitive Function. Journal of the American College of Cardiology BACKGROUND:Lipid-lowering therapy with statins and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition are effective strategies in reducing cardiovascular disease risk; however, concerns remain about potential long-term adverse neurocognitive effects. OBJECTIVES:This genetics-based study aimed to evaluate the relationships of long-term PCSK9 inhibition and statin use on neurocognitive outcomes. METHODS:We extracted single-nucleotide polymorphisms in 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) and PCSK9 from predominantly European ancestry-based genome-wide association studies summary-level statistics of low-density lipoprotein cholesterol and performed drug-target Mendelian randomization, proxying the potential neurocognitive impact of drug-based PCSK9 and HMGCR inhibition using a range of outcomes to capture the complex facets of cognition and dementia. RESULTS:Using data from a combined sample of ∼740,000 participants, we observed a neutral cognitive profile related to genetic PCSK9 inhibition, with no significant effects on cognitive performance, memory performance, or cortical surface area. Conversely, we observed several adverse associations for HMGCR inhibition with lowered cognitive performance (beta: -0.082; 95% CI: -0.16 to -0.0080; P = 0.03), reaction time (beta = 0.00064; 95% CI: 0.00030-0.00098; P = 0.0002), and cortical surface area (beta = -0.18; 95% CI: -0.35 to -0.014; P = 0.03). Neither PCSK9 nor HMGCR inhibition impacted biomarkers of Alzheimer's disease progression or Lewy body dementia risk. Consistency of findings across Mendelian randomization methods accommodating different assumptions about genetic pleiotropy strengthens causal inference. CONCLUSIONS:Using a wide range of cognitive function and dementia endpoints, we failed to find genetic evidence of an adverse PCSK9-related impact, suggesting a neutral cognitive profile. In contrast, we observed adverse neurocognitive effects related to HMGCR inhibition, which may well be outweighed by the cardiovascular benefits of statin use, but nonetheless may warrant pharmacovigilance. 10.1016/j.jacc.2022.05.041
SGLT2 Inhibition, Choline Metabolites, and Cardiometabolic Diseases: A Mediation Mendelian Randomization Study. Diabetes care OBJECTIVE:To investigate the causal role of choline metabolites mediating sodium-glucose cotransporter 2 (SGLT2) inhibition in coronary artery disease (CAD) and type 2 diabetes (T2D) using Mendelian randomization (MR). RESEARCH DESIGN AND METHODS:A two-sample two-step MR was used to determine 1) causal effects of SGLT2 inhibition on CAD and T2D; 2) causal effects of three choline metabolites, total choline, phosphatidylcholine, and glycine, on CAD and T2D; and 3) mediation effects of these metabolites. Genetic proxies for SGLT2 inhibition were identified as variants in the SLC5A2 gene that were associated with both levels of gene expression and hemoglobin A1c. Summary statistics for metabolites were from UK Biobank, CAD from CARDIoGRAMplusC4D (Coronary ARtery DIsease Genome wide Replication and Meta-analysis [CARDIoGRAM] plus The Coronary Artery Disease [C4D] Genetics) consortium, and T2D from DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) and the FinnGen study. RESULTS:SGLT2 inhibition (per 1 SD, 6.75 mmol/mol [1.09%] lowering of HbA1c) was associated with lower risk of T2D and CAD (odds ratio [OR] 0.25 [95% CI 0.12, 0.54], and 0.51 [0.28, 0.94], respectively) and positively with total choline (β 0.39 [95% CI 0.06, 0.72]), phosphatidylcholine (0.40 [0.13, 0.67]), and glycine (0.34 [0.05, 0.63]). Total choline (OR 0.78 [95% CI 0.68, 0.89]) and phosphatidylcholine (OR 0.81 [0.72, 0.91]) were associated with T2D but not with CAD, while glycine was associated with CAD (0.94 [0.91, 0.98]) but not with T2D. Mediation analysis showed evidence of indirect effect of SGLT2 inhibition on T2D through total choline (0.91 [0.83, 0.99]) and phosphatidylcholine (0.93 [0.87, 0.99]) with a mediated proportion of 8% and 5% of the total effect, respectively, and on CAD through glycine (0.98 [0.96, 1.00]) with a mediated proportion of 2%. The results were well validated in at least one independent data set. CONCLUSIONS:Our study identified the causal roles of SGLT2 inhibition in choline metabolites. SGLT2 inhibition may influence T2D and CAD through different choline metabolites. 10.2337/dc22-0323
Glutathione oxidation unmasks proarrhythmic vulnerability of chronically hyperglycemic guinea pigs. Xie Chaoqin,Biary Nora,Tocchetti Carlo G,Aon Miguel A,Paolocci Nazareno,Kauffman Justin,Akar Fadi G American journal of physiology. Heart and circulatory physiology Chronic hyperglycemia in type-1 diabetes mellitus is associated with oxidative stress (OS) and sudden death. Mechanistic links remain unclear. We investigated changes in electrophysiological (EP) properties in a model of chronic hyperglycemia before and after challenge with OS by GSH oxidation and tested reversibility of EP remodeling by insulin. Guinea pigs survived for 1 mo following streptozotocin (STZ) or saline (sham) injection. A treatment group received daily insulin for 2 wk to reverse STZ-induced hyperglycemia (STZ + Ins). EP properties were measured using high-resolution optical action potential mapping before and after challenge of hearts with diamide. Despite elevation of glucose levels in STZ compared with sham-operated (P = 0.004) and STZ + Ins (P = 0.002) animals, average action potential duration (APD) and arrhythmia propensity were not altered at baseline. Diamide promoted early (<10 min) formation of arrhythmic triggers reflected by a higher arrhythmia scoring index in STZ (P = 0.045) and STZ + Ins (P = 0.033) hearts compared with sham-operated hearts. APD heterogeneity underwent a more pronounced increase in response to diamide in STZ and STZ + Ins hearts compared with sham-operated hearts. Within 30 min, diamide resulted in spontaneous incidence of ventricular tachycardia and ventricular fibrillation (VT/VF) in 3/6, 2/5, 1/5, and 0/4 STZ, STZ + Ins, sham-operated, and normal hearts, respectively. Hearts prone to VT/VF exhibited greater APD heterogeneity (P = 0.010) compared with their VT/VF-free counterparts. Finally, altered EP properties in STZ were not rescued by insulin. In conclusion, GSH oxidation enhances APD heterogeneity and increases arrhythmia scoring index in a guinea pig model of chronic hyperglycemia. Despite normalization of glycemic levels by insulin, these proarrhythmic properties are not reversed, suggesting the importance of targeting antioxidant defenses for arrhythmia suppression. 10.1152/ajpheart.00026.2012
Glutathione-related substances maintain cardiomyocyte contractile function in hypoxic conditions. Scientific reports Severe hypoxia leads to decline in cardiac contractility and induces arrhythmic events in part due to oxidative damage to cardiomyocyte proteins including ion transporters. This results in compromised handling of Ca ions that trigger heart contractile machinery. Here, we demonstrate that thiol-containing compounds such as N-acetylcysteine (NAC), glutathione ethyl ester (et-GSH), oxidized tetraethylglutathione (tet-GSSG), oxidized glutathione (GSSG) and S-nitrosoglutathione (GSNO) are capable of reducing negative effects of hypoxia on isolated rat cardiomyocytes. Preincubation of cardiomyocytes with 0.1 mM GSNO, 0.5 mM et-GSH, GSSG, tet-GSSG or with 10 mM NAC allows cells 5-times longer tolerate the hypoxic conditions and elicit regular Ca transients in response to electric pacing. The shape of Ca transients generated in the presence of GSNO, et-GSH and NAC was similar to that observed in normoxic control cardiomyocytes. The leader compound, GSNO, accelerated by 34% the recovery of normal contractile function of isolated rat heart subjected to ischemia-reperfusion. GSNO increased glutathionylation of Na,K-ATPase alpha-2 subunit, the principal ion-transporter of cardiac myocyte sarcolemma, which prevents irreversible oxidation of Na,K-ATPase and regulates its function to support normal Ca ion handling in hypoxic cardiomyocytes. Altogether, GSNO appears effective cardioprotector in hypoxic conditions worth further studies toward its cardiovascular application. 10.1038/s41598-019-41266-2
Contribution of Glutathione-S-Transferases Polymorphism and Risk of Coronary Artery Diseases: A Meta-Analysis. Current aging science BACKGROUND:Oxidative stress is one of the risk components in the development of coronary artery diseases (CAD). Genetic polymorphism in major antioxidant genes like Glutathione- S-Transferases (GST) has been associated with increased CAD susceptibility and severity. OBJECTIVE:To get a precise evaluation and to update the association, a meta-analysis on GST (GSTM1, GSTT1, and GSTP1) polymorphism with CAD was performed. Moreover, the combined effect of GSTM1/GSTT1 null genotypes on CAD risk has not yet been studied, but it has the highest risk of developing diseases. MATERIALS AND METHODS:PubMed, Embase, and Web of Science were systematically searched for eligible studies. Case-control studies in the English language and with genotypic frequency were selected in order to provide data and calculate the odds ratio (OR). OR with 95% CI was calculated, and a random effect model was used. NOS scale was used to assess the quality of the included studies. RESULTS:Meta-analysis indicated that the GSTM1 null genotype and GSTP1 (Ile105Val) polymorphism is significantly associated with CAD risk with a pooled OR-1.38, p=0.01 for GSTM1 and OR-1.19, p=0.04 for GSTP1. The dual null genotype of GSTM1-GSTT1 has the highest risk for CAD development (OR-1.59, p=0.003), and there is no significant association between GSTT1 null genotype with CAD. In the subgroup analysis, GSTM1 showed an increased risk for Asians (OR- 1.68, p=<0.01) and smokers (OR-1.98, p=<0.01). Publication bias was not observed. CONCLUSION:The findings suggest that the GSTM1 and GSTP1 polymorphism can be a predictive factor for CAD risk, and a larger sample size is required further to confirm the association. 10.2174/1874609815666220304193925
Protective Biomolecular Mechanisms of Glutathione Sodium Salt in Ischemia-Reperfusion Injury in Patients with Acute Coronary Syndrome-ST-Elevation Myocardial Infarction. Cells Ischemia-Reperfusion Injury (IRI) is responsible for adverse outcomes in patients with ST-Elevation Myocardial Infarction (STEMI). Oxidative stress, resulting from the production of Reactive Oxygen Species (ROS) and low availability of Glutathione (GSH), are the two main mediators of IRI. The effectiveness of exogenous antioxidant therapy in this scenario is still debated, since the encouraging results obtained in animal models have not been fully reproduced in clinical studies. In this review we focus on the role of GSH, specifically on the biomolecular mechanisms that preserve myocardial cells from damage due to reperfusion. In this regard, we provide an extensive discussion about GSH intrinsic antioxidant properties, its current applications in clinical practice, and the future perspectives. 10.3390/cells11243964
Glutathione "Redox Homeostasis" and Its Relation to Cardiovascular Disease. Bajic Vladan P,Van Neste Christophe,Obradovic Milan,Zafirovic Sonja,Radak Djordje,Bajic Vladimir B,Essack Magbubah,Isenovic Esma R Oxidative medicine and cellular longevity More people die from cardiovascular diseases (CVD) than from any other cause. Cardiovascular complications are thought to arise from enhanced levels of free radicals causing impaired "redox homeostasis," which represents the interplay between oxidative stress (OS) and reductive stress (RS). In this review, we compile several experimental research findings that show sustained shifts towards OS will alter the homeostatic redox mechanism to cause cardiovascular complications, as well as findings that show a prolonged antioxidant state or RS can similarly lead to such cardiovascular complications. This experimental evidence is specifically focused on the role of glutathione, the most abundant antioxidant in the heart, in a redox homeostatic mechanism that has been shifted towards OS or RS. This may lead to impairment of cellular signaling mechanisms and elevated pools of proteotoxicity associated with cardiac dysfunction. 10.1155/2019/5028181
Iron in Cardiovascular Disease: Challenges and Potentials. Li Shizhen,Zhang Xiangyu Frontiers in cardiovascular medicine Iron is essential for many biological processes. Inadequate or excess amount of body iron can result in various pathological consequences. The pathological roles of iron in cardiovascular disease (CVD) have been intensively studied for decades. Convincing data demonstrated a detrimental effect of iron deficiency in patients with heart failure and pulmonary arterial hypertension, but it remains unclear for the pathological roles of iron in other cardiovascular diseases. Meanwhile, ferroptosis is an iron-dependent cell death that is distinct from apoptosis, necroptosis, and other types of cell death. Ferroptosis has been reported in several CVDs, namely, cardiomyopathy, atherosclerotic cardiovascular disease, and myocardial ischemia/reperfusion injury. Iron chelation therapy seems to be an available strategy to ameliorate iron overload-related disorders. It is still a challenge to accurately clarify the pathological roles of iron in CVD and search for effective medical intervention. In this review, we aim to summarize the pathological roles of iron in CVD, and especially highlight the potential mechanism of ferroptosis in these diseases. 10.3389/fcvm.2021.707138
Evaluation of bi-directional causal association between depression and cardiovascular diseases: a Mendelian randomization study. Psychological medicine BACKGROUND:Depression and cardiovascular disease (CVD) are associated with each other but their relationship remains unclear. We aim to determine whether genetic predisposition to depression are causally linked to CVD [including coronary artery disease (CAD), myocardial infarction (MI), stroke and atrial fibrillation (AF)]. METHODS:Using summary statistics from the largest genome-wide association studies (GWAS) or GWAS meta-analysis of depression (primary analysis: = 500 199), broad depression (help-seeking behavior for problems with nerves, anxiety, tension or depression; secondary analysis: = 322 580), CAD ( = 184 305), MI ( = 171 875), stroke ( = 446 696) and AF ( = 1 030 836), genetic correlation was tested between two depression phenotypes and CVD [MI, stroke and AF (not CAD as its correlation was previously confirmed)]. Causality was inferred between correlated traits by Mendelian Randomization analyses. RESULTS:Both depression phenotypes were genetically correlated with MI (depression: = 0.169; = 9.03 × 10; broad depression: = 0.123; = 1 × 10) and AF (depression: = 0.112; = 7.80 × 10; broad depression: = 0.126; = 3.62 × 10). Genetically doubling the odds of depression was causally associated with increased risk of CAD (OR = 1.099; 95% CI 1.031-1.170; = 0.004) and MI (OR = 1.146; 95% CI 1.070-1.228; = 1.05 × 10). Adjustment for blood lipid levels/smoking status attenuated the causality between depression and CAD/MI. Null causal association was observed for CVD on depression. A similar pattern of results was observed in the secondary analysis for broad depression. CONCLUSIONS:Genetic predisposition to depression may have positive causal roles on CAD/MI. Genetic susceptibility to self-awareness of mood problems may be a strong causal risk factor of CAD/MI. Blood lipid levels and smoking may potentially mediate the causal pathway. Prevention and early diagnosis of depression are important in the management of CAD/MI. 10.1017/S0033291720003566
Association of an HDL Apolipoproteomic Score With Coronary Atherosclerosis and Cardiovascular Death. Natarajan Pradeep,Collier Tim S,Jin Zhicheng,Lyass Asya,Li Yiwei,Ibrahim Nasrien E,Mukai Renata,McCarthy Cian P,Massaro Joseph M,D'Agostino Ralph B,Gaggin Hanna K,Bystrom Cory,Penn Marc S,Januzzi James L Journal of the American College of Cardiology BACKGROUND:Concentrations of circulating apolipoproteins are strongly linked to risk for coronary artery disease (CAD). The relative importance of the additional knowledge of apolipoprotein concentrations within specific lipoprotein species for CAD risk prediction is limited. OBJECTIVES:This study sought to evaluate the performance of a high-density lipoprotein (HDL) apolipoproteomic score, based on targeted mass spectrometry of HDL-associated apolipoproteins, for the detection of angiographic CAD and outcomes. METHODS:HDL-associated apolipoprotein (apo) A-1, apoC-1, apoC-2, apoC-3, and apoC-4 were measured in 943 participants without prevalent myocardial infarction (MI) referred for coronary angiography in the CASABLANCA (Catheter Sampled Blood Archive in Cardiovascular Diseases) study. A composite HDL apolipoproteomic score (pCAD) was associated with likelihood of obstructive CAD (≥70% lesion in ≥1 vessel) and with incident cardiovascular outcomes over 4-year follow-up. RESULTS:There were 587 (62.2%) patients with coronary stenosis. The pCAD score was associated with the presence of obstructive CAD (odds ratio: 1.39; 95% confidence interval [CI]: 1.14 to 1.69; p < 0.001), independently of conventional cardiovascular risk factors including circulating plasma apoA-1 and apoB. The C-index for pCAD was 0.63 (95% CI: 0.59 to 0.67) for the presence of obstructive CAD. Although pCAD was not associated with cardiovascular mortality among all individuals (hazard ratio: 1.24; 95% CI: 0.93 to 1.66; p = 0.15), there was evidence of association for individuals with obstructive CAD (hazard ratio: 1.48; 95% CI: 1.07 to 2.05; p = 0.019). CONCLUSIONS:An HDL apolipoproteomic score is associated with the presence of CAD, independent of circulating apoA-1 and apoB concentrations and other conventional cardiovascular risk factors. Among individuals with CAD, this score may be independently associated cardiovascular death. (The CASABLANCA Study: Catheter Sampled Blood Archive in Cardiovascular Diseases [CASABLANCA]; NCT00842868). 10.1016/j.jacc.2019.01.073
Novel methodologies for biomarker discovery in atherosclerosis. Hoefer Imo E,Steffens Sabine,Ala-Korpela Mika,Bäck Magnus,Badimon Lina,Bochaton-Piallat Marie-Luce,Boulanger Chantal M,Caligiuri Giuseppina,Dimmeler Stefanie,Egido Jesus,Evans Paul C,Guzik Tomasz,Kwak Brenda R,Landmesser Ulf,Mayr Manuel,Monaco Claudia,Pasterkamp Gerard,Tuñón Jose,Weber Christian, European heart journal Identification of subjects at increased risk for cardiovascular events plays a central role in the worldwide efforts to improve prevention, prediction, diagnosis, and prognosis of cardiovascular disease and to decrease the related costs. Despite their high predictive value on population level, traditional risk factors fail to fully predict individual risk. This position paper provides a summary of current vascular biomarkers other than the traditional risk factors with a special focus on the emerging -omics technologies. The definition of biomarkers and the identification and use of classical biomarkers are introduced, and we discuss the limitations of current biomarkers such as high sensitivity C-reactive protein (hsCRP) or N-terminal pro-brain natriuretic peptide (NT-proBNP). This is complemented by circulating plasma biomarkers, including high-density lipoprotein (HDL), and the conceptual shift from HDL cholesterol levels to HDL composition/function for cardiovascular risk assessment. Novel sources for plasma-derived markers include microparticles, microvesicles, and exosomes and their use for current omics-based analytics. Measurement of circulating micro-RNAs, short RNA sequences regulating gene expression, has attracted major interest in the search for novel biomarkers. Also, mass spectrometry and nuclear magnetic resonance spectroscopy have become key complementary technologies in the search for new biomarkers, such as proteomic searches or identification and quantification of small metabolites including lipids (metabolomics and lipidomics). In particular, pro-inflammatory lipid metabolites have gained much interest in the cardiovascular field. Our consensus statement concludes on leads and needs in biomarker research for the near future to improve individual cardiovascular risk prediction. 10.1093/eurheartj/ehv236
Joint Genetic Inhibition of PCSK9 and CETP and the Association With Coronary Artery Disease: A Factorial Mendelian Randomization Study. JAMA cardiology Importance:Cholesteryl ester transfer protein inhibition (CETP) has been shown to increase levels of high-density lipoprotein cholesterol (HDL-C) and reduce levels of low-density lipoprotein cholesterol (LDL-C). Current LDL-C target attainment is low, and novel phase 3 trials are underway to investigate whether CETP inhibitors result in reduction of cardiovascular disease risk in high-risk patients who may be treated with PCSK9-inhibiting agents. Objective:To explore the associations of combined reduction of CETP and PCSK9 concentrations with risk of coronary artery disease (CAD) and other clinical and safety outcomes. Design, Setting, and Participants:Two-sample 2 × 2 factorial Mendelian randomization study in a general population sample that includes data for UK Biobank participants of European ancestry. Exposures:Separate genetic scores were constructed for CETP and PCSK9 plasma protein concentrations, which were combined to determine the associations of combined genetically reduced CETP and PCSK9 concentrations with disease. Main Outcomes and Measures:Blood lipid and lipoprotein concentrations, blood pressure, CAD, age-related macular degeneration, type 2 diabetes, any stroke and ischemic stroke, Alzheimer disease, vascular dementia, heart failure, atrial fibrillation, chronic kidney disease, asthma, and multiple sclerosis. Results:Data for 425 354 UKB participants were included; the median (IQR) age was 59 years (51-64), and 229 399 (53.9%) were female. The associations of lower CETP and lower PCSK9 concentrations with CAD are similar when scaled per 10-mg/dL reduction in LDL-C concentrations (CETP: odds ratio [OR], 0.74; 95% CI, 0.67 to 0.81; PCSK9: OR, 0.75; 95% CI, 0.71 to 0.79). Combined exposure to lower CETP and PCSK9 concentrations was associated with an additive magnitude with lipids and all outcomes, and we did not observe any nonadditive interactions, most notably for LDL-C (CETP: effect size, -1.11 mg/dL; 95% CI, -1.40 to -0.82; PCSK9: effect size, -2.13 mg/dL; 95% CI, -2.43 to -1.84; combined: effect size, -3.47 mg/dL; 95% CI, -3.76 to -3.18; P = .34 for interaction) and CAD (CETP: OR, 0.96; 95% CI, 0.94 to 1.00; PCSK9: OR, 0.94; 95% CI, 0.91 to 0.97; combined: OR, 0.90; 95% CI, 0.87 to 0.93; P = .83 for interaction). In addition, when corrected for multiple testing, lower CETP concentrations were associated with increased age-related macular degeneration (OR, 1.11; 95% CI, 1.04 to 1.19). Conclusions and Relevance:Our results suggest that joint inhibition of CETP and PCSK9 has additive effects on lipid traits and disease risk, including a lower risk of CAD. Further research may explore whether a combination of CETP- and PCSK9-related therapeutics can benefit high-risk patients who are unable to reach treatment targets with existing options. 10.1001/jamacardio.2022.2333
Fundamental Pathobiology of Coronary Atherosclerosis and Clinical Implications for Chronic Ischemic Heart Disease Management-The Plaque Hypothesis: A Narrative Review. JAMA cardiology Importance:Recent clinical and imaging studies underscore that major adverse cardiac events (MACE) outcomes are associated not solely with severe coronary obstructions (ischemia hypothesis or stenosis hypothesis), but with the plaque burden along the entire coronary tree. New research clarifies the pathobiologic mechanisms responsible for plaque development/progression/destabilization leading to MACE (plaque hypothesis), but the translation of these insights to clinical management strategies has lagged. This narrative review elaborates the plaque hypothesis and explicates the current understanding of underlying pathobiologic mechanisms, the provocative destabilizing influences, the diagnostic and therapeutic implications, and their actionable clinical management approaches to optimize the management of patients with chronic coronary disease. Observations:Clinical trials of management strategies for patients with chronic coronary artery disease demonstrate that while MACE rate increases progressively with the anatomic extent of coronary disease, revascularization of the ischemia-producing obstruction does not forestall MACE. Most severely obstructive coronary lesions often remain quiescent and seldom destabilize to cause a MACE. Coronary lesions that later provoke acute myocardial infarction often do not narrow the lumen critically. Invasive and noninvasive imaging can identify the plaque anatomic characteristics (plaque burden, plaque topography, lipid content) and local hemodynamic/biomechanical characteristics (endothelial shear stress, plaque structural stress, axial plaque stress) that can indicate the propensity of individual plaques to provoke a MACE. Conclusions and Relevance:The pathobiologic construct concerning the culprit region of a plaque most likely to cause a MACE (plaque hypothesis), which incorporates multiple convergent plaque features, informs the evolution of a new management strategy capable of identifying the high-risk portion of plaque wherever it is located along the course of the coronary artery. Ongoing investigations of high-risk plaque features, coupled with technical advances to enable prognostic characterization in real time and at the point of care, will soon enable evaluation of the entire length of the atheromatous coronary artery and broaden the target(s) of our therapeutic intervention to include all regions of the plaque (both flow limiting and nonflow limiting). 10.1001/jamacardio.2022.3926
Association of LPA Variants With Risk of Coronary Disease and the Implications for Lipoprotein(a)-Lowering Therapies: A Mendelian Randomization Analysis. JAMA cardiology Importance:Human genetic studies have indicated that plasma lipoprotein(a) (Lp[a]) is causally associated with the risk of coronary heart disease (CHD), but randomized trials of several therapies that reduce Lp(a) levels by 25% to 35% have not provided any evidence that lowering Lp(a) level reduces CHD risk. Objective:To estimate the magnitude of the change in plasma Lp(a) levels needed to have the same evidence of an association with CHD risk as a 38.67-mg/dL (ie, 1-mmol/L) change in low-density lipoprotein cholesterol (LDL-C) level, a change that has been shown to produce a clinically meaningful reduction in the risk of CHD. Design, Setting, and Participants:A mendelian randomization analysis was conducted using individual participant data from 5 studies and with external validation using summarized data from 48 studies. Population-based prospective cohort and case-control studies featured 20 793 individuals with CHD and 27 540 controls with individual participant data, whereas summarized data included 62 240 patients with CHD and 127 299 controls. Data were analyzed from November 2016 to March 2018. Exposures:Genetic LPA score and plasma Lp(a) mass concentration. Main Outcomes and Measures:Coronary heart disease. Results:Of the included study participants, 53% were men, all were of white European ancestry, and the mean age was 57.5 years. The association of genetically predicted Lp(a) with CHD risk was linearly proportional to the absolute change in Lp(a) concentration. A 10-mg/dL lower genetically predicted Lp(a) concentration was associated with a 5.8% lower CHD risk (odds ratio [OR], 0.942; 95% CI, 0.933-0.951; P = 3 × 10-37), whereas a 10-mg/dL lower genetically predicted LDL-C level estimated using an LDL-C genetic score was associated with a 14.5% lower CHD risk (OR, 0.855; 95% CI, 0.818-0.893; P = 2 × 10-12). Thus, a 101.5-mg/dL change (95% CI, 71.0-137.0) in Lp(a) concentration had the same association with CHD risk as a 38.67-mg/dL change in LDL-C level. The association of genetically predicted Lp(a) concentration with CHD risk appeared to be independent of changes in LDL-C level owing to genetic variants that mimic the relationship of statins, PCSK9 inhibitors, and ezetimibe with CHD risk. Conclusions and Relevance:The clinical benefit of lowering Lp(a) is likely to be proportional to the absolute reduction in Lp(a) concentration. Large absolute reductions in Lp(a) of approximately 100 mg/dL may be required to produce a clinically meaningful reduction in the risk of CHD similar in magnitude to what can be achieved by lowering LDL-C level by 38.67 mg/dL (ie, 1 mmol/L). 10.1001/jamacardio.2018.1470
Shared mechanisms between coronary heart disease and depression: findings from a large UK general population-based cohort. Molecular psychiatry While comorbidity between coronary heart disease (CHD) and depression is evident, it is unclear whether the two diseases have shared underlying mechanisms. We performed a range of analyses in 367,703 unrelated middle-aged participants of European ancestry from UK Biobank, a population-based cohort study, to assess whether comorbidity is primarily due to genetic or environmental factors, and to test whether cardiovascular risk factors and CHD are likely to be causally related to depression using Mendelian randomization. We showed family history of heart disease was associated with a 20% increase in depression risk (95% confidence interval [CI] 16-24%, p < 0.0001), but a genetic risk score that is strongly associated with CHD risk was not associated with depression. An increase of 1 standard deviation in the CHD genetic risk score was associated with 71% higher CHD risk, but 1% higher depression risk (95% CI 0-3%; p = 0.11). Mendelian randomization analyses suggested that triglycerides, interleukin-6 (IL-6), and C-reactive protein (CRP) are likely causal risk factors for depression. The odds ratio for depression per standard deviation increase in genetically-predicted triglycerides was 1.18 (95% CI 1.09-1.27; p = 2 × 10); per unit increase in genetically-predicted log-transformed IL-6 was 0.74 (95% CI 0.62-0.89; p = 0.0012); and per unit increase in genetically-predicted log-transformed CRP was 1.18 (95% CI 1.07-1.29; p = 0.0009). Our analyses suggest that comorbidity between depression and CHD arises largely from shared environmental factors. IL-6, CRP and triglycerides are likely to be causally linked with depression, so could be targets for treatment and prevention of depression. 10.1038/s41380-019-0395-3
Construction and validation of molecular subtypes of coronary artery disease based on ferroptosis-related genes. BMC cardiovascular disorders BACKGROUND:This study aims to construct a reliable diagnostic model for coronary artery disease (CAD) patients and explore its potential mechanism by consensus molecular subtypes of ferroptosis-related genes. METHODS:GSE12288 and GSE20680 were downloaded from Gene Expression Omnibus database. CAD patients were divided into different molecular subtypes according to the expression level of ferroptosis-related genes. Then, the distribution of differentially expressed genes, functional annotations and immune infiltration cells between the two subtypes were compared. Finally, a prognostic model of ferroptosis-related genes in CAD was constructed and verified. RESULTS:Two different molecular subtypes of CAD were obtained according to the expression level of ferroptosis-related genes. Then, a total of 1944 differentially expressed genes (DEGs) were found, among which, 236 genes were up-regulated and 1708 genes were down-regulated. In addition, 43 DEGs were ferroptosis-related genes. Functional enrichment analysis showed that these DEGs between two subtypes of CAD were mainly enriched in immune-related pathways and processes, such as T cell receptor, mTOR, NOD-like receptor and Toll-like receptor signaling pathways. We also found that 21 immune cells were significantly changed between two subtypes of CAD. The LASSO method was performed to identify and construct the 16 ferroptosis-related genes-based diagnostic signature. Diagnostic efficiency of diagnostic signature measured by AUC in the training set and validation cohort was 0.971 and 0.899, respectively. CONCLUSIONS:This study contributes to a more comprehensive understanding of the mechanism of ferroptosis-related genes in CAD. 10.1186/s12872-022-02719-1
Identification of Potential Ferroptosis-Related Biomarkers and Immune Infiltration in Human Coronary Artery Atherosclerosis. Liu Hui,Xiang Chunhua,Wang Zhaohui,Song Yi International journal of general medicine Objective:Ferroptosis is a specific subtype of programmed cell death, which plays an essential role in the immune-associated disease, atherosclerosis (AS). The purpose of this study was to identify potential ferroptosis-related gene biomarkers and its association with immune infiltration characteristics in atherosclerosis with bioinformatics methods. Methods:Differentially expressed genes (DEGs) between AS and control groups were screened from GSE40231, analyzed for functional enrichment and then intersected with ferroptosis-related genes. Then, a random forest model was constructed based on these differentially expressed ferroptosis-related genes (DE-FRGs) and validated with dataset GSE132651. The performance of the models was evaluated with the area under receiver operating characteristic curves (AUC). Finally, we analyzed the correlation between DE-FRGs above and the characteristics of immune infiltration via CIBERSORT method. Results:Six DE-FRGs (IL6, ANGPTL7, CDKN1A, AKR1C3, NOX4 and VLDLR) were detected based on dataset of GSE40231. Furthermore, a random forest model was constructed based on them with a compelling diagnostic performance of AUC = 0.8974 in the validation dataset GSE132651. In addition, the proportion of follicular helper T (Tfh) cells was significantly higher in AS group (P < 0.001). And we found significant correlation relationship between Tfh and expression level of ANGPTL7 (R = 0.35, P < 0.01), CDKN1A (R = 0.4, P < 0.0001), AKR1C3 (R = 0.64, P < 0.0001), NOX4 (R = 0.32, P < 0.01) and VLDLR (R = -0.43, P < 0.0001). Conclusion:This study identified 6 DE-FRGs and validated a predicted model for the early prediction of AS, which also proved the close relationship between ferroptosis and immunity in the pathogenesis of AS. 10.2147/IJGM.S346482
Causal associations of short and long sleep durations with 12 cardiovascular diseases: linear and nonlinear Mendelian randomization analyses in UK Biobank. European heart journal AIMS:Observational studies have suggested strong associations between sleep duration and many cardiovascular diseases (CVDs), but causal inferences have not been confirmed. We aimed to determine the causal associations between genetically predicted sleep duration and 12 CVDs using both linear and nonlinear Mendelian randomization (MR) designs. METHODS AND RESULTS:Genetic variants associated with continuous, short (≤6 h) and long (≥9 h) sleep durations were used to examine the causal associations with 12 CVDs among 404 044 UK Biobank participants of White British ancestry. Linear MR analyses showed that genetically predicted sleep duration was negatively associated with arterial hypertension, atrial fibrillation, pulmonary embolism, and chronic ischaemic heart disease after correcting for multiple tests (P < 0.001). Nonlinear MR analyses demonstrated nonlinearity (L-shaped associations) between genetically predicted sleep duration and four CVDs, including arterial hypertension, chronic ischaemic heart disease, coronary artery disease, and myocardial infarction. Complementary analyses provided confirmative evidence of the adverse effects of genetically predicted short sleep duration on the risks of 5 out of the 12 CVDs, including arterial hypertension, pulmonary embolism, coronary artery disease, myocardial infarction, and chronic ischaemic heart disease (P < 0.001), and suggestive evidence for atrial fibrillation (P < 0.05). However, genetically predicted long sleep duration was not associated with any CVD. CONCLUSION:This study suggests that genetically predicted short sleep duration is a potential causal risk factor of several CVDs, while genetically predicted long sleep duration is unlikely to be a causal risk factor for most CVDs. 10.1093/eurheartj/ehab170
Polygenic Risk Scoring for Coronary Heart Disease: The First Risk Factor. Natarajan Pradeep Journal of the American College of Cardiology 10.1016/j.jacc.2018.08.1041
New Cardiovascular Risk Assessment Techniques for Primary Prevention: JACC Review Topic of the Week. Journal of the American College of Cardiology Risk factor-based models fail to accurately estimate risk in select populations, in particular younger individuals. A sizable number of people are also classified as being at intermediate risk, for whom the optimal preventive strategy could be more precise. Several personalized risk prediction tools, including coronary artery calcium scoring, polygenic risk scores, and metabolic risk scores may be able to improve risk assessment, pending supportive outcome data from clinical trials. Other tools may well emerge in the near future. A multidimensional approach to risk prediction holds the promise of precise risk prediction. This could allow for targeted prevention minimizing unnecessary costs and risks while maximizing benefits. High-risk individuals could also be identified early in life, creating opportunities to arrest the development of nascent coronary atherosclerosis and prevent future clinical events. 10.1016/j.jacc.2022.05.015
Taller height and risk of coronary heart disease and cancer: A within-sibship Mendelian randomization study. eLife Background:Taller people have a lower risk of coronary heart disease but a higher risk of many cancers. Mendelian randomization (MR) studies in unrelated individuals (population MR) have suggested that these relationships are potentially causal. However, population MR studies are sensitive to demography (population stratification, assortative mating) and familial (indirect genetic) effects. Methods:In this study, we performed within-sibship MR analyses using 78,988 siblings, a design robust against demography and indirect genetic effects of parents. For comparison, we also applied population MR and estimated associations with measured height. Results:Within-sibship MR estimated that 1 SD taller height lowers the odds of coronary heart disease by 14% (95% CI: 3-23%) but increases the odds of cancer by 18% (95% CI: 3-34%), highly consistent with population MR and height-disease association estimates. There was some evidence that taller height reduces systolic blood pressure and low-density lipoprotein cholesterol, which may mediate some of the protective effects of taller height on coronary heart disease risk. Conclusions:For the first time, we have demonstrated that the purported effects of height on adulthood disease risk are unlikely to be explained by demographic or familial factors, and so likely reflect an individual-level causal effect. Disentangling the mechanisms via which height affects disease risk may improve the understanding of the etiologies of atherosclerosis and carcinogenesis. Funding:This project was conducted by researchers at the MRC Integrative Epidemiology Unit (MC_UU_00011/1) and also supported by a Norwegian Research Council Grant number 295989. 10.7554/eLife.72984
Estimating dose-response relationships for vitamin D with coronary heart disease, stroke, and all-cause mortality: observational and Mendelian randomisation analyses. The lancet. Diabetes & endocrinology BACKGROUND:Randomised trials of vitamin D supplementation for cardiovascular disease and all-cause mortality have generally reported null findings. However, generalisability of results to individuals with low vitamin D status is unclear. We aimed to characterise dose-response relationships between 25-hydroxyvitamin D (25[OH]D) concentrations and risk of coronary heart disease, stroke, and all-cause mortality in observational and Mendelian randomisation frameworks. METHODS:Observational analyses were undertaken using data from 33 prospective studies comprising 500 962 individuals with no known history of coronary heart disease or stroke at baseline. Mendelian randomisation analyses were performed in four population-based cohort studies (UK Biobank, EPIC-CVD, and two Copenhagen population-based studies) comprising 386 406 middle-aged individuals of European ancestries, including 33 546 people who developed coronary heart disease, 18 166 people who had a stroke, and 27 885 people who died. Primary outcomes were coronary heart disease, defined as fatal ischaemic heart disease (International Classification of Diseases 10th revision code I20-I25) or non-fatal myocardial infarction (I21-I23); stroke, defined as any cerebrovascular disease (I60-I69); and all-cause mortality. FINDINGS:Observational analyses suggested inverse associations between incident coronary heart disease, stroke, and all-cause mortality outcomes with 25(OH)D concentration at low 25(OH)D concentrations. In population-wide genetic analyses, there were no associations of genetically-predicted 25(OH)D with coronary heart disease, stroke, or all-cause mortality. However, for the participants with vitamin D deficiency (25[OH]D concentration <25 nmol/L), genetic analyses provided strong evidence for an inverse association with all-cause mortality (odds ratio [OR] per 10 nmol/L increase in genetically-predicted 25[OH]D concentration 0·69 [95% CI 0·59-0·80]; p<0·0001) and non-significant inverse associations for stroke (0·85 [0·70-1·02], p=0·09) and coronary heart disease (0·89 [0·76-1·04]; p=0·14). A finer stratification of participants found inverse associations between genetically-predicted 25(OH)D concentrations and all-cause mortality up to around 40 nmol/L. INTERPRETATION:Stratified Mendelian randomisation analyses suggest a causal relationship between 25(OH)D concentrations and mortality for individuals with low vitamin D status. Our findings have implications for the design of vitamin D supplementation trials, and potential disease prevention strategies. FUNDING:British Heart Foundation, Medical Research Council, National Institute for Health Research, Health Data Research UK, Cancer Research UK, and International Agency for Research on Cancer. 10.1016/S2213-8587(21)00263-1
Strengthening the Reporting of Observational Studies in Epidemiology Using Mendelian Randomization: The STROBE-MR Statement. JAMA Importance:Mendelian randomization (MR) studies use genetic variation associated with modifiable exposures to assess their possible causal relationship with outcomes and aim to reduce potential bias from confounding and reverse causation. Objective:To develop the STROBE-MR Statement as a stand-alone extension to the STROBE (Strengthening the Reporting of Observational Studies in Epidemiology) guideline for the reporting of MR studies. Design, Setting, and Participants:The development of the STROBE-MR Statement followed the Enhancing the Quality and Transparency of Health Research (EQUATOR) framework guidance and used the STROBE Statement as a starting point to draft a checklist tailored to MR studies. The project was initiated in 2018 by reviewing the literature on the reporting of instrumental variable and MR studies. A group of 17 experts, including MR methodologists, MR study design users, developers of previous reporting guidelines, and journal editors, participated in a workshop in May 2019 to define the scope of the Statement and draft the checklist. The draft checklist was published as a preprint in July 2019 and discussed on the preprint platform, in social media, and at the 4th Mendelian Randomization Conference. The checklist was then revised based on comments, further refined through 2020, and finalized in July 2021. Findings:The STROBE-MR checklist is organized into 6 sections (Title and Abstract, Introduction, Methods, Results, Discussion, and Other Information) and includes 20 main items and 30 subitems. It covers both 1-sample and 2-sample MR studies that assess 1 or multiple exposures and outcomes, and addresses MR studies that follow a genome-wide association study and are reported in the same article. The checklist asks authors to justify why MR is a helpful method to address the study question and state prespecified causal hypotheses. The measurement, quality, and selection of genetic variants must be described and attempts to assess validity of MR-specific assumptions should be well reported. An item on data sharing includes reporting when the data and statistical code required to replicate the analyses can be accessed. Conclusions and Relevance:STROBE-MR provides guidelines for reporting MR studies. Improved reporting of these studies could facilitate their evaluation by editors, peer reviewers, researchers, clinicians, and other readers, and enhance the interpretation of their results. 10.1001/jama.2021.18236
Alcohol Consumption, Aldehyde Dehydrogenase 2 Gene Polymorphisms, and Cardiovascular Health in Korea. Yonsei medical journal Alcohol consumption is a serious health issue in Korea in terms of the amount consumed and the behavior related to its consumption. Aldehyde dehydrogenase 2 (ALDH2) is a key enzyme in alcohol metabolism that degrades acetaldehyde to nontoxic acetic acid. The enzyme is coded by the ALDH2 gene, which is commonly polymorphic in East Asian populations. A point mutation in the ALDH2 gene (the rs671 allele) yields an inactive form of ALDH2 that causes acetaldehyde accumulation in the body after alcohol consumption, thereby inhibiting normal alcohol metabolism. Individuals who are homozygous for polymorphism in ALDH2 tend to refrain from drinking alcohol, decreasing their chances of developing alcoholism and exposure to the associated risks. Mendelian randomization (MR) studies have demonstrated that alcohol consumption predicted by ALDH2 genotype is causally related to cardiovascular risks. Moreover, recent MR studies suggest that the ALDH2 variant has mechanistic effects on some disease outcomes or mortality through increased blood levels of acetaldehyde, showing differences therein between heterozygotes (ALDH2*2*2) and homozygotes (ALDH2*1*2) in those who consume alcohol. Accordingly, consideration of ALDH2 genotype in alcohol prevention programs is warranted. In conclusion, strategies that incorporate genetic information and provide an evidential basis from which to help people make informed decisions on alcohol consumption are urgently required. 10.3349/ymj.2017.58.4.689
ALDH2---The Genetic Polymorphism and Enzymatic Activity Regulation: Their Epidemiologic and Clinical Implications. Zhang Rui,Wang Jiali,Xue Mengyang,Xu Feng,Chen Yuguo Current drug targets BACKGROUND:The human aldehyde dehydrogenase 2 (ALDH2) is the most effective enzyme in the detoxification of alcohol metabolite acetaldehyde. The ALDH2*2 mutation is caused by a single nucleotide substitution which results in a nearly inactive form of ALDH2 enzyme. The ALDH2 genotype has been used as a surrogate of alcohol to get causal inferences of alcohol in related diseases implementing Mendelian randomization approach. In addition, ALDH2 enzyme has significant effect on different diseases, indicating the potential therapeutic value of ALDH2 regulators including both activators like Alda-1 and inhibitors such as daidzin and daidzein. OBJECTIVE:In this review, we aim to systematically discuss the implications of ALDH2 genotype and ALDH2 enzyme regulators, highlighting their epidemiological and clinical importance, respectively. CONCLUSION:ALDH2 polymorphism is shown to be a genetic instrument for alcohol use in Mendelian randomization analysis. ALDH2 regulators exhibit potential therapeutic value as the important roles of ALDH2 in various diseases. Both the genetic polymorphism and enzyme activity regulation of ALDH2 are of great importance to their epidemiologic and clinical applications. 10.2174/1389450116666150727115118
Genome-wide association meta-analysis and Mendelian randomization analysis confirm the influence of ALDH2 on sleep durationin the Japanese population. Nishiyama Takeshi,Nakatochi Masahiro,Goto Atsushi,Iwasaki Motoki,Hachiya Tsuyoshi,Sutoh Yoichi,Shimizu Atsushi,Wang Chaochen,Tanaka Hideo,Watanabe Miki,Hosono Akihiro,Tamai Yuya,Yamada Tamaki,Yamaji Taiki,Sawada Norie,Fukumoto Kentaro,Otsuka Kotaro,Tanno Kozo,Tomita Hiroaki,Kojima Kaname,Nagasaki Masao,Hozawa Atsushi,Hishida Asahi,Sasakabe Tae,Nishida Yuichiro,Hara Megumi,Ito Hidemi,Oze Isao,Nakamura Yohko,Mikami Haruo,Ibusuki Rie,Takezaki Toshiro,Koyama Teruhide,Kuriyama Nagato,Endoh Kaori,Kuriki Kiyonori,Turin Tanvir C,Naoyuki Takashima,Katsuura-Kamano Sakurako,Uemura Hirokazu,Okada Rieko,Kawai Sayo,Naito Mariko,Momozawa Yukihide,Kubo Michiaki,Sasaki Makoto,Yamamoto Masayuki,Tsugane Shoichiro,Wakai Kenji,Suzuki Sadao Sleep Usual sleep duration has substantial heritability and is associated with various physical and psychiatric conditions as well as mortality. However, for its genetic locus, only PAX8 and VRK2 have been replicated in previous genome-wide association studies (GWAS). We conducted a GWAS meta-analysis of self-reported usual sleep duration using three population-based cohorts totaling 31 230 Japanese individuals. A genome-wide significant locus was identified at 12q24 (p-value < 5.0 × 10-8). Subsequently, a functional variant in the ALDH2 locus, rs671, was replicated in an independent sample of 5140 Japanese individuals (p-value = 0.004). The association signal, however, disappeared after adjusting for alcohol consumption, indicating the possibility that the rs671 genotype modifies sleep duration via alcohol consumption. This hypothesis explained a modest genetic correlation observed between sleep duration and alcohol consumption (rG = 0.23). A Mendelian randomization analysis using rs671 and other variants as instrumental variables confirmed this by showing a causal effect of alcohol consumption, but not of coffee consumption on sleep duration. Another genome-wide significant locus was identified at 5q33 after adjusting for drinking frequency. However, this locus was not replicated, nor was the PAX8 and VRK2. Our study has confirmed that a functional ALDH2 variant, rs671, most strongly influences on usual sleep duration possibly via alcohol consumption in the Japanese population, and presumably in East Asian populations. This highlights the importance of considering the involvement of alcohol consumption in future GWAS of usual sleep duration, even in non-East Asian populations, where rs671 is monomorphic. 10.1093/sleep/zsz046
Alcohol use disorders and the heart. Addiction (Abingdon, England) Alcohol use is an important preventable and modifiable cause of non-communicable disease, and has complex effects on the cardiovascular system that vary with dose. Observational and prospective studies have consistently shown a lower risk of cardiovascular and all-cause mortality in people with low levels of alcohol consumption when compared to abstainers (the 'J'-shaped curve). Maximum potential benefit occurs at 0.5 to one standard drinks (7-14 g pure ethanol) per day for women (18% lower all-cause mortality, 95% confidence interval (CI) = 13-22%) and one to two standard drinks (14-28 g ethanol) per day for men (17% lower all-cause mortality, 95% CI = 15-19%). However, this evidence is contested, and overall the detrimental effects of alcohol far outweigh the beneficial effects, with the risk of premature mortality increasing steadily after an average consumption of 10 g ethanol/day. Blood pressure (BP) is increased by regular alcohol consumption in a dose-dependent manner, with a relative risk for hypertension (systolic BP > 140 mm Hg or diastolic > 90 mm Hg) of 1.7 for 50 g ethanol/day and 2.5 at 100 g/day. Important reductions in BP readings can be expected after as little as 1 month of abstinence from alcohol. Heavy alcohol consumption in a binge pattern is associated with the development of acute cardiac arrhythmia, even in people with normal heart function. Atrial fibrillation is the most common arrhythmia associated with chronic high-volume alcohol intake, and above 14 g alcohol/day the relative risk increases 10% for every extra standard drink (14 g ethanol). Ethanol and its metabolites have toxic effects on cardiac myocytes, and alcoholic cardiomyopathy (ACM) accounts for a third of all cases of non-ischaemic dilated cardiomyopathy. Screening people drinking alcohol above low-volume levels and delivering a brief intervention may prevent the development of cardiovascular complications. Although people with established cardiovascular disease show improved outcomes with a reduction to low-volume alcohol consumption, there is no safe amount of alcohol to drink and patients with ACM should aim for abstinence in order to optimize medical treatment. 10.1111/add.14703
Association of Habitual Alcohol Intake With Risk of Cardiovascular Disease. JAMA network open Importance:Observational studies have consistently proposed cardiovascular benefits associated with light alcohol consumption, while recent genetic analyses (ie, mendelian randomization studies) have suggested a possible causal link between alcohol intake and increased risk of cardiovascular disease. However, traditional approaches to genetic epidemiology assume a linear association and thus have not fully evaluated dose-response estimates of risk across different levels of alcohol intake. Objectives:To assess the association of habitual alcohol intake with cardiovascular disease risk and to evaluate the direction and relative magnitude of cardiovascular risk associated with different amounts of alcohol consumption. Design, Setting, and Participants:This cohort study used the UK Biobank (2006-2010, follow-up until 2016) to examine confounding in epidemiologic associations between alcohol intake and cardiovascular diseases. Using both traditional (ie, linear) and nonlinear mendelian randomization, potential associations between alcohol consumption and cardiovascular diseases (eg, hypertension and coronary artery disease) as well as corresponding association shapes were assessed. Data analysis was conducted from July 2019 to January 2022. Exposures:Genetic predisposition to alcohol intake. Main Outcomes and Measures:The association between alcohol consumption and cardiovascular diseases, including hypertension, coronary artery disease, myocardial infarction, stroke, heart failure, and atrial fibrillation. Results:This study included 371 463 participants (mean [SD] age, 57.0 [7.9] years; 172 400 [46%] men), who consumed a mean (SD) 9.2 (10.6) standard drinks per week. Overall, 121 708 participants (33%) had hypertension. Light to moderate alcohol consumption was associated with healthier lifestyle factors, adjustment for which attenuated the cardioprotective epidemiologic associations with modest intake. In linear mendelian randomization analyses, a 1-SD increase in genetically predicted alcohol consumption was associated with 1.3-fold (95% CI, 1.2-1.4) higher risk of hypertension (P < .001) and 1.4-fold (95% CI, 1.1-1.8) higher risk of coronary artery disease (P = .006). Nonlinear mendelian randomization analyses suggested nonlinear associations between alcohol consumption and both hypertension and coronary artery disease: light alcohol intake was associated with minimal increases in cardiovascular risk, whereas heavier consumption was associated with exponential increases in risk of both clinical and subclinical cardiovascular disease. Conclusions and Relevance:In this cohort study, coincident, favorable lifestyle factors attenuated the observational benefits of modest alcohol intake. Genetic epidemiology suggested that alcohol consumption of all amounts was associated with increased cardiovascular risk, but marked risk differences exist across levels of intake, including those accepted by current national guidelines. 10.1001/jamanetworkopen.2022.3849
Alcohol intake and cardiovascular risk factors: A Mendelian randomisation study. Cho Yoonsu,Shin So-Youn,Won Sungho,Relton Caroline L,Davey Smith George,Shin Min-Jeong Scientific reports Mendelian randomisation studies from Asia suggest detrimental influences of alcohol on cardiovascular risk factors, but such associations are observed mainly in men. The absence of associations of genetic variants (e.g. rs671 in ALDH2) with such risk factors in women - who drank little in these populations - provides evidence that the observations are not due to genetic pleiotropy. Here, we present a Mendelian randomisation study in a South Korean population (3,365 men and 3,787 women) that 1) provides robust evidence that alcohol consumption adversely affects several cardiovascular disease risk factors, including blood pressure, waist to hip ratio, fasting blood glucose and triglyceride levels. Alcohol also increases HDL cholesterol and lowers LDL cholesterol. Our study also 2) replicates sex differences in associations which suggests pleiotropy does not underlie the associations, 3) provides further evidence that association is not due to pleiotropy by showing null effects in male non-drinkers, and 4) illustrates a way to measure population-level association where alcohol intake is stratified by sex. In conclusion, population-level instrumental variable estimation (utilizing interaction of rs671 in ALDH2 and sex as an instrument) strengthens causal inference regarding the largely adverse influence of alcohol intake on cardiovascular health in an Asian population. 10.1038/srep18422
Relationship between alcohol use, blood pressure and hypertension: an association study and a Mendelian randomisation study. Zhao Pian-Pian,Xu Liang-Wen,Sun Tao,Wu Yin-Yin,Zhu Xiao-Wei,Zhang Bo,Cheng Zhi,Cai Xiao,Liu Yu-Chao,Zhao Ting-Ting,Wu Ting-Ting,Ma Hai-Yan,Wang Li,Zhang Xing-Wei,Yang Lei,Zheng Hou-Feng Journal of epidemiology and community health BACKGROUND:Past studies have found a strong relationship between alcohol drinking and human health. METHODS:In this study, we first tested the association of rs671 with alcohol use in 2349 participants in southeast China. We then evaluated the causal impact between alcohol use and cardiovascular traits through a Mendelian randomisation (MR) analysis. RESULTS:We found strong evidence for the association of rs671 in the gene with alcohol drinking (p=6.08×10; OR G=4.50, 95% CI 3.67 to 5.52). We found that female G carriers of rs671 had a higher proportion of non-drinkers than male G carriers (88.01% vs 38.70%). In non-drinkers, the female G allele frequency was higher than the male G allele frequency (71.1% vs 55.2%). MR analysis suggested that alcohol use had a causal effect on blood pressure (increasing 9.46 mm Hg for systolic blood pressure (p=9.67×10) and 7.50 mm Hg for diastolic blood pressure (p=9.62×10)), and on hypertension in men (p=0.011; OR =1.19, 95% CI 1.04 to 1.36) and in pooled samples (p=0.013; OR =1.20, 95% CI 1.04 to 1.39), but not in women. We did not observe a causal effect of alcohol use on body mass index and lipid levels; further studies are needed to clarify the non-causal relationship. CONCLUSIONS:Compared to never-drinkers, current and previous alcohol use had a causal effect on blood pressure and hypertension in pooled samples and in men. These results reflect Chinese culture which does not encourage women to drink. 10.1136/jech-2018-211185
Exploring causal associations of alcohol with cardiovascular and metabolic risk factors in a Chinese population using Mendelian randomization analysis. Taylor Amy E,Lu Feng,Carslake David,Hu Zhibin,Qian Yun,Liu Sijun,Chen Jiaping,Shen Hongbing,Smith George Davey Scientific reports Observational studies suggest that moderate alcohol consumption may be protective for cardiovascular disease, but results may be biased by confounding and reverse causality. Mendelian randomization, which uses genetic variants as proxies for exposures, can minimise these biases and therefore strengthen causal inference. Using a genetic variant in the ALDH2 gene associated with alcohol consumption, rs671, we performed a Mendelian randomization analysis in 1,712 diabetes cases and 2,076 controls from Nantong, China. Analyses were performed using linear and logistic regression, stratified by sex and diabetes status. The A allele of rs671 was strongly associated with reduced odds of being an alcohol drinker in all groups, but prevalence of alcohol consumption amongst females was very low. The A allele was associated with reduced systolic and diastolic blood pressure and decreased total and HDL cholesterol in males. The A allele was also associated with decreased triglyceride levels, but only robustly in diabetic males. There was no strong evidence for associations between rs671 and any outcomes in females. Our results suggest that associations of alcohol consumption with blood pressure and HDL-cholesterol are causal. Alcohol also appeared to have adverse effects on triglyceride levels, although this may be restricted to diabetics. 10.1038/srep14005
Moderate alcohol use and cardiovascular disease from Mendelian randomization. Au Yeung Shiu Lun,Jiang Chaoqiang,Cheng Kar Keung,Cowling Benjamin J,Liu Bin,Zhang Weisen,Lam Tai Hing,Leung Gabriel M,Schooling C Mary PloS one BACKGROUND:Observational studies show moderate alcohol use negatively associated with ischemic heart disease (IHD) and cardiovascular disease (CVD). However, healthier attributes among moderate users compared to never users may confound the apparent association. A potentially less biased way to examine the association is Mendelian randomization, using alcohol metabolizing genes which influence alcohol use. METHODS:We used instrumental variable analysis with aldehyde dehydrogenase 2 (ALDH2) genotypes (AA/GA/GG) as instrumental variables for alcohol use to examine the association of alcohol use (10 g ethanol/day) with CVD risk factors (blood pressure, lipids and glucose) and morbidity (self-reported IHD and CVD) among men in the Guangzhou Biobank Cohort Study. RESULTS:ALDH2 genotypes were a credible instrument for alcohol use (F-statistic 74.6). Alcohol was positively associated with HDL-cholesterol (0.05 mmol/L per alcohol unit, 95% confidence interval (CI) 0.02 to 0.08) and diastolic blood pressure (1.15 mmHg, 95% CI 0.23 to 2.07) but not with systolic blood pressure (1.00 mmHg, 95% CI -0.74 to 2.74), LDL-cholesterol (0.03 mmol/L, 95% CI -0.03 to 0.08), log transformed triglycerides (0.03 mmol/L, 95% CI -0.01 to 0.08) or log transformed fasting glucose (0.01 mmol/L, 95% CI -0.006 to 0.03), self-reported CVD (odds ratio (OR) 0.98, 95% CI 0.76 to 1.27) or self-reported IHD (OR 1.10, 95% CI 0.83 to 1.45). CONCLUSION:Low to moderate alcohol use among men had the expected effects on most CVD risk factors but not fasting glucose. Larger studies are needed to confirm the null associations with IHD, CVD and fasting glucose. 10.1371/journal.pone.0068054
Alcohol consumption and diabetes risk in a Chinese population: a Mendelian randomization analysis. Peng Miaomiao,Zhang Jiaoyue,Zeng Tianshu,Hu Xiang,Min Jie,Tian Shenghua,Wang Ying,Liu Geng,Wan Limin,Huang Qiulan,Hu Shengqing,Chen Lulu Addiction (Abingdon, England) AIM:To assess the causality between alcohol intake, diabetes risk and related traits. DESIGN:Mendelian randomization (MR) study. Subgroup analysis, standard instrumental variable analysis and local average treatment effect (LATE) methods were applied to assess linear and non-linear causality. SETTING:China. PARTICIPANTS:A total of 4536 participants, including 721 diabetes cases. FINDINGS:Carriage of an ALDH2 rs671 A allele reduced alcohol consumption by 44.63% [95% confidence interval (CI) = -49.44%, -39.37%]. In males, additional carriage of an A allele was significantly connected to decreased diabetes risk for the overall population [odds ratio (OR) = 0.716, 95% CI = 0.567-0.904, P = 0.005] or moderate drinkers (OR = 0.564, 95% CI = 0.355-0.894, P = 0.015). In instrumental variable (IV) analysis, increasing alcohol consumption by 1.7-fold was associated with an incidence-rate ratio of 1.32 (95% CI = 1.06-1.67, P = 0.014) for diabetes risk, and elevated alcohol intake was causally connected to natural log-transformed fasting, 2-hour post-load plasma glucose (β = 0.036, 95% CI = 0.018-0.054; β = 0.072, 95% CI = 0.035-0.108) and insulin resistance [homeostatic model assessment for IR (HOMA-IR] (β = 0.104, 95% CI = 0.039-0.169), but was not associated with beta-cell function (HOMA-beta). In addition, the LATE method did not identify significant U-shaped causality between alcohol consumption and diabetes-related traits. In females, the effects of alcohol intake on all the outcomes were non-significant. CONCLUSION:Among men in China, higher alcohol intake appears to be causally associated with increased diabetes risk and worsened related traits, even for moderate drinkers. This study found no significant U-shaped causality between alcohol consumption and diabetes-related traits. 10.1111/add.14475
Is aldehyde dehydrogenase 2 a credible genetic instrument for alcohol use in Mendelian randomization analysis in Southern Chinese men? Au Yeung Shiu Lun,Jiang ChaoQiang,Cheng Kar Keung,Liu Bin,Zhang WeiSen,Lam Tai Hing,Leung Gabriel M,Schooling C Mary International journal of epidemiology BACKGROUND:Mendelian randomization studies provide a means of assessing causal relations without interventions, but require valid genetic instruments. We assessed the credibility of aldehyde dehydrogenase 2 (ALDH2) as a genetic instrument for alcohol use in Southern Chinese men. METHODS:We genotyped the single nucleotide polymorphism rs671 of ALDH2 in 4867 men from the Guangzhou Biobank Cohort Study. We used linear regression to assess the strength of the association of ALDH2 variants with alcohol use, whether ALDH2 variants were independently associated with socio-economic position or other potential confounders and whether associations of ALDH2 variants with cardiovascular risk factors (systolic and diastolic blood pressure, HDL- and LDL-cholesterol, fasting glucose), triglycerides, body mass index, self reported cardiovascular disease, self-reported ischaemic heart disease, cognitive function (delayed 10-word recall and Mini Mental State Examination score) and liver function (alanine transaminase and aspartate transaminase) were fully mediated by alcohol use. RESULTS:The minor allele frequency (A) of ALDH2 was 0.29. The F statistic for ALDH2 variants was 75.0, suggesting that substantial weak instrument bias is unlikely. ALDH2 variants were not associated with socio-economic position, smoking or physical activity. ALDH2 variants were only associated with diastolic blood pressure and HDL-cholesterol, but these genetic associations with blood pressure and HDL-cholesterol were attenuated after adjusting for alcohol use, suggesting the apparent genetic associations were possibly mediated by alcohol use. CONCLUSIONS:ALDH2 variants are a credible genetic instrument for Mendelian randomization studies of alcohol use and many attributes of health in Southern Chinese men. 10.1093/ije/dys221
Mendelian randomization as applied to coronary heart disease, including recent advances incorporating new technology. Lewis Sarah J Circulation. Cardiovascular genetics 10.1161/CIRCGENETICS.109.880955
Alcohol intake and blood pressure: a systematic review implementing a Mendelian randomization approach. Chen Lina,Smith George Davey,Harbord Roger M,Lewis Sarah J PLoS medicine BACKGROUND:Alcohol has been reported to be a common and modifiable risk factor for hypertension. However, observational studies are subject to confounding by other behavioural and sociodemographic factors, while clinical trials are difficult to implement and have limited follow-up time. Mendelian randomization can provide robust evidence on the nature of this association by use of a common polymorphism in aldehyde dehydrogenase 2 (ALDH2) as a surrogate for measuring alcohol consumption. ALDH2 encodes a major enzyme involved in alcohol metabolism. Individuals homozygous for the null variant (*2*2) experience adverse symptoms when drinking alcohol and consequently drink considerably less alcohol than wild-type homozygotes (*1*1) or heterozygotes. We hypothesise that this polymorphism may influence the risk of hypertension by affecting alcohol drinking behaviour. METHODS AND FINDINGS:We carried out fixed effect meta-analyses of the ALDH2 genotype with blood pressure (five studies, n = 7,658) and hypertension (three studies, n = 4,219) using studies identified via systematic review. In males, we obtained an overall odds ratio of 2.42 (95% confidence interval [CI] 1.66-3.55, p = 4.8 x 10(-6)) for hypertension comparing *1*1 with *2*2 homozygotes and an odds ratio of 1.72 (95% CI 1.17-2.52, p = 0.006) comparing heterozygotes (surrogate for moderate drinkers) with *2*2 homozygotes. Systolic blood pressure was 7.44 mmHg (95% CI 5.39-9.49, p = 1.1 x 10(-12)) greater among *1*1 than among *2*2 homozygotes, and 4.24 mmHg (95% CI 2.18-6.31, p = 0.00005) greater among heterozygotes than among *2*2 homozygotes. CONCLUSIONS:These findings support the hypothesis that alcohol intake has a marked effect on blood pressure and the risk of hypertension. 10.1371/journal.pmed.0050052
Alcohol consumption and subclinical and clinical coronary heart disease: a Mendelian randomization analysis. European journal of preventive cardiology AIMS:The potential effect of alcohol consumption on coronary heart disease (CHD) remains unclear. We used the variant rs671 in the aldehyde dehydrogenase 2 gene (ALDH2) as an instrument to investigate the causal role of alcohol intake in subclinical and clinical CHD. METHODS:We conducted two Mendelian randomization studies: a cross-sectional study of coronary artery calcification (CAC) on computed tomography of 1029 healthy men (mean age, 63.8 years) and a case-control study of 421 men with CHD [acute coronary syndrome (ACS) or stable angina pectoris] who underwent coronary revascularization and 842 age-matched male controls. RESULTS:In the CAC study, medians (25%tiles, 75%tiles) of alcohol consumption by ALDH2-rs671 *2 homozygotes [n = 86 (8.4%)], *1*2 heterozygotes [n = 397 (38.5%)], and *1 homozygotes [n = 546 (53.1%)] were 0.0 (0.0, 0.0), 28.0 (0.0, 129.0), and 224.0 (84.0, 350.0) g/week, respectively. In age-adjusted Poisson regression with robust error variance, compared with *2 homozygotes, relative risks for prevalent CAC score >0, ≥100, and ≥300 in *1 homozygotes were 1.29 (95% confidence interval, 1.06-1.57), 1.76 (1.05-2.96), and 1.81 (0.80-4.09), respectively. In age-adjusted ordinal logistic regression for CAC distributions, we observed higher odds among *1 homozygotes [odds ratio, 2.19 (1.39-3.46)] and even among *1*2 heterozygotes [1.77 (1.11-2.82)] compared with *2 homozygotes. In the case-control study, conditional logistic regression revealed lower prevalence of *1 homozygotes among men with CHD [odds ratio, 0.54 (0.35-0.82)], especially ACS [0.46 (0.27-0.77)], than controls. CONCLUSION:Our findings indicate a positive association of alcohol consumption with CAC burden but an inverse association with clinical CHD, especially ACS. 10.1093/eurjpc/zwac156
Causal associations of alcohol consumption with cardiovascular diseases and all-cause mortality among Chinese males. The American journal of clinical nutrition BACKGROUND:The causal effects of moderate alcohol consumption on cardiovascular diseases (CVDs) are continuously debated, especially on coronary artery disease (CAD). OBJECTIVES:We aimed to explore the causal associations of alcohol consumption with CVDs and all-cause mortality among Chinese males. METHODS:A prospective cohort study was conducted in 40,386 Chinese males, with 17,676 being genotyped for the rs671 variant in the aldehyde dehydrogenase 2 (ALDH2) gene. A Cox proportional hazards model was conducted to estimate the effects of self-reported alcohol consumption. Mendelian randomization (MR) analysis was performed to explore the causality using rs671 as an instrumental variable. RESULTS:During the follow-up of 303,353 person-years, 2406 incident CVDs and 3195 all-cause mortalities were identified. J-shaped associations of self-reported alcohol consumption with incident CVD and all-cause mortality were observed, showing decreased risks for light (≤25 g/d) and moderate drinkers (25-≤60 g/d). However, MR analyses revealed a linear association of genetically predicted alcohol consumption with the incident CVD (P-trend = 0.02), including both CAD (P-trend = 0.03) and stroke (P-trend = 0.02). The HRs (95% CIs) for incident CVD across increasing tertiles of genetically predicted alcohol consumption were 1 (reference), 1.18 (1.01, 1.38), and 1.22 (1.03, 1.46). After excluding heavy drinkers, the risk of incident CVD and all-cause mortality was increased by 27% and 20% per standard drink increment of genetically predicted alcohol consumption, respectively. CONCLUSIONS:Our analyses extend the evidence of the harmful effect of alcohol consumption to total CVD (including CAD) and all-cause mortality, highlighting the potential health benefits of lowering alcohol consumption, even among light-to-moderate male drinkers. 10.1093/ajcn/nqac159
Genome-wide association study of alcohol consumption and genetic overlap with other health-related traits in UK Biobank (N=112 117). Clarke T-K,Adams M J,Davies G,Howard D M,Hall L S,Padmanabhan S,Murray A D,Smith B H,Campbell A,Hayward C,Porteous D J,Deary I J,McIntosh A M Molecular psychiatry Alcohol consumption has been linked to over 200 diseases and is responsible for over 5% of the global disease burden. Well-known genetic variants in alcohol metabolizing genes, for example, ALDH2 and ADH1B, are strongly associated with alcohol consumption but have limited impact in European populations where they are found at low frequency. We performed a genome-wide association study (GWAS) of self-reported alcohol consumption in 112 117 individuals in the UK Biobank (UKB) sample of white British individuals. We report significant genome-wide associations at 14 loci. These include single-nucleotide polymorphisms (SNPs) in alcohol metabolizing genes (ADH1B/ADH1C/ADH5) and two loci in KLB, a gene recently associated with alcohol consumption. We also identify SNPs at novel loci including GCKR, CADM2 and FAM69C. Gene-based analyses found significant associations with genes implicated in the neurobiology of substance use (DRD2, PDE4B). GCTA analyses found a significant SNP-based heritability of self-reported alcohol consumption of 13% (se=0.01). Sex-specific analyses found largely overlapping GWAS loci and the genetic correlation (rG) between male and female alcohol consumption was 0.90 (s.e.=0.09, P-value=7.16 × 10). Using LD score regression, genetic overlap was found between alcohol consumption and years of schooling (rG=0.18, s.e.=0.03), high-density lipoprotein cholesterol (rG=0.28, s.e.=0.05), smoking (rG=0.40, s.e.=0.06) and various anthropometric traits (for example, overweight, rG=-0.19, s.e.=0.05). This study replicates the association between alcohol consumption and alcohol metabolizing genes and KLB, and identifies novel gene associations that should be the focus of future studies investigating the neurobiology of alcohol consumption. 10.1038/mp.2017.153
Not just correlative: a new pathway defines how an ALDH2 SNP contributes to atherosclerosis. Gibb Andrew A,Elrod John W The Journal of clinical investigation Individuals with the rs671 SNP in the gene encoding aldehyde dehydrogenase 2 (ALDH2) are at increased risk of cardiovascular disease (CVD); however, it has been unclear if this mutation contributes to CVD development. In this issue of the JCI, Zhong et al. perform an elegant set of experiments that reveal a pathway wherein the ALDH2 rs671 mutant is phosphorylated by AMPK and translocates to the nucleus where it represses the transcription of a lysosomal H+ pump subunit that is critical for lipid degradation and foam cell formation, as occurs in atherosclerosis. The discovery of this pathway may explain how subjects harboring ALDH2 rs671 are at a greater risk for numerous other disease states and thereby provide new targets for therapeutic intervention. 10.1172/JCI125433
Genetic contributors to variation in alcohol consumption vary by race/ethnicity in a large multi-ethnic genome-wide association study. Jorgenson E,Thai K K,Hoffmann T J,Sakoda L C,Kvale M N,Banda Y,Schaefer C,Risch N,Mertens J,Weisner C,Choquet H Molecular psychiatry Alcohol consumption is a complex trait determined by both genetic and environmental factors, and is correlated with the risk of alcohol use disorders. Although a small number of genetic loci have been reported to be associated with variation in alcohol consumption, genetic factors are estimated to explain about half of the variance in alcohol consumption, suggesting that additional loci remain to be discovered. We conducted a genome-wide association study (GWAS) of alcohol consumption in the large Genetic Epidemiology Research in Adult Health and Aging (GERA) cohort, in four race/ethnicity groups: non-Hispanic whites, Hispanic/Latinos, East Asians and African Americans. We examined two statistically independent phenotypes reflecting subjects' alcohol consumption during the past year, based on self-reported information: any alcohol intake (drinker/non-drinker status) and the regular quantity of drinks consumed per week (drinks/week) among drinkers. We assessed these two alcohol consumption phenotypes in each race/ethnicity group, and in a combined trans-ethnic meta-analysis comprising a total of 86 627 individuals. We observed the strongest association between the previously reported single nucleotide polymorphism (SNP) rs671 in ALDH2 and alcohol drinker status (odd ratio (OR)=0.40, P=2.28 × 10) in East Asians, and also an effect on drinks/week (beta=-0.17, P=5.42 × 10) in the same group. We also observed a genome-wide significant association in non-Hispanic whites between the previously reported SNP rs1229984 in ADH1B and both alcohol consumption phenotypes (OR=0.79, P=2.47 × 10 for drinker status and beta=-0.19, P=1.91 × 10 for drinks/week), which replicated in Hispanic/Latinos (OR=0.72, P=4.35 × 10 and beta=-0.21, P=2.58 × 10, respectively). Although prior studies reported effects of ADH1B and ALDH2 on lifetime measures, such as risk of alcohol dependence, our study adds further evidence of the effect of the same genes on a cross-sectional measure of average drinking. Our trans-ethnic meta-analysis confirmed recent findings implicating the KLB and GCKR loci in alcohol consumption, with strongest associations observed for rs7686419 (beta=-0.04, P=3.41 × 10 for drinks/week and OR=0.96, P=4.08 × 10 for drinker status), and rs4665985 (beta=0.04, P=2.26 × 10 for drinks/week and OR=1.04, P=5 × 10 for drinker status), respectively. Finally, we also obtained confirmatory results extending previous findings implicating AUTS2, SGOL1 and SERPINC1 genes in alcohol consumption traits in non-Hispanic whites. 10.1038/mp.2017.101
ALDH2 Gene rs671 Polymorphism May Decrease the Risk of Essential Hypertension. Mei Xiao-Fei,Hu Sheng-Da,Liu Peng-Fei,Li Fei,Zhou Xian-Yong,Zhou Ya-Feng,Chen Tan International heart journal Aldehyde dehydrogenase-2 (ALDH2) rs671 G>A polymorphism can influence the activity of ALDH2 and may be associated with the risk of essential hypertension (EH). Although many previous studies have explored such a relationship, the conclusion is still controversial.The PubMed, Embase, and China National Knowledge Infrastructure databases were searched on the ALDH2 gene and EH. We used the Newcastle-Ottawa Scale to evaluate the quality of the study. Then we calculated the strength of relationship between ALDH2 rs671 mutation and EH by utilizing odds ratios and 95% confidence intervals. Besides, subgroup analysis and sensitivity analysis were performed and the publication bias was assessed.There were 12 studies containing 8153 cases and 10,162 controls. Our meta-analysis showed significant association between ALDH2 rs671 polymorphism and EH in four genetic models (the allele model, the homozygote model, the heterozygote model, and the dominant model), whereas it did not indicate this connection in the recessive model. However, a trend of decreased risk still could be seen. Furthermore, we also found an obvious association between rs671 mutation and the risk of EH in the male group than in the female group in all five genetic models.We concluded that ALDH2 rs671 G>A polymorphism may decrease the risk of EH. Furthermore, susceptibility to EH reduced in males but not in females. As a variant in ALDH2, rs671 G>A could be an attractive candidate for genetic therapy of EH. In addition, more case-control studies should be conducted to strengthen our conclusion and evaluate the gene-gene and gene-environment interactions between the ALDH2 gene and EH. 10.1536/ihj.19-259
ALDH2 and Stroke: A Systematic Review of the Evidence. Xu Haixia,Zhang Yingmei,Ren Jun Advances in experimental medicine and biology Cerebral stroke is one of the leading causes of mortality and disability worldwide. The prevalence of cerebral stroke is the result of the synergistic effect of genetic susceptibility and numerous vascular risk factors, including hypertension, diabetes, excessive alcohol intake, obesity, and dyslipidemia. Mitochondrial aldehyde dehydrogenase (ALDH2) is a vital enzyme metabolizing various acetaldehyde and toxic aldehydes. The ALDH2 enzymatic activity is severely decreased in the individuals with ALDH2*2 gene mutation, especially in East Asians. Increasing epidemiological surveys have revealed that ALDH2 genetic polymorphism is closely associated with the increasing incidence of cardiovascular risk factors and cerebral stroke. Evidence from experimental studies has also suggested that ALDH2 facilitates the clearance of reactive aldehydes and reduces the size of cerebral infarct. Therefore, targeting ALDH2 may represent a promising avenue for protection against stroke injury. This review will mainly focus on clinical and epidemiological evidence and the underlying molecular mechanisms involved in the protective effect of ALDH2 in stroke-related injury. 10.1007/978-981-13-6260-6_11
Contribution of ALDH2 polymorphism to alcoholism-associated hypertension. Hu Nan,Zhang Yingmei,Nair Sreejayan,Culver Bruce W,Ren Jun Recent patents on endocrine, metabolic & immune drug discovery Chronic alcohol intake is considered as an independent lifestyle factor that may influence the risk of a number of cardiovascular anomalies including hypertension. In healthy adults, binge drinking and chronic alcohol ingestion lead to the onset and development of hypertension although the precise mechanism(s) remains obscure. Although oxidative stress and endothelial injury have been postulated to play a major contributing role to alcoholism-induced hypertension, recent evidence depicted a rather unique role for the genotype of the acetaldehyde-metabolizing enzyme mitochondrial aldehyde dehydrogenase (ALDH2), which is mainly responsible for detoxifying ethanol consumed, in alcoholism-induced elevation of blood pressure. Genetic polymorphism of ALDH2 in human results in altered ethanol pharmacokinetic properties and ethanol metabolism, leading to accumulation of the ethanol metabolite acetaldehyde following alcohol intake. The unfavorable consequence of the ALDH2 variants is believed to be governed by the accumulation of the ethanol metabolite acetaldehyde. Presence of the mutant or inactive ALDH2*2 gene often results in an increased risk of hypertension in human. Such association between blood pressure and ALDH2 enzymatic activity may be affected by the interplay between gene and environment, such as life style and ethnicity. The aim of this mini-review is to summarize the possible contribution of ALDH2 genetic polymorphism in the onset and development of alcoholism-related development of hypertension. Furthermore, the double-edged sword of ALDH2 gene and genetic polymorphism in alcoholism and alcoholic tissue damage and relevant patents will be discussed. 10.2174/1872214808666141020162000
ALDH2 protects against stroke by clearing 4-HNE. Guo Jin-Min,Liu Ai-Jun,Zang Pu,Dong Wen-Zhe,Ying Li,Wang Wei,Xu Pu,Song Xu-Rui,Cai Jun,Zhang She-Qing,Duan Jun-Li,Mehta Jawahar L,Su Ding-Feng Cell research Aldehyde dehydrogenase 2 (ALDH2) is a mitochondrial enzyme that metabolizes ethanol and toxic aldehydes such as 4-hydroxy-2-nonenal (4-HNE). Using an unbiased proteomic search, we identified ALDH2 deficiency in stroke-prone spontaneously hypertensive rats (SHR-SP) as compared with spontaneously hypertensive rats (SHR). We concluded the causative role of ALDH2 deficiency in neuronal injury as overexpression or activation of ALDH2 conferred neuroprotection by clearing 4-HNE in in vitro studies. Further, ALDH2-knockdown rats revealed the absence of neuroprotective effects of PKCε. Moderate ethanol administration that is known to exert protection against stroke was shown to enhance the detoxification of 4-HNE, and to protect against ischemic cerebral injury through the PKCε-ALDH2 pathway. In SHR-SP, serum 4-HNE level was persistently elevated and correlated inversely with the lifespan. The role of 4-HNE in stroke in humans was also suggested by persistent elevation of its plasma levels for at least 6 months after stroke. Lastly, we observed that 21 of 1 242 subjects followed for 8 years who developed stroke had higher initial plasma 4-HNE levels than those who did not develop stroke. These findings suggest that activation of the ALDH2 pathway may serve as a useful index in the identification of stroke-prone subjects, and the ALDH2 pathway may be a potential target of therapeutic intervention in stroke. 10.1038/cr.2013.69
Double-edged sword of ALDH2 mutations: one polymorphism can both benefit and harm the cardiovascular system. European heart journal 10.1093/eurheartj/ehaa444
Genetics and alcoholism. Nature reviews. Gastroenterology & hepatology Alcohol is widely consumed; however, excessive use creates serious physical, psychological and social problems and contributes to the pathogenesis of many diseases. Alcohol use disorders (that is, alcohol dependence and alcohol abuse) are maladaptive patterns of excessive drinking that lead to serious problems. Abundant evidence indicates that alcohol dependence (alcoholism) is a complex genetic disease, with variations in a large number of genes affecting a person's risk of alcoholism. Some of these genes have been identified, including two genes involved in the metabolism of alcohol (ADH1B and ALDH2) that have the strongest known affects on the risk of alcoholism. Studies continue to reveal other genes in which variants affect the risk of alcoholism or related traits, including GABRA2, CHRM2, KCNJ6 and AUTS2. As more variants are analysed and studies are combined for meta-analysis to achieve increased sample sizes, an improved picture of the many genes and pathways that affect the risk of alcoholism will be possible. 10.1038/nrgastro.2013.86
Conventional and genetic evidence on alcohol and vascular disease aetiology: a prospective study of 500 000 men and women in China. Lancet (London, England) BACKGROUND:Moderate alcohol intake has been associated with reduced cardiovascular risk in many studies, in comparison with abstinence or with heavier drinking. Studies in east Asia can help determine whether these associations are causal, since two common genetic variants greatly affect alcohol drinking patterns. We used these two variants to assess the relationships between cardiovascular risk and genotype-predicted mean alcohol intake in men, contrasting the findings in men with those in women (few of whom drink). METHODS:The prospective China Kadoorie Biobank enrolled 512 715 adults between June 25, 2004, and July 15, 2008, from ten areas of China, recording alcohol use and other characteristics. It followed them for about 10 years (until Jan 1, 2017), monitoring cardiovascular disease (including ischaemic stroke, intracerebral haemorrhage, and myocardial infarction) by linkage with morbidity and mortality registries and electronic hospital records. 161 498 participants were genotyped for two variants that alter alcohol metabolism, ALDH2-rs671 and ADH1B-rs1229984. Adjusted Cox regression was used to obtain the relative risks associating disease incidence with self-reported drinking patterns (conventional epidemiology) or with genotype-predicted mean male alcohol intake (genetic epidemiology-ie, Mendelian randomisation), with stratification by study area to control for variation between areas in disease rates and in genotype-predicted intake. FINDINGS:33% (69 897/210 205) of men reported drinking alcohol in most weeks, mainly as spirits, compared with only 2% (6245/302 510) of women. Among men, conventional epidemiology showed that self-reported alcohol intake had U-shaped associations with the incidence of ischaemic stroke (n=14 930), intracerebral haemorrhage (n=3496), and acute myocardial infarction (n=2958); men who reported drinking about 100 g of alcohol per week (one to two drinks per day) had lower risks of all three diseases than non-drinkers or heavier drinkers. In contrast, although genotype-predicted mean male alcohol intake varied widely (from 4 to 256 g per week-ie, near zero to about four drinks per day), it did not have any U-shaped associations with risk. For stroke, genotype-predicted mean alcohol intake had a continuously positive log-linear association with risk, which was stronger for intracerebral haemorrhage (relative risk [RR] per 280 g per week 1·58, 95% CI 1·36-1·84, p<0·0001) than for ischaemic stroke (1·27, 1·13-1·43, p=0·0001). For myocardial infarction, however, genotype-predicted mean alcohol intake was not significantly associated with risk (RR per 280 g per week 0·96, 95% CI 0·78-1·18, p=0·69). Usual alcohol intake in current drinkers and genotype-predicted alcohol intake in all men had similarly strong positive associations with systolic blood pressure (each p<0·0001). Among women, few drank and the studied genotypes did not predict high mean alcohol intake and were not positively associated with blood pressure, stroke, or myocardial infarction. INTERPRETATION:Genetic epidemiology shows that the apparently protective effects of moderate alcohol intake against stroke are largely non-causal. Alcohol consumption uniformly increases blood pressure and stroke risk, and appears in this one study to have little net effect on the risk of myocardial infarction. FUNDING:Chinese Ministry of Science and Technology, Kadoorie Charitable Foundation, National Natural Science Foundation of China, British Heart Foundation, Cancer Research UK, GlaxoSmithKline, Medical Research Council, and Wellcome Trust. 10.1016/S0140-6736(18)31772-0
Targeting aldehyde dehydrogenase 2: new therapeutic opportunities. Chen Che-Hong,Ferreira Julio Cesar Batista,Gross Eric R,Mochly-Rosen Daria Physiological reviews A family of detoxifying enzymes called aldehyde dehydrogenases (ALDHs) has been a subject of recent interest, as its role in detoxifying aldehydes that accumulate through metabolism and to which we are exposed from the environment has been elucidated. Although the human genome has 19 ALDH genes, one ALDH emerges as a particularly important enzyme in a variety of human pathologies. This ALDH, ALDH2, is located in the mitochondrial matrix with much known about its role in ethanol metabolism. Less known is a new body of research to be discussed in this review, suggesting that ALDH2 dysfunction may contribute to a variety of human diseases including cardiovascular diseases, diabetes, neurodegenerative diseases, stroke, and cancer. Recent studies suggest that ALDH2 dysfunction is also associated with Fanconi anemia, pain, osteoporosis, and the process of aging. Furthermore, an ALDH2 inactivating mutation (termed ALDH2*2) is the most common single point mutation in humans, and epidemiological studies suggest a correlation between this inactivating mutation and increased propensity for common human pathologies. These data together with studies in animal models and the use of new pharmacological tools that activate ALDH2 depict a new picture related to ALDH2 as a critical health-promoting enzyme. 10.1152/physrev.00017.2013
Prevention of aortic dissection and aneurysm via an ALDH2-mediated switch in vascular smooth muscle cell phenotype. European heart journal AIMS:Aortic aneurysm/dissection (AAD) is a life-threatening disorder lacking effective pharmacotherapeutic remedies. Aldehyde dehydrogenase 2 (ALDH2) polymorphism is tied with various risk factors for AAD including hypertension, atherosclerosis, and hypercholesterolaemia although direct correlation between the two remains elusive. METHODS AND RESULTS:Two independent case-control studies were conducted involving 307 AAD patients and 399 healthy controls in two geographically distinct areas in China. Our data revealed that subjects carrying mutant ALDH2 gene possessed a ∼50% reduced risk of AAD compared with wild-type (WT) alleles. Using 3-aminopropionitrile fumarate (BAPN)- and angiotensin II (Ang II)-induced AAD animal models, inhibition of ALDH2 was found to retard development of AAD. Mechanistically, ALDH2 inhibition ablated pathological vascular smooth muscle cell (VSMC) phenotypical switch through interaction with myocardin, a determinant of VSMC contractile phenotype. Using microarray and bioinformatics analyses, ALDH2 deficiency was found to down-regulate miR-31-5p, which further altered myocardin mRNA level. Gain-of-function and loss-of-function studies verified that miR-31-5p significantly repressed myocardin level and aggravated pathological VSMC phenotypical switch and AAD, an effect that was blunted by ALDH2 inhibition. We next noted that ALDH2 deficiency increased Max expression and decreased miR-31-5p level. Moreover, ALDH2 mutation or inhibition down-regulated levels of miR-31-5p while promoting myocardin downstream contractile genes in the face of Ang II in primary human VSMCs. CONCLUSIONS:ALDH2 deficiency is associated with a lower risk of AAD in patients and mice, possibly via suppressing VSMC phenotypical switch in a miR-31-5p-myocardin-dependent manner. These findings favour a role for ALDH2 and miR-31-5p as novel targets for AAD therapy. 10.1093/eurheartj/ehaa352
Developmental trajectory and environmental moderation of the effect of ALDH2 polymorphism on alcohol use. Irons Daniel E,Iacono William G,Oetting William S,McGue Matt Alcoholism, clinical and experimental research BACKGROUND:In the aldehyde dehydrogenase 2 (ALDH2) gene, the ALDH2*2 allele, prevalent in East Asian populations, encodes an enzyme with severely reduced activity, thereby disrupting the normal metabolism of alcohol. Possession of the ALDH2*2 allele has been repeatedly shown to be associated with lower risk for alcohol dependence and reduced alcohol use. However, relatively few studies have considered whether the magnitude of the effect of ALDH2 polymorphism upon drinking is related to developmental stage or varies by environmental context. METHODS:In a longitudinally assessed sample of 356 adopted adolescents and young adults of East Asian descent, we examined the progression over time of the relationship between ALDH2 genotype and multiple measures of drinking behavior. We also sought to determine whether the environmental influences of nonbiological parent and elder sibling alcohol use and misuse, as well as deviant peer behavior, moderated the effect of ALDH2 genotype upon alcohol use. RESULTS:Across all measures of alcohol use, the association between ALDH2*2 allele possession and reduced drinking went from negligible to moderate between mid-adolescence and early adulthood. A combined index of adoptive parent alcohol use and misuse consistently moderated the protective effect of the ALDH2*2 allele across the measures of quantity and frequency of alcohol use, and symptomology, such that high parental alcohol use and misuse reduced the protective effect of the ALDH2*2 allele, while low parental alcohol use and misuse enhanced the effect of the allele. Neither a combined index of elder sibling alcohol use and misuse, nor deviant peer behavior was consistently related to the effect of ALDH2 genotype. CONCLUSIONS:The protective effect of the ALDH2*2 allele increases over the course of adolescence and young adulthood and is modified by the environmental influence of parental alcohol use and misuse. As such, ALDH2 provides a model system for exploring the nature of gene-environment interplay across development. 10.1111/j.1530-0277.2012.01809.x
Associations between aldehyde dehydrogenase 2 (ALDH2) genetic polymorphisms, drinking status, and hypertension risk in Japanese adult male workers: a case-control study. Ota Mitsunori,Hisada Aya,Lu Xi,Nakashita Chihiro,Masuda Shouta,Katoh Takahiko Environmental health and preventive medicine OBJECTIVES:We sought to identify associations between aldehyde dehydrogenase 2 (ALDH2), alcohol consumption, and hypertension in Japanese men. METHODS:The study participants were 1,225 male Japanese workers. We collected lifestyle information, body measurements, blood biochemical parameters, blood pressure measurements, and ALDH2 genotyping data during medical examinations conducted between March 2004 and January 2005 at a work facility and an affiliated company. Lifestyle data on alcohol intake and smoking were collected using self-administered questionnaires at the same time as when the aforementioned measurements were obtained. RESULTS:The genotype frequencies of ALDH2 genetic polymorphisms were 62.6, 32.7, and 4.7% for *1/*1, *1/*2, and *2/*2, respectively. Systolic blood pressure and diastolic blood pressure in the *1/*2 or *2/*2 group were significantly lower than those in the *1/*1 group (P < 0.001). Multiple regression analysis (stepwise method) for blood pressure according to ALDH2 genetic polymorphism revealed that the amount of daily alcohol intake affected systolic blood pressure in participants who harbored the ALDH2 genetic polymorphism *1/*2 or *2/*2. CONCLUSIONS:The interaction between alcohol intake and ALDH2 genetic polymorphisms might affect systolic blood pressure in adult male workers. 10.1007/s12199-015-0490-2
Activation of aldehyde dehydrogenase 2 (ALDH2) confers cardioprotection in protein kinase C epsilon (PKCvarepsilon) knockout mice. Budas Grant R,Disatnik Marie-Hélène,Chen Che-Hong,Mochly-Rosen Daria Journal of molecular and cellular cardiology Acute administration of ethanol can reduce cardiac ischemia/reperfusion injury. Previous studies demonstrated that the acute cytoprotective effect of ethanol on the myocardium is mediated by protein kinase C epsilon (PKCvarepsilon). We recently identified aldehyde dehydrogenase 2 (ALDH2) as a PKCvarepsilon substrate, whose activation is necessary and sufficient to confer cardioprotection in vivo. ALDH2 metabolizes cytotoxic reactive aldehydes, such as 4-hydroxy-2-nonenal (4-HNE), which accumulate during cardiac ischemia/reperfusion. Here, we used a combination of PKCvarepsilon knockout mice and a direct activator of ALDH2, Alda-44, to further investigate the interplay between PKCvarepsilon and ALDH2 in cardioprotection. We report that ethanol preconditioning requires PKCvarepsilon, whereas direct activation of ALDH2 reduces infarct size in both wild type and PKCvarepsilon knockout hearts. Our data suggest that ALDH2 is downstream of PKCvarepsilon in ethanol preconditioning and that direct activation of ALDH2 can circumvent the requirement of PKCvarepsilon to induce cytoprotection. We also report that in addition to ALDH2 activation, Alda-44 prevents 4-HNE induced inactivation of ALDH2 by reducing the formation of 4-HNE-ALDH2 protein adducts. Thus, Alda-44 promotes metabolism of cytotoxic reactive aldehydes that accumulate in ischemic myocardium. Taken together, our findings suggest that direct activation of ALDH2 may represent a method of harnessing the cardioprotective effect of ethanol without the side effects associated with alcohol consumption. 10.1016/j.yjmcc.2009.10.030
Autophagy in ALDH2-elicited cardioprotection against ischemic heart disease: slayer or savior? Zhang Yingmei,Ren Jun Autophagy The mitochondrial isoform of aldehyde dehydrogenase (ALDH2) plays a key role in the metabolism of acetaldehyde and other toxic aldehydes. A recent seminal finding has indicated a potential role of ALDH2 activation in the cardioprotection against ischemic injury. Data from our group unveiled a myocardial protective effect of ALDH2 against ischemia/reperfusion (I/R) injury possibly through detoxification of toxic aldehydes: and a differential regulation of autophagy mediated by AMPK-mTOR and Akt-mTOR signaling cascades during ischemia and reperfusion, respectively. These findings suggest not only the therapeutic potential of ALDH2 against I/R injury but also a pivotal role of the AMPK-Akt-mTOR signaling in the paradoxical autophagic regulation of cardiomyocyte survival. 10.4161/auto.6.8.13652
Aldehyde Dehydrogenase 2 (ALDH2) Glu504Lys Polymorphism Affects Collateral Circulation and Short-Term Prognosis of Acute Cerebral Infarction Patients. Qu Yun,Zhang Huilong,Li Haiyong,Yu Limei,Sun Ying,Chen Yuguo Medical science monitor : international medical journal of experimental and clinical research BACKGROUND Acute cerebral infarction is a major clinical subtype of ischemic stroke that has become a leading cause of death and disability worldwide. Aldehyde dehydrogenase 2 (ALDH2) is an important oxidative enzyme in alcohol metabolism. The polymorphism of ALDH2 Glu504Lys polymorphism modifies the activity of this enzyme. However, the potential association between the allelic variation of ALDH2 Glu504Lys with collateral circulation and short-term prognosis of acute cerebral infarction remains unclear. MATERIAL AND METHODS A total of 394 patients with acute cerebral infarction were recruited for ALDH2 genotyping using direct sequencing. Cerebrovascular stenosis and collateral circulation were evaluated by digital subtraction angiography (DSA). Short-term prognosis was assessed in accordance with the modified Ranking Scale (mRS). RESULTS We identified 297 as EAS and 394 as IAS. There were more patients with occluded blood vessel in the opened group and far fewer in the unopened group. ALDH2 polymorphism was significantly different among the primary, secondary, and tertiary opened groups. ALDH2 gene Glu504Lys was significantly associated with short-term prognosis. The genotype GA+AA of ALDH2 gene Glu504Lys locus was an independent risk factor of poor 90-day prognosis. CONCLUSIONS ALDH2 Glu504Lys could be a risk factor for collateral circulation and a negative predictor for short-term prognosis in acute cerebral infarction in Han Chinese. ALDH2 Glu504Lys could be a new therapeutic target for patients with acute cerebral infarction. 10.12659/msm.905206
Variant Aldehyde Dehydrogenase 2 (ALDH2*2) Is a Risk Factor for Coronary Spasm and ST-Segment Elevation Myocardial Infarction. Journal of the American Heart Association BACKGROUND:Mitochondrial aldehyde dehydrogenase 2 (ALDH2) plays a key role in removing toxic aldehydes. Deficient variant ALDH2*2 genotype is prevalent in up to 40% of the East Asians and reported to be associated with acute myocardial infarction (AMI). To elucidate the mechanisms underlying the association of ALDH2*2 with AMI, we compared the clinical features of AMI patients with ALDH2*2 to those with wild-type ALDH2*1/*1. METHODS AND RESULTS:The study subjects consisted of 202 Japanese patients with acute ST-segment elevation myocardial infarction (STEMI) (156 men and 46 women; mean age, 67.3±12.0) who underwent primary percutaneous coronary intervention (PCI). In 85 patients, provocation test for coronary spasm was also done 6 month post-PCI. ALDH2 genotyping was performed by direct application of the TaqMan polymerase chain system. Of the 202 patients, 103 (51.0%) were carriers of ALDH2*2 and 99 (49.0%) those of ALDH2*1/*1. There were no differences in clinical features between ALDH2*2 and ALDH2*1/*1 carrier groups except higher frequencies of coronary spasm and alcohol flush syndrome (AFS) (88.6% vs 56.1%; P=0.001 and 94.3% vs 17.6%; P<0.001), less-frequent alcohol habit (14.6% vs 51.5%; P<0.001), and higher peak plasma creatine phophokinase levels (2224 vs 1617 mg/dL; P=0.002) in the ALDH2*2 than the ALDH2*1/*1 carrier group. CONCLUSIONS:ALDH2*2 is prevalent (51.0%) among Japanese STEMI patients, and those with ALDH2*2 had higher frequencies of coronary spasm and AFS and more-severe myocardial injury compared to those with ALDH2*1/*1. 10.1161/JAHA.116.003247
Aldehyde dehydrogenase-2 as a therapeutic target. Kimura Mitsuru,Yokoyama Akira,Higuchi Susumu Expert opinion on therapeutic targets : Aldehyde dehydrogenase-2 (ALDH2) is a main contributor of the alcohol elimination process. Functional polymorphism in the ALDH2 gene and its inactive form causes unpleasant flushing responses after alcohol consumption and prevents excessive alcohol intake. ALDH2 plays a key role in removing endogenous aldehydes like 4-hydroxy-2-nonenal (4-HNE) and malondialdehyde (MDA) produced by lipid peroxidation triggered by oxidative stress. Additionally, ALDH2 is involved in the elimination of metabolites of neurotransmitters like 3,4-dihydroxyphenylacetaldehyde (DOPAL) and 3,4-dihydroxyphenylglycoaldehyde (DOPGAL) in the central nervous system (CNS).: We examine the role of ALDH2 polymorphism in disease, aging and alcohol addiction and discuss its pharmacological targeting. Case-control studies indicate that the deficiency of ALDH2 activity influences the risk of numerous diseases while animal models show that ALDH2 activator Alda-1, could reduce cardiac ischemic damage. Moreover, many studies have reported the protective effect of Alda-1 against the development of neurodegenerative diseases. The literature search was conducted using PubMed and Cochrane Library up to August 2019.: ALDH2 is a promising therapeutic target in numerous diseases. The targeting of ALDH2 has much potential but requires further investigations and analysis to explore and establish its future potential role for the clinic. 10.1080/14728222.2019.1690454
Genetic polymorphisms in the gene and the risk of ischemic stroke in a Chinese han population. Oncotarget BACKGROUND:Previous studies have shown that aldehyde dehydrogenase 2 () plays a role in ischemic stroke progression. In recent years, the activation of the pathway have been reported serving as a useful index in the identification of stroke-prone participants, and the pathway may be a potential target for the therapeutic intervention in ischemic stroke. MATERIALS AND METHODS:We evaluated six tagging single-nucleotide polymorphisms (SNPs) of the gene in a case-control study from Hainan of China (488 cases, 503 controls). We used SPSS version 17.0 statistical software, Excel software and other analysis software to explore associations between SNPs and the risk of ischemic stroke various genetic models (additive, dominant, and recessive). RESULTS:Through statistical analysis, we found that rs886205 [odds ratio (OR) = 6.39; 95% confidence interval (CI) = 1.19-34.38; = 0.03] and rs7296651 (OR = 9.29; 95% CI = 1.37-63.21; = 0.02) were associated with increased risk of ischemic stroke in recessive model analysis. In addition, we established that the "AA" genotype (OR = 5.99; 95% CI = 1.11-32.23; = 0.037) for rs886205 and the "AA" genotype (OR = 8.93; 95% CI = 1.31-60.78; = 0.025) for rs7296651 were associated with increased ischemic stroke risk. CONCLUSIONS:Our results provide evidence that variants of gene polymorphisms influence the risk of developing ischemic stroke in Han Chinese population. 10.18632/oncotarget.21803
Impacts of common variants in ALDH2 on coronary artery disease patients. Zhao Jinzhao,You Ling,Wang Dao Wen,Cui Wei Gene Genome-wide association studies (GWAS) have identified Aldehyde dehydrogenase 2 (ALDH2) as a susceptibility locus for coronary artery disease (CAD) previously. However, the impacts of common variants in this gene on CAD and its outcomes have not been extensively studied. This study explored the association between the Tagging SNPs in ALDH2 and CAD as well as its main outcomes. Six common variants in ALDH2 were selected as tagging SNPs and two cohorts containing 7296 individuals were genotyped to investigate the impacts of ALDH2 on CAD and its main outcomes. The results show that the variant rs671 in ALDH2 is associated with an increased risk of CAD in southern Chinese (OR=1.26, 95%CI: 1.07-1.48, p=0.004), while not in northern Chinese (OR=1.00, 95%CI: 0.86-1.50, p=0.94). Meanwhile, we find that rs671 genotypes may not influence the outcomes of CAD (HR=1.11, 95%CI: 0.892-1.38, p=0.346). Additionally, we also tested the effect of rs671 genotype on CAD severity, while no significant association was found between them. In the subgroup analysis, the results revealed that rs671 were significantly associated with CAD (OR=1.24, 95%CI: 1.11-1.38, p<0.001) in non-alcoholic subjects. Overall, our findings indicate that the associations between rs671 in ALDH2 and CAD are regional disparity, and rs671 genotypes may not influence the main outcomes of CAD. 10.1016/j.gene.2016.03.022
Novel and prevalent non-East Asian ALDH2 variants; Implications for global susceptibility to aldehydes' toxicity. EBioMedicine BACKGROUND:Aldehyde dehydrogenase 2 (ALDH2) catalyzes the detoxification of aliphatic aldehydes, including acetaldehyde. About 45% of Han Chinese (East Asians), accounting for 8% of humans, carry a single point mutation in ALDH2*2 (E504K) that leads to accumulation of toxic reactive aldehydes. METHODS:Sequencing of a small Mexican cohort and a search in the ExAC genomic database for additional ALDH2 variants common in various ethnic groups was set to identify missense variants. These were evaluated in vitro, and in cultured cells expressing these new and common variants. FINDINGS:In a cohort of Hispanic donors, we identified 2 novel mutations in ALDH2. Using the ExAC genomic database, we found these identified variants and at least three other ALDH2 variants with a single point mutation among Latino, African, South Asian, and Finnish ethnic groups, at a frequency of >5/1000. Although located in different parts of the ALDH2 molecule, these common ALDH2 mutants exhibited a significant reduction in activity compared with the wild type enzyme in vitro and in 3T3 cells overexpressing each of the variants, and a greater ethanol-induced toxicity. As Alda-1, previously identified activator, did not activate some of the new mutant ALDH2 enzymes, we continued the screen and identified Alda-64, which is effective in correcting the loss of activity in most of these new and common ALDH2 variants. INTERPRETATION:Since ~80% of the world population consumes ethanol and since acetaldehyde accumulation contributes to a variety of diseases, the identification of additional inactivating variants of ALDH2 in different ethnic groups may help develop new 'precision medicine' for carriers of these inactive ALDH2. 10.1016/j.ebiom.2020.102753
ALDH2*2 Allele is a Negative Risk Factor for Cerebral Infarction in Chinese Women. Li Qiao-Yan,Zhao Ning-Min,Ma Jian-Jun,Duan Hong-Fei,Ma Yong-Cheng,Zhang Wei,Zhao Hong-Wei,Qin Yu-Hua Biochemical genetics Unlike its reported role in the cardiovascular diseases, little information is available for mitochondrial aldehyde dehydrogenase 2 (ALDH2) in the cerebrovascular function. We investigated the different effects of ALDH2 genotypes on the risk of cerebral infarction between the genders, because different genders had different smoking and/or dinking status which are also risk factors for cerebral infarction. 247 healthy Chinese Han people (controls, group 1), 287 Chinese Han male patients with cerebral infarction (group 2), and 82 Chinese Han female patients with cerebral infarction (group 3) were involved in this study. The frequencies of the ALDH2*2 allele in group 3 were significantly higher than those in other groups (with P = 0.001 and P = 0.002, respectively). The difference of ALDH2*2 allele frequency between group 1 and group 2 was not significant (P = 0.652). After adjustment for smoking and drinking status, the male patients without smoking or drinking status (group 4) had higher ALDH2*2 allele frequency than group 1, but the difference was still not significant (P = 0.139). Thus, we conclude that ALDH2*2 allele may be a significant negative risk factor for cerebral infarction in Chinese women [odds ratio (OR) = 2.207, 95% CI 1.416-3.439]. But for Chinese male patients, the negative effects of ALDH2*2 allele on cerebral infarction which might be concealed by other risk factors were not significant. 10.1007/s10528-015-9686-9
Diabetic Aldehyde Dehydrogenase 2 Mutant (ALDH2*2) Mice Are More Susceptible to Cardiac Ischemic-Reperfusion Injury Due to 4-Hydroxy-2-Nonenal Induced Coronary Endothelial Cell Damage. Pan Guodong,Roy Bipradas,Palaniyandi Suresh Selvaraj Journal of the American Heart Association Background Aldehyde dehydrogenase-2 (ALDH2), a mitochondrial enzyme, detoxifies reactive aldehydes such as 4-hydroxy-2-nonenal (4HNE). A highly prevalent E487K mutation in ALDH2 (ALDH2*2) in East Asian people with intrinsic low ALDH2 activity is implicated in diabetic complications. 4HNE-induced cardiomyocyte dysfunction was studied in diabetic cardiac damage; however, coronary endothelial cell (CEC) injury in myocardial ischemia-reperfusion injury (IRI) in diabetic mice has not been studied. Therefore, we hypothesize that the lack of ALDH2 activity exacerbates 4HNE-induced CEC dysfunction which leads to cardiac damage in ALDH2*2 mutant diabetic mice subjected to myocardial IRI. Methods and Results Three weeks after diabetes mellitus (DM) induction, hearts were subjected to IRI either in vivo via left anterior descending artery occlusion and release or ex vivo IRI by using the Langendorff system. The cardiac performance was assessed by conscious echocardiography in mice or by inserting a balloon catheter in the left ventricle in the ex vivo model. Just 3 weeks of DM led to an increase in cardiac 4HNE protein adducts and, cardiac dysfunction, and a decrease in the number of CECs along with reduced myocardial ALDH2 activity in ALDH2*2 mutant diabetic mice compared with their wild-type counterparts. Systemic pretreatment with Alda-1 (10 mg/kg per day), an activator of both ALDH2 and ALDH2*2, led to a reduction in myocardial infarct size and dysfunction, and coronary perfusion pressure upon cardiac IRI by increasing CEC population and coronary arteriole opening. Conclusions Low ALDH2 activity exacerbates 4HNE-mediated CEC injury and thereby cardiac dysfunction in diabetic mouse hearts subjected to IRI, which can be reversed by ALDH2 activation. 10.1161/JAHA.121.021140
Dominance of the mutant ALDH2(2) allele in the expression of human stomach aldehyde dehydrogenase-2 activity. Chao Y C,Liou S R,Tsai S F,Yin S J Proceedings of the National Science Council, Republic of China. Part B, Life sciences About half of Chinese individuals lack mitochondrial aldehyde dehydrogenase-2 (ALDH2) activity, which is responsible for the oxidation of acetaldehyde produced during ethanol metabolism. The ALDH2 deficiency in Chinese has been implicated in alcohol flush reaction and reported to be a negative risk factor for development of alcohol dependence. To assess the effects of inactive ALDH2 subunits, encoded by the mutant ALDH2(2) allele, on the catalytic activity of tetrameric enzyme molecules, we have phenotyped ALDH2 from 30 gastroendoscopic biopsies by using agarose isoelectric focusing and determined the genotypes from leukocytes of the same individuals by using polymerase-chain-reaction amplification and hybridization with allele-specific oligonucleotide probes. Sixteen subjects were homozygous for the ALDH2(1) allele, one was homozygous for ALDH2(2), and thirteen were the heterozygous genotype. None of the subjects with the mutant homozygotic and the heterozygotic genotypes exhibited the ALDH2 activity band or intermediate bands between ALDH2 and ALDH1 on isoelectric focusing gels. Our results support the notion that the mutant allele is dominant and that the heterotetrameric ALDH2 molecules containing the mutant subunits are enzymatically inactive or far less active.
Acetaldehyde dehydrogenase 2 interactions with LDLR and AMPK regulate foam cell formation. Zhong Shanshan,Li Luxiao,Zhang Yu-Lei,Zhang Lili,Lu Jianhong,Guo Shuyuan,Liang Ningning,Ge Jing,Zhu Mingjiang,Tao Yongzhen,Wu Yun-Cheng,Yin Huiyong The Journal of clinical investigation Acetaldehyde dehydrogenase 2 (ALDH2) is a mitochondrial enzyme detoxifying acetaldehyde and endogenous lipid aldehydes; previous studies suggest a protective role of ALDH2 against cardiovascular disease (CVD). Around 40% of East Asians carrying the single nucleotide polymorphism (SNP) ALDH2 rs671 have an increased incidence of CVD. However, the role of ALDH2 in CVD beyond alcohol consumption remains poorly defined. Here we report that ALDH2/LDLR double knockout (DKO) mice have decreased atherosclerosis compared with LDLR-KO mice, whereas ALDH2/APOE-DKO mice have increased atherosclerosis, suggesting an unexpected interaction of ALDH2 with LDLR. Further studies demonstrate that in the absence of LDLR, AMPK phosphorylates ALDH2 at threonine 356 and enables its nuclear translocation. Nuclear ALDH2 interacts with HDAC3 and represses transcription of a lysosomal proton pump protein ATP6V0E2, critical for maintaining lysosomal function, autophagy, and degradation of oxidized low-density lipid protein. Interestingly, an interaction of cytosolic LDLR C-terminus with AMPK blocks ALDH2 phosphorylation and subsequent nuclear translocation, whereas ALDH2 rs671 mutant in human macrophages attenuates this interaction, which releases ALDH2 to the nucleus to suppress ATP6V0E2 expression, resulting in increased foam cells due to impaired lysosomal function. Our studies reveal a novel role of ALDH2 and LDLR in atherosclerosis and provide a molecular mechanism by which ALDH2 rs671 SNP increases CVD. 10.1172/JCI122064
ALDH2, a novel protector against stroke? Sun Aijun,Ren Jun Cell research In a recent paper published in Cell Research, an association between expression of mitochondrial aldehyde dehydrogenase (ALDH2), a mitochondrial chaperon expressed in the brain, and the prevalence of stroke is revealed. This finding indicates that ALDH2 may serve as a potential endogenous neuroprotective target and a promising therapeutic strategy for the management of stroke. 10.1038/cr.2013.76
The ALDH2 gene rs671 polymorphism is not associated with essential hypertension. Li Zhan-Ming,Kong Chao-Yue,Sun Ke-Yu,Wang Li-Shun Clinical and experimental hypertension (New York, N.Y. : 1993) Essential hypertension (EH) is a worldwide problem. Acetaldehyde dehydrogenase 2 (ALDH2) gene has been suggested to be correlated with EH. However, the results are inconsistent. This study aimed to investigate the associations of ALDH2 rs671 polymorphism with EH in a Chinese Han population in Shanghai. Genotype of ALDH2 rs671 was analyzed in 1923 EH patients and 1115 control subjects. We found no association between ALDH2 rs671 and EH risk or EH-related quantitative blood chemistry values. Furthermore, a meta-analysis was performed and the summary results from 11220 patients and 8339 control subjects were consistent with our findings. These results indicated that rs671 of ALDH2 may not associate with the risk of EH. 10.1080/10641963.2017.1299749
Acetaldehyde Enhances Alcohol Sensitivity and Protects against Alcoholism: Evidence from Alcohol Metabolism in Subjects with Variant Gene Allele. Chen Yi-Chyan,Yang Li-Fang,Lai Ching-Long,Yin Shih-Jiun Biomolecules Alcoholism is a complex behavior trait influenced by multiple genes as well as by sociocultural factors. Alcohol metabolism is one of the biological determinants that can significantly influence drinking behaviors. Alcohol sensitivity is thought to be a behavioral trait marker for susceptibility to develop alcoholism. The subjective perceptions would be an indicator for the alcohol preference. To investigate alcohol sensitivity for the variants and , sixty healthy young males with different combinatory and genotypes, ( = 23), ( = 27), and ( = 10), participated in the study. The subjective perceptions were assessed by a structured scale, and blood ethanol and acetaldehyde were determined by GC and HPLC after an alcohol challenge in two dose sessions (0.3 g/kg or 0.5 g/kg ethanol). The principal findings are (1) dose-dependent increase of blood ethanol concentration, unaffected by or ; (2) significant build-up of blood acetaldehyde, strikingly influenced by the gene allele and correlated with the dose of ingested alcohol; (3) the increased heart rate and subjective sensations caused by acetaldehyde accumulation in the heterozygotes; (4) no significant effect of polymorphism in alcohol metabolism or producing the psychological responses. The study findings provide the evidence of acetaldehyde potentiating the alcohol sensitivity and feedback to self-control the drinking amount. The results indicate that plays a major role for acetaldehyde-related physiological negative responses and prove the genetic protection against development of alcoholism in East Asians. 10.3390/biom11081183
[Aldehyde dehydrogenase (ALDH2) polymorphism and drinking behavior]. Luo Huai-Rong,Zhang Ya-Ping Yi chuan = Hereditas An atypical allele (ALDH2*2) in low K(m) aldehyde dehydrogenase (ALDH2), which is highly prevalent in Asians, may influence drinking behavior because of higher production of acetaldehyde in the liver. High alcohol sensitivity such as flushing after drinking has been shown to be mainly due to the atypical ALDH2 genotypes. The atypical allele is associated with alcohol-induced liver injury and some cancers. Recently, the researches on the polymorphisms not only in the gene itself but also its frequencies in different Asian populations have been made great progress. Three factors, including different sex, age and geography, were also analyzed with the genotypes of ALDH2 in Chinese populations.
ALDH2 deficiency inhibits Ox-LDL induced foam cell formation via suppressing CD36 expression. Wei Shujian,Zhang Luetao,Bailu Wang ,Zhao Yu,Dong Qianqian,Pan Chang,Li Chuanbao,He Dayu,Yuan Qiuhuan,Xu Feng,Chen Yuguo Biochemical and biophysical research communications Foam cell formation plays an important role in the initiation and progression of atherosclerosis. Aldehyde dehydrogenase 2 (ALDH2), a key enzyme for aldehyde metabolism, is associated with coronary artery disease and affects atherosclerotic plaque vulnerability. However, the role of ALDH2 in foam cell formation remains unclear. Using peritoneal macrophages from ALDH2-deficient and control mice, we found that ALDH2 deficiency suppressed foam cell formation induced by oxidized low-density lipoproteins (ox-LDL) but not acetylated low-density lipoproteins (ac-LDL) ex vivo. After incubation with ox-LDL, ALDH2-deficient macrophages expressed lower levels of CD36 but the expression of other lipid metabolism-related proteins including SRA, LOX-1, ABCA-1, ABCG-1 and ACAT-1 was not changed in ALDH2 macrophages. Using CD36 inhibitor, we confirmed that CD36 contributes to the effect of ALDH2 on foam cell formation. PPARγ was downregulated in ox-LDL treated ALDH2 macrophages. 4-HNE was increased by ALDH2 deficiency and high concentration of 4-HNE suppressed the expression of PPARγ. These data suggest that ALDH2 plays an important role in foam cell formation via 4-HNE/PPARγ/CD36 pathway. 10.1016/j.bbrc.2019.02.012
[Fundamental Properties of Aldehyde Dehydrogenase 2 (ALDH2) and the Importance of the ALDH2 Polymorphism]. Matsumoto Akiko Nihon eiseigaku zasshi. Japanese journal of hygiene Human aldehyde dehydrogenase 2 (ALDH2) is a 56 kDa mitochondrial protein that forms homodimers through hydrogen bonding interactions between the Glu487 and Arg475 residues of two ALDH2 proteins. Two ALDH2 homodimers can interact to form an ALDH2 tetramer. ALDH2 is widely distributed throughout the organs of the body. In addition to its dehydrogenase activity, ALDH2 also exhibits esterase and reductase activities, with the main substrates for these three activities being aldehydes, 4-nitrophenyl acetate and nitroglycerin, respectively. ALDH2 can be readily inhibited by a wide variety of endogenous and exogenous chemicals, but the induction or activation of this enzyme remains unlikely. The polymorphism of ALDH2 to the corresponding ALDH2*2 variant results in a severe deficiency in ALDH2 activity, and this particular polymorphism is prevalent among people of Mongoloid descent. It seems reasonable to expect that people with the ALDH2*2 variant would be more vulnerable to stress and diseases because ALDH2 defends the human body against toxic aldehydes. However, it has been suggested that people with the ALDH2*2 variant are protected by alternative stress-defending systems. The ALDH2*2 variant has been reported to be associated with many different kinds of diseases, although the mechanisms underlying these associations have not yet been elucidated. ALDH2 polymorphism has a significant impact on human health; further studies are therefore required to determine the practical implications of this polymorphism in the fields of preventive and clinical medicine. 10.1265/jjh.71.55
The contribution of tissue-grouped BMI-associated gene sets to cardiometabolic-disease risk: a Mendelian randomization study. Verkouter Inge,de Mutsert Renée,Smit Roelof A J,Trompet Stella,Rosendaal Frits R,van Heemst Diana,Willems van Dijk Ko,Noordam Raymond International journal of epidemiology BACKGROUND:Body mass index (BMI)-associated loci are used to explore the effects of obesity using Mendelian randomization (MR), but the contribution of individual tissues to risks remains unknown. We aimed to identify tissue-grouped pathways of BMI-associated loci and relate these to cardiometabolic disease using MR analyses. METHODS:Using Genotype-Tissue Expression (GTEx) data, we performed overrepresentation tests to identify tissue-grouped gene sets based on mRNA-expression profiles from 634 previously published BMI-associated loci. We conducted two-sample MR with inverse-variance-weighted methods, to examine associations between tissue-grouped BMI-associated genetic instruments and type 2 diabetes mellitus (T2DM) and coronary artery disease (CAD), with use of summary-level data from published genome-wide association studies (T2DM: 74 124 cases, 824 006 controls; CAD: 60 801 cases, 123 504 controls). Additionally, we performed MR analyses on T2DM and CAD using randomly sampled sets of 100 or 200 BMI-associated genetic variants. RESULTS:We identified 17 partly overlapping tissue-grouped gene sets, of which 12 were brain areas, where BMI-associated genes were differentially expressed. In tissue-grouped MR analyses, all gene sets were similarly associated with increased risks of T2DM and CAD. MR analyses with randomly sampled genetic variants on T2DM and CAD resulted in a distribution of effect estimates similar to tissue-grouped gene sets. CONCLUSIONS:Overrepresentation tests revealed differential expression of BMI-associated genes in 17 different tissues. However, with our biology-based approach using tissue-grouped MR analyses, we did not identify different risks of T2DM or CAD for the BMI-associated gene sets, which was reflected by similar effect estimates obtained by randomly sampled gene sets. 10.1093/ije/dyaa070
Multiple Sclerosis and the Risk of Cardiovascular Diseases: A Mendelian Randomization Study. Frontiers in immunology Background:Observational studies suggested that multiple sclerosis (MS) is associated with cardiovascular diseases (CVDs). However, the causal association has not been fully elucidated. Thus, we aim to assess the causality of the associations of MS with risk of CVDs. Methods:A two-sample Mendelian randomization (MR) study was performed to explore the causality. Genetic instruments were identified for MS from a genome-wide association study (GWAS) involving 115,803 individuals. Summary-level data for CVDs were obtained from different GWAS meta-analysis studies. MR analysis was conducted mainly using the inverse-variance weighted (IVW) method. Sensitivity analyses were further performed to ensure the robustness of the results. Results:This MR study found suggestive evidence that genetic liability to MS was associated with an increased risk of coronary artery disease (CAD) [odds ratio (OR), 1.02; 95% confidence interval (CI), 1.00-1.04; = 0.03], myocardial infarction (MI) (OR, 1.03; 95% CI, 1.00-1.06; = 0.01), heart failure (HF) (OR, 1.02; 95% CI, 1.00-1.04; = 0.02), all-cause stroke (AS) (OR, 1.02; 95% CI, 1.00-1.05; = 0.02), and any ischemic stroke (AIS) (OR, 1.02; 95% CI, 1.00-1.05; = 0.04). The null-association was observed between MS and the other CVDs. Further analyses found little evidence of pleiotropy. Conclusions:We provided suggestive genetic evidence for the causal associations of MS with increased risk of CAD, MI, HF, AS, and AIS, which highlighted the significance of active monitoring and prevention of cardiovascular risk to combat cardiovascular comorbidities in MS patients. 10.3389/fimmu.2022.861885
Assessing causal estimates of the association of obesity-related traits with coronary artery disease using a Mendelian randomization approach. Zhang Xue,Lv Wan-Qiang,Qiu Bo,Zhang Li-Jun,Qin Jian,Tang Feng-Juan,Wang Hai-Tao,Li Hua-Jie,Hao Ya-Rong Scientific reports Obesity-related traits have been associated with coronary artery disease (CAD) in observational studies, but these associations may be biased by confounding factors and reverse causation. In this study, we specifically conducted two-sample Mendelian randomization (MR) analyses to overcome these limitations and test the associations of obesity-related traits (other than body mass index (BMI)) (n = 322,154) with CAD (22,233 cases and 64,762 controls) by using summary-level data from previous studies. The methods utilized to estimate these associations included the inverse-variance weighted method, the weighted median method and MR-Egger regression. Our results supported causal effects of BMI, hip circumference (HC), waist circumference (WC), and waist-hip ratio (WHR) on CAD. The associations of BMI-adjusted HC and WC with CAD were reversed, unlike that of WHR. In MR analyses excluding overlapping single nucleotide polymorphisms (SNPs) from obesity-related traits, the associations of these traits with CAD were preserved. The associations of BMI-adjusted HC and WC with CAD require further investigation, as collider stratification may be occurring. Additionally, central adiposity (measured by WHR) separated from general adiposity (measured by BMI) and general adiposity might pose similar risks for CAD. In clinical practice, physicians should pay attention to the potential effects of different obesity-related traits on CAD. 10.1038/s41598-018-25305-y
Is periodontitis a risk factor for ischaemic stroke, coronary artery disease and subclinical atherosclerosis? A Mendelian randomization study. Atherosclerosis BACKGROUND AND AIMS:Observational studies have reported an association between periodontitis and cardiovascular disease but whether this association is causal is uncertain. We therefore used Mendelian randomization to test whether periodontitis is causally associated with stroke, coronary artery disease, or subclinical atherosclerosis. METHODS:A two-sample Mendelian randomization analysis was carried out using five single nucleotide polymorphisms previously associated with periodontitis in genome-wide association studies. Summary data were drawn from MEGASTROKE and combined with de novo analyses of UK Biobank for stroke and its major subtypes (up to 44,221 cases, 739,957 controls) and CARDIoGRAMplusC4D and UK Biobank for coronary artery disease (122,733 cases, 424,528 controls). We used existing data on carotid intima-media thickness in UK Biobank as a marker of subclinical atherosclerosis (N = 22,179). Causal estimates were obtained using inverse-variance weighted Mendelian randomization. Sensitivity analyses were performed using weighted median and MR-Egger approaches. RESULTS:No association was found between periodontitis and any stroke (odds ratio [OR] per doubling in the odds of periodontitis 0.99, 95% confidence interval [CI] 0.97 to 1.02), ischaemic stroke (OR 1.00, 95% CI 0.97 to 1.03) or its major subtypes (p > 0.4), or coronary artery disease (OR 1.01, 95% CI 0.99 to 1.03). Similarly, we found no association for periodontitis and subclinical atherosclerosis (β -0.002, 95% CI -0.004 to 0.001). These results were consistent across a series of sensitivity analyses. CONCLUSIONS:These findings provide no robust evidence for a causal relationship between periodontitis and stroke or coronary artery disease. This suggests that associations reported in observational studies may represent confounding. 10.1016/j.atherosclerosis.2020.09.029
Association between Circulating Antioxidants and Longevity: Insight from Mendelian Randomization Study. BioMed research international BACKGROUND:Antioxidants attracted long-standing attention as promising preventive agents worldwide. Previous observational studies have reported that circulating antioxidants are associated with reduced mortality; however, randomized clinical trials indicate neutral or harmful impacts. The association of long-term circulating antioxidant exposure with longevity is still unclear. OBJECTIVES:We aim to determine whether long-term circulating antioxidant exposure is causally associated with longevity in the general population using the two-sample Mendelian randomization (MR) design. METHODS:Genetic instruments for circulating antioxidants (ascorbate, lycopene, selenium, beta-carotene, and retinol) and antioxidant metabolites (ascorbate, alpha-tocopherol, gamma-tocopherol, and retinol) were identified from the largest up-to-date genome-wide association studies (GWASs). Summary statistics of these instruments with individual survival to the 90 vs. 60 percentile age (11,262 cases and 25,483 controls) and parental lifespan ( = 1,012,240 individuals) were extracted. The causal effect was estimated using the inverse-variance weighted method in the main analysis and complemented by multiple sensitivity analyses to test the robustness of results. RESULTS:We found that genetically determined higher concentration of circulating retinol (vitamin A) metabolite was casually associated with a higher odds of longevity (OR, 1.07; 95% CI, 1.02-1.13; < 0.01) and increased parental lifespan (lifespan years per 10-fold increase: 0.17; 95% CI, 0.07-0.27; < 0.01). Present evidence did not support a causal impact of circulating ascorbate (vitamin C), tocopherol (vitamin E), lycopene, selenium or beta-carotene on life expectancy. No evidence was identified to show the pleiotropic effects had biased the results. CONCLUSIONS:Long-term higher exposure to retinol metabolite is causally associated with longevity in the general population. Future MR analyses could assess the current findings further by utilizing additional genetic variants and greater samples from large-scale GWASs. 10.1155/2022/4012603
Aldehyde Dehydrogenase-2 Roles in Ischemic Cardiovascular Disease. Liu Xiangwei,Sun Aijun Current drug targets BACKGROUND:Coronary heart disease is the leading cause of mortality and morbidity, incurring a major burden of medical care. Even with increasing application of emergent recanalization (PCI and CABG) therapy, ischemia and ischemic reperfusion injury remain as the dominant pathological process that damages cardiomyocytes. Mitochondrial Aldehyde dehydrogenase-2 (ALDH2) is a multifunctional enzyme catalyzing the oxidation of aldehydes. OBJECTIVE:Accumulating data have shown that ALDH2 can help restore mitochondria function by eliminating toxic aldehyde and participating in cellular signaling important for cell adaption and survival. This article reviews the biology and pathobiology roles of ALDH2 in the ischemic cardiovascular disease, focusing on the genetic evidence associated with the oriental patients. CONCLUSION:The ALDH2*2 mutant allele (deficiency genotype) is present in nearly half of the East Asian population. Development of a safe way to restore ALDH2 function in this population thus has unique clinical implication. 10.2174/1389450117666160912174417
ALDH2 and Cardiovascular Disease. Chen Che-Hong,Ferreira Julio C B,Mochly-Rosen Daria Advances in experimental medicine and biology Aldehyde dehydrogenase 2 (ALDH2) is a non-cytochrome P450 mitochondrial aldehyde oxidizing enzyme. It is best known for its role in the metabolism of acetaldehyde, a common metabolite from alcohol drinking. More evidences have been accumulated in recent years to indicate a greater role of ALDH2 in the metabolism of other endogenous and exogenous aldehydes, especially lipid peroxidation-derived reactive aldehyde under oxidative stress. Many cardiovascular diseases are associated with oxidative stress and mitochondria dysfunction. Considering that an estimated 560 million East Asians carry a common ALDH2 deficient variant which causes the well-known alcohol flushing syndrome due to acetaldehyde accumulation, the importance of understanding the role of ALDH2 in these diseases should be highlighted. There are several unfavorable cardiovascular conditions that are associated with ALDH2 deficiency. This chapter reviews the function of ALDH2 in various pathological conditions of the heart in relation to aldehyde toxicity. It also highlights the importance and clinical implications of interaction between ALDH2 deficiency and alcohol drinking on cardiovascular disease among the East Asians. 10.1007/978-981-13-6260-6_3
The role of aldehyde dehydrogenase 2 in cardiovascular disease. Nature reviews. Cardiology Aldehyde dehydrogenase 2 (ALDH2) is a mitochondrial enzyme involved in the detoxification of alcohol-derived acetaldehyde and endogenous aldehydes. The inactivating ALDH2 rs671 polymorphism, present in up to 8% of the global population and in up to 50% of the East Asian population, is associated with increased risk of cardiovascular conditions such as coronary artery disease, alcohol-induced cardiac dysfunction, pulmonary arterial hypertension, heart failure and drug-induced cardiotoxicity. Although numerous studies have attributed an accumulation of aldehydes (secondary to alcohol consumption, ischaemia or elevated oxidative stress) to an increased risk of cardiovascular disease (CVD), this accumulation alone does not explain the emerging protective role of ALDH2 rs671 against ageing-related cardiac dysfunction and the development of aortic aneurysm or dissection. ALDH2 can also modulate risk factors associated with atherosclerosis, such as cholesterol biosynthesis and HDL biogenesis in hepatocytes and foam cell formation and efferocytosis in macrophages, via non-enzymatic pathways. In this Review, we summarize the basic biology and the clinical relevance of the enzymatic and non-enzymatic, tissue-specific roles of ALDH2 in CVD, and discuss the future directions in the research and development of therapeutic strategies targeting ALDH2. A thorough understanding of the complex roles of ALDH2 in CVD will improve the diagnosis, management and prognosis of patients with CVD who harbour the ALDH2 rs671 polymorphism. 10.1038/s41569-023-00839-5
The role of glycaemic and lipid risk factors in mediating the effect of BMI on coronary heart disease: a two-step, two-sample Mendelian randomisation study. Diabetologia AIMS/HYPOTHESIS:The extent to which effects of BMI on CHD are mediated by glycaemic and lipid risk factors is unclear. In this study we examined the effects of these traits using genetic evidence. METHODS:We used two-sample Mendelian randomisation to determine: (1) the causal effect of BMI on CHD (60,801 case vs 123,504 control participants), type 2 diabetes (34,840 case vs 114,981 control participants), fasting glucose (n = 46,186), insulin (n = 38,238), HbA (n = 46,368) and LDL-cholesterol, HDL-cholesterol and triacylglycerols (n = 188,577); (2) the causal effects of glycaemic and lipids traits on CHD; and (3) the extent to which these traits mediate any effect of BMI on CHD. RESULTS:One SD higher BMI (~ 4.5 kg/m) was associated with higher risk of CHD (OR 1.45 [95% CI 1.27, 1.66]) and type 2 diabetes (1.96 [95% CI 1.35, 2.83]), higher levels of fasting glucose (0.07 mmol/l [95% CI 0.03, 0.11]), HbA (0.05% [95% CI 0.01, 0.08]), fasting insulin (0.18 log pmol/l [95% CI 0.14, 0.22]) and triacylglycerols (0.20 SD [95% CI 0.14, 0.26]) and lower levels of HDL-cholesterol (-0.23 SD [95% CI -0.32, -0.15]). There was no evidence for a causal relation between BMI and LDL-cholesterol. The causal associations of higher triacylglycerols, HbA and diabetes risk with CHD risk remained after performing sensitivity analyses that considered different models of horizontal pleiotropy. The BMI-CHD effect reduced from 1.45 to 1.16 (95% CI 0.99, 1.36) and to 1.36 (95% CI 1.19, 1.57) with genetic adjustment for triacylglycerols or HbA, respectively, and to 1.09 (95% CI 0.94, 1.27) with adjustment for both. CONCLUSIONS/INTERPRETATION:Increased triacylglycerol levels and poor glycaemic control appear to mediate much of the effect of BMI on CHD. 10.1007/s00125-017-4396-y
The total and direct effects of systolic and diastolic blood pressure on cardiovascular disease and longevity using Mendelian randomisation. Scientific reports The 2017 American College of Cardiology/American Heart Association (ACC/AHA) blood pressure (BP) guidelines lowered the hypertension threshold to ≥ 130/80 mmHg, but the role of diastolic BP remains contested. This two-sample mendelian randomisation study used replicated genetic variants predicting systolic and diastolic BP applied to the UK Biobank and large genetic consortia, including of cardiovascular diseases and parental lifespan, to obtain total and direct effects. Systolic and diastolic BP had positive total effects on CVD (odds ratio (OR) per standard deviation 2.15, 95% confidence interval (CI) 1.95, 2.37 and OR 1.91, 95% CI 1.73, 2.11, respectively). Direct effects were similar for systolic BP (OR 1.83, 95% CI 1.48, 2.25) but completely attenuated for diastolic BP (1.18, 95% CI 0.97, 1.44), although diastolic BP was associated with coronary artery disease (OR 1.24, 95% CI 1.03, 1.50). Systolic and diastolic BP had similarly negative total (- 0.20 parental attained age z-score, 95% CI - 0.22, - 0.17 and - 0.17, 95% CI - 0.20, - 0.15, respectively) and direct negative effects on longevity. Our findings suggest systolic BP has larger direct effects than diastolic BP on CVD, but both have negative effects (total and direct) on longevity, supporting the 2017 ACC/AHA guidelines lowering both BP targets. 10.1038/s41598-021-00895-2
Causal associations of sleep apnea, snoring with cardiovascular diseases, and the role of body mass index: a two-sample Mendelian randomization study. European journal of preventive cardiology AIMS:Previously, observational studies have identified associations between sleep apnea (SA) and cardiovascular diseases (CVDs), whereas whether the associations are causal remain unclear. METHODS AND RESULTS:We used the bi-directional, two-sample Mendelian randomization (MR) study to assess the existence and direction of the causal relationship between SA or snoring and CVDs. Multivariable MR (MVMR) was used to assess the direct effect of SA on CVDs after adjusting for body mass index (BMI). Single-nucleotide polymorphisms (SNPs) associated with SA and snoring were obtained from the latest genome-wide association study, which combined five cohorts with a total number of 25 008 SA cases and 172 050 snoring cases (total = 523 366). Among the analytic sample of 523 366 individuals (25 008 SA cases and 172 050 snoring cases), and after correcting for multiple testing, inverse-variance weighted (IVW) showed that SA and snoring increased the risk of hypertension [odds ratio (OR) = 1.03, 95% CI 1.02-1.05 and 1.05, 1.03-1.07], and coronary artery disease (CAD) (1.41,1.19-1.67 and 1.61,1.26-2.07) with all false-discovery rate (FDR) < 0.05, but such associations were decreased dramatically after adjusting for BMI using MVMR-IVW (0.06 < FDRBMI adjusted < 0.20). SA and snoring were not associated with atrial fibrillation (AF), heart failure (HF), or stroke. The presence of hypertension may increase the risk of SA (1.53, 1.04-2.25), but this association did not pass multiple comparisons (FDR > 0.05). DISCUSSION:Our results suggest that SA and snoring increased the risk of hypertension and CAD, and these associations may partly be driven by BMI. Conversely, no evidence of CVDs causally influencing SA or snoring was found. 10.1093/eurjpc/zwad005
Plasma homocysteine levels and risk of congestive heart failure or cardiomyopathy: A Mendelian randomization study. Frontiers in cardiovascular medicine Background:Although observational studies have demonstrated associations between elevated plasma homocysteine levels and the risk of cardiovascular diseases, controversy remains. Objective:This study investigated the causal association of plasma homocysteine levels with congestive heart failure and cardiomyopathy risk. Methods:We performed a two-sample Mendelian randomization (MR) study of congestive heart failure ( = 218,792), cardiomyopathy ( = 159,811), and non-ischemic cardiomyopathy ( = 187,152). Genetic summary data on the association of single-nucleotide polymorphisms with homocysteine were extracted from the most extensive genome-wide association study of 44,147 individuals. MR analyses, including the random-effect inverse variance-weighted (IVW) meta-analysis, weighted median, simple median, maximum likelihood, penalized weighted median, MR-PRESSO, and MR-Egger regression, were used to estimate the associations between the selected single-nucleotide polymorphisms and congestive heart failure or cardiomyopathy. Results:The MR analyses revealed no causal role of higher genetically predicted plasma homocysteine levels with congestive heart failure risk (random-effect IVW, odds ratio [OR] per standard deviation (SD) increase in homocysteine levels = 1.753, 95% confidence interval [CI] = 0.674-4.562, = 0.250), cardiomyopathy (random-effect IVW, OR per SD increase in homocysteine levels = 0.805, 95% CI = 0.583 to 1.020, = 0.189), or non-ischemic cardiomyopathy (random-effect IVW, OR per SD increase in homocysteine levels = 1.064, 95% CI = 0.927-1.222, = 0.379). The results were consistent with other analytical methods and sensitivity analyses. Conclusion:Genetically predicted homocysteine level was not associated with congestive heart failure or cardiomyopathy risk. It is unlikely that homocysteine-lowering therapy decreases the incidence or improves the outcomes of congestive heart failure and cardiomyopathy. 10.3389/fcvm.2023.1030257
Morning plasma cortisol as a cardiovascular risk factor: findings from prospective cohort and Mendelian randomization studies. European journal of endocrinology OBJECTIVE:The identification of new causal risk factors has the potential to improve cardiovascular disease (CVD) risk prediction and the development of new treatments to reduce CVD deaths. In the general population, we sought to determine whether cortisol is a causal risk factor for CVD and coronary heart disease (CHD). DESIGN AND METHODS:Three approaches were adopted to investigate the association between cortisol and CVD/CHD. First, we used multivariable regression in two prospective nested case-control studies (total 798 participants, 313 incident CVD/CHD with complete data). Second, a random-effects meta-analysis of these data and previously published prospective associations was performed (total 6680 controls, 696 incident CVD/CHD). Finally, one- and two-sample Mendelian randomization analyses were performed (122,737 CHD cases, 547,261 controls for two-sample analyses). RESULTS:In the two prospective nested case-control studies, logistic regression adjusting for sex, age, BMI, smoking and time of sampling, demonstrated a positive association between morning plasma cortisol and incident CVD (OR: 1.28 per 1 SD higher cortisol, 95% CI: 1.06-1.54). In the meta-analysis of prospective studies, the equivalent result was OR: 1.18, 95% CI: 1.06-1.31. Results from the two-sample Mendelian randomization were consistent with these positive associations: OR: 1.06, 95% CI: 0.98-1.15. CONCLUSIONS:All three approaches demonstrated a positive association between morning plasma cortisol and incident CVD. Together, these findings suggest that elevated morning cortisol is a causal risk factor for CVD. The current data suggest strategies targeted at lowering cortisol action should be evaluated for their effects on CVD. 10.1530/EJE-19-0161
Investigating Causal Relations Between Sleep-Related Traits and Risk of Type 2 Diabetes Mellitus: A Mendelian Randomization Study. Gao Xue,Sun Heli,Zhang Yu,Liu Long,Wang Juping,Wang Tong Frontiers in genetics Objective:Extensive literature put forward the link between sleep and type 2 diabetes mellitus (T2DM), however, little is known about the underlying causality of the associations. Here we aim to assess the causal relationships between five major sleep-related traits and T2DM. Design Setting and Participants:Two-sample Mendelian randomization (MR) was utilized to investigate the potential causal relations. Independent genetic variants associated with five sleep-related phenotypes-insomnia, sleep duration, short sleep duration, long sleep duration, and morningness-were chosen as instrumental variables to estimate the causal associations with T2DM. Summary statistics were acquired from the genome-wide association studies of UK Biobank and 23andMe (for sleep-related measures), the DIAbetes Genetics Replication And Meta-analysis and the FinnGen (for T2DM). Main Methods:Individual Cochran's Q statistic was applied to remove the pleiotropic instruments, global Q statistics and MR-Egger regression were adopted to test for the global heterogeneity and horizontal pleiotropy of the screened instruments, respectively. Two T2DM cohorts were selected to analyze their associations with sleep traits. A modified inverse variance weighted (IVW) estimate was performed to combine the ratio estimators from each instrument and acquire the causal estimate, alternative methods including IVW with first-order weights, simple and weighted median estimations, and MR-Egger regression were conducted as sensitivity analyses, to ensure the robustness and solidity of the findings. Results:Two-sample MR supported findings for an adverse effect of genetically predicted insomnia on T2DM risk (odds ratio [OR] = 1.14, 95% confidence interval [CI]: 1.09-1.19, = 1.29E-08) at the Bonferroni-adjusted level of significance ( < 0.005). We further investigated the causal role of T2DM on insomnia but obtained a non-significant estimation. There was also little evidence for the causal effect of other sleep-related measures on T2DM. Results were largely consistent when leveraging two different T2DM cohorts, and were robust among various sensitivity analyses. Conclusion:Findings provide significant evidence for an adverse effect of insomnia on T2DM risk. The study extends fundamental knowledge to further understanding of the pathophysiological mechanisms of T2DM, and points out the non-negligible role of insomnia on epidemiologic intervention and clinical therapeutics of T2DM. 10.3389/fgene.2020.607865
Genetic aetiology of blood pressure relates to aortic stiffness with bi-directional causality: evidence from heritability, blood pressure polymorphisms, and Mendelian randomization. European heart journal AIMS:Haemodynamic determinants of blood pressure (BP) include cardiac output (CO), systemic vascular resistance (SVR), and arterial stiffness. We investigated the heritability of these phenotypes, their association with BP-related single-nucleotide polymorphisms (SNPs), and the causal association between BP and arterial stiffness. METHODS AND RESULTS:We assessed BP, central BP components, and haemodynamic properties (during a single visit) including CO, SVR, and pulse wave velocity (PWV, measure of arterial stiffness) in 3531 (1934 monozygotic, 1586 dizygotic) female TwinsUK participants. Heritability was estimated using structural equation modelling. Association with 984 BP-associated SNP was examined using least absolute shrinkage and selection operator (LASSO) and generalized estimating equation regression. One and two-sample Mendelian randomization (MR) was used to estimate the causal direction between BP and arterial stiffness including data on 436 419 UK Biobank participants. We found high heritability for systolic and pulsatile components of BP (>50%) and PWV (65%) with overlapping genes accounting for >50% of their observed correlation. Environmental factors explained most of the variability of CO and SVR (>80%). Regression identified SNPs (n = 5) known to be associated with BP to also be associated with PWV. One-sample MR showed evidence of bi-directional causal association between BP and PWV in TwinsUK participants. Two-sample MR, confirmed a bi-directional causal effect of PWV on BP (inverse variance weighted (IVW) beta = 0.11, P < 0.02) and BP on arterial stiffness (IVW beta = 0.004, P < 0.0001). CONCLUSION:The genetic basis of BP is mediated not only by genes regulating BP but also by genes that influence arterial stiffness. Mendelian randomization indicates a bi-directional causal association between BP and arterial stiffness. 10.1093/eurheartj/ehaa238
Effect of linoleic acid on ischemic heart disease and its risk factors: a Mendelian randomization study. BMC medicine BACKGROUND:The role of n-6 polyunsaturated fatty acids (PUFAs) in ischemic heart disease (IHD) is controversial, and dietary guidelines vary. Observationally, lower saturated fat intake and higher intake of vegetable oils rich in linoleic acid (LA), the main n-6 PUFA, is associated with lower IHD and diabetes; however, randomized controlled trials have not fully corroborated these benefits. We assessed how genetically predicted LA affected IHD and its risk factors, including diabetes, lipids, and blood pressure. We also assessed the role of LA in reticulocyte count, the red blood cell precursor, which has recently been identified as a possible causal factor in IHD. METHODS:Two-sample instrumental variable analysis with genetic instruments, i.e., Mendelian randomization, was used to obtain unconfounded estimates using genetic variants strongly (p value < 5 × 10) and solely associated with LA, applied to an IHD case (n ≤ 76,014)-control (n ≤ 264,785) study (mainly based on the meta-analysis of CARDIoGRAMplusC4D 1000 Genomes and UK Biobank CAD SOFT GWAS), the DIAbetes Genetics Replication And Meta-analysis diabetes case (n = 26,676)-control (n = 132,532) study, lipids from the Global Lipids Genetics Consortium Results (n = 196,475), and reticulocyte count and blood pressure from the UK Biobank (n ≤ 361,194). A weighted median and Mendelian randomization Egger were used for sensitivity analysis. RESULTS:Genetically predicted LA was not associated with IHD or systolic blood pressure. Genetically predicted higher serum LA was associated with lower diabetes (odds ratio (OR) 0.97 per percentage in total fatty acid increase in LA, 95% confidence interval (CI) 0.96 to 0.99) and lower lipids (low-density lipoprotein, high-density lipoprotein, and total cholesterol), but may be associated with higher diastolic blood pressure. The findings were robust to different single nucleotide polymorphism (SNP) selections, analytic methods, and correction for multiple testing. CONCLUSIONS:Our novel study suggests a benefit of LA for diabetes and lipids but no benefit for IHD, blood pressure, or reticulocyte count. Explicating these paradoxical findings would facilitate identification of effective new interventions for diabetes and IHD. 10.1186/s12916-019-1293-x
Fat mass and fat-free mass in relation to cardiometabolic diseases: a two-sample Mendelian randomization study. Larsson S C,Burgess S Journal of internal medicine 10.1111/joim.13078
Associations of Arachidonic Acid Synthesis with Cardiovascular Risk Factors and Relation to Ischemic Heart Disease and Stroke: A Univariable and Multivariable Mendelian Randomization Study. Zhang Ting,Au Yeung Shiu-Lun,Schooling C Mary Nutrients Arachidonic acid (AA), a major long-chain omega-6 polyunsaturated fatty acid, is associated with ischemic heart disease (IHD) and stroke. We assessed bi-directional associations of AA synthesis reflected by plasma phospholipid AA with CVD risk factors, and identified mediators of associations of AA with IHD and stroke using Mendelian randomization (MR). We used two-sample MR to assess bi-directional associations of AA synthesis with lipids, blood pressure, adiposity, and markers of inflammation and coagulation. We used multivariable MR to assess mediators of associations of AA with IHD and stroke. Genetically predicted AA (% of total fatty acids increase) was positively associated with apolipoprotein B (ApoB, 0.022 standard deviations (SD), 95% confidence interval (CI) 0.010, 0.034), high-density (0.030 SD, 95% CI 0.012, 0.049) and low-density lipoprotein cholesterol (LDL-C, 0.016 SD, 95% CI 0.004, 0.027) and lower triglycerides (-0.031 SD, 95% CI -0.049, -0.012) but not with other traits. Genetically predicted these traits gave no association with AA. The association of AA with IHD was attenuated adjusting for ApoB or LDL-C. Genetically predicted AA was associated with lipids but not other traits. Given ApoB is thought to be the key lipid in IHD, the association of AA with IHD is likely mediated by ApoB. 10.3390/nu13051489
Causal effect of Lipoprotein-associated phospholipase A2 activity on coronary artery disease and myocardial Infarction: A Two-Sample Mendelian Randomization study. Clinica chimica acta; international journal of clinical chemistry BACKGROUND:Lipoprotein-associated phospholipase A2 (Lp-PLA2) activity has been reported to be associated with coronary artery disease (CAD) and myocardial infarction (MI). However, whether Lp-PLA2 is a causal risk factor for CAD and MI remains unclear. Herein, we performed a two-sample mendelian randomization (MR) study to assess the causal effect of Lp-PLA2 activity on CAD and MI. METHODS:We selected 7 single-nucleotide polymorphisms (SNPs) associated with Lp-PLA2 activity as instrumental variables based on the data from Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium with 13,664 European individuals. Summary data about CAD and MI were obtained from Coronary Artery Disease Genome-wide Replication and Meta-analysis plus the Coronary Artery Disease Genetics (CARDIOGRAMPLUSC4D) consortium with 60,801 CAD cases and 43,676 MI cases (mostly European). The inverse-variance weighted method was applied to assess the causal associations of Lp-PLA2 activity with CAD and MI in the main analysis. RESULTS:The main inverse-variance weighted (IVW) MR analysis showed that 1-SD increment in genetically determined LP-PLA2 activity was associated with increased risks of CAD (odds ratio, 5.93; 95% CI, 2.91-12.07; p value = 9.43 × 10) and MI (odds ratio, 4.71; 95% CI, 2.49-8.90; p value = 1.86 × 10). MR-Egger regression showed no evidence of pleiotropic bias. The causal associations were consistent in sensitivity analyses with multiple MR methods, in which showed Lp-PLA2 activity was causally associated with an increased risk of CAD and MI. CONCLUSIONS:In this two-sample MR study, high Lp-PLA2 activity was a causal risk factor for CAD and MI, indicating that Lp-PLA2 activity may be a promising intervention target in reducing the risk of CAD and MI. 10.1016/j.cca.2021.10.039
A Mendelian randomization study of the effect of calcium on coronary artery disease, myocardial infarction and their risk factors. Xu Lin,Lin Shi Lin,Schooling C Mary Scientific reports Meta-analyses of randomized controlled trials (RCTs) suggest calcium could have adverse effects on cardiovascular disease, although these findings are controversial. To clarify, we assessed whether people with genetically higher calcium had a higher risk of coronary artery disease (CAD), myocardial infarction (MI) and their risk factors. We used a two-sample Mendelian randomization study. We identified genetic variants (single nucleotide polymorphisms (SNPs)) that independently contributed to serum calcium at genome-wide significance which we applied to large extensively genotyped studies of CAD, MI, diabetes, lipids, glycaemic traits and adiposity to obtain unconfounded estimates, with body mass index (BMI) as a control outcome. Based on 4 SNPs each 1 mg/dl increase in calcium was positively associated with CAD (odds ratio (OR) 1.49, 95% confidence interval (CI) 1.02-2.17), MI (OR 1.58, 95% CI 1.06-2.35), LDL-cholesterol (0.21 standard deviations, 95% CI 0.01-0.4), total cholesterol (0.21 standard deviations, 95% CI 0.03-0.38) and possibly triglycerides (0.19 standard deviations, 95% CI -0.1-0.48), but was unlikely related to BMI although the estimate lacked precision. Sensitivity analysis using 13 SNPs showed a higher risk for CAD (OR 1.87, 95% CI 1.14-3.08). Our findings, largely consistent with the experimental evidence, suggest higher serum calcium may increase the risk of CAD. 10.1038/srep42691
A Causal Relationship between Vitamin C Intake with Hyperglycemia and Metabolic Syndrome Risk: A Two-Sample Mendelian Randomization Study. Antioxidants (Basel, Switzerland) Excessive oxidative stress can contribute to metabolic syndrome (MetS), and antioxidants can protect against its development. Vitamin C (VC) is a well-known antioxidant, and observational studies have associated a deficiency with an increased MetS risk. This study tested the hypothesis that dietary VC intake caused an inverse relation of MetS and its components risk using a two-sample Mendelian randomization (MR) method in adults ≥40 years in a city hospital-based (n = 58,701) and Ansan/Ansung plus rural (n = 13,598) cohorts. Independent genetic variants associated with dietary VC intake were explored using a genome-wide association study (GWAS) with significance levels of p < 5 × 10−5 and linkage disequilibrium (r2 threshold of 0.001), after adjusting for the covariates related to MetS, in a city hospital-based cohort (n = 52,676) excluding the participants having vitamin supplementation. MR methods, including inverse-variance weighting (IVW), weighted median, MR-Egger, and weighted model, were used to determine the causal relationship between the dietary VC intake and the risk of MetS and its components in Ansan/Ansung plus rural cohorts (n = 11,733). Heterogeneity and leave-one-out sensitivity analyses were conducted. Energy intake, as well as other nutrient intakes, were significantly lower in the low VC intake group than in the high VC intake group, but the incidence of MetS and its components, including hyperglycemia, hypertriglyceridemia, and hypertension, was observationally higher in inadequate low VC intake in the combined cohorts. In MR analysis, insufficient dietary VC intake increased the risk of MetS, hyperglycemia, hypertriglyceridemia, and hypertension in an IVW (p < 0.05). In contrast, only the serum fasting blood glucose concentration was significantly associated with VC intake in weight median analysis (p < 0.05), but there was no significant association of low dietary VC with MetS and its components in MR-Egger. There was no likelihood of heterogeneity and horizontal pleiotropy in MetS and its components. A single genetic variant did not affect their association in the leave-one-out sensitivity analysis. In conclusion, insufficient dietary VC intake potentially increased the MetS and hyperglycemia risk in Asian adults. Low VC intake can contribute to increasing type 2 diabetes incidence in Asians. 10.3390/antiox11050857
Low Intelligence Predicts Higher Risks of Coronary Artery Disease and Myocardial Infarction: Evidence From Mendelian Randomization Study. Yang Fangkun,Hu Teng,Chen Songzan,Wang Kai,Qu Zihao,Cui Hanbin Frontiers in genetics Low intelligence has been shown to be associated with a high risk of cardiovascular disease in observational studies. It remains unclear whether the association is causal. This study aimed to explore the causal association of intelligence with coronary artery disease (CAD) and myocardial infarction (MI). A two-sample Mendelian randomization study was designed to infer the causality. A total of 121 single nucleotide polymorphisms were selected as a genetic instrumental variable for intelligence. Summary data on CAD ( = 184,305) and MI ( = 171,875) were obtained from the Coronary ARtery DIsease Genome-wide Replication and Meta-analysis (CARDIoGRAM) plus The Coronary Artery Disease (C4D) Genetics (CARDIoGRAMplusC4D) consortium and the FinnGen study. Inverse variance weighting method was used to calculate the effect estimates. Sensitivity analyses including other statistical models and leave-one-out analysis were conducted to verify the robustness of results. MR-Egger test was performed to assess the pleiotropy. Genetically predicted higher intelligence was significantly associated with lower risk of CAD (OR, .76; 95%CI, .69-.85; = 1.5 × 10) and MI (OR, .78; 95%CI, .70-.87; = 7.9 × 10). The results remained consistent in the majority of the sensitivity analyses and were repeated in the FinnGen datasets. MR-Egger test suggested no evidence of directional pleiotropy for the association with coronary artery disease (intercept = -.01, = .19) and myocardial infarction (intercept = -.01, = .06). This Mendelian randomization analysis provided genetic evidence for the causal association between low intelligence and increased risks of CAD and MI. 10.3389/fgene.2022.756901
Associations Between Vitamin D Levels and Risk of Heart Failure: A Bidirectional Mendelian Randomization Study. Frontiers in nutrition Background:Although studies suggest that concentrations of serum 25-hydroxyvitamin D (25(OH)D) are lower in individuals with Heart Failure (HF), the beneficial effects of vitamin D supplementation are controversial. Therefore, in this study, we aimed to determine whether there is a causal relationship between serum Vitamin D (VD) levels and HF. Methods:We obtained genetic instruments from the largest available genome-wide association study (GWAS) of European descent for 25(OH)D (443, 734 individuals) to investigate the association with HF (47,309 cases, 930,014 controls), and vice versa. Two-sample bidirectional Mendelian Randomization (MR) analysis was performed to infer the causality. In addition to the primary analysis using inverse variance-weighted (IVW) MR, we applied five additional methods to control for pleiotropy [MR-Egger, weighted median, Maximum-likelihood, MR-robust adjusted profile score (MR-RAPS) and MR-pleiotropy residual sum and outlier (MR-PRESSO)] and compared their respective MR estimates. We also performed a sensitivity analysis to ensure that our results were robust. Results:Mendelian randomized analysis showed that increased serum 25(OH)D was associated with a lower risk of HF in the IVW method (odds ratio [OR] = 0. 81;95%CI, 0.70-0.94, = 0.006). In the reverse MR analyses, the genetic predisposition to HF was negatively correlated with serum 25(OH)D level (OR = 0. 89;95%CI, (0.82-0.97), = 0.009). Conclusion:Our study revealed the possible causal role of 25(OH)D on decreasing the risk for HF. Meanwhile, reverse MR analysis suggested that HF may be associated with lower vitamin D levels, it could be the potential implications for dietary recommendations. 10.3389/fnut.2022.910949
Blood pressure and risk of venous thromboembolism: a cohort analysis of 5.5 million UK adults and Mendelian randomization studies. Cardiovascular research AIMS:Evidence for the effect of elevated blood pressure (BP) on the risk of venous thromboembolism (VTE) has been conflicting. We sought to assess the association between systolic BP and the risk of VTE. METHODS AND RESULTS:Three complementary studies comprising an observational cohort analysis, a one-sample and two-sample Mendelian randomization were conducted using data from 5 588 280 patients registered in the Clinical Practice Research Datalink (CPRD) dataset and 432 173 UK Biobank participants with valid genetic data. Summary statistics of International Network on Venous Thrombosis genome-wide association meta-analysis was used for two-sample Mendelian randomization. The primary outcome was the first occurrence of VTE event, identified from hospital discharge reports, death registers, and/or primary care records. In the CPRD cohort, 104 017(1.9%) patients had a first diagnosis of VTE during the 9.6-year follow-up. Each 20 mmHg increase in systolic BP was associated with a 7% lower risk of VTE [hazard ratio: 0.93, 95% confidence interval (CI): (0.92-0.94)]. Statistically significant interactions were found for sex and body mass index, but not for age and subtype of VTE (pulmonary embolism and deep venous thrombosis). Mendelian randomization studies provided strong evidence for the association between systolic BP and VTE, both in the one-sample [odds ratio (OR): 0.69, (95% CI: 0.57-0.83)] and two-sample analyses [OR: 0.80, 95% CI: (0.70-0.92)]. CONCLUSION:We found an increased risk of VTE with lower BP, and this association was independently confirmed in two Mendelian randomization analyses. The benefits of BP reduction are likely to outweigh the harms in most patient groups, but in people with predisposing factors for VTE, further BP reduction should be made cautiously. 10.1093/cvr/cvac135
Systemic lupus erythematosus and the risk of cardiovascular diseases: A two-sample Mendelian randomization study. Frontiers in cardiovascular medicine Background:Previous observational studies have suggested that the causal role of systemic lupus erythematosus (SLE) in the risk of cardiovascular diseases (CVDs) remained inconsistent. In this study, we aimed to investigate the causal relationship between SLE and CVDs by two-sample Mendelian randomization (MR) analysis. Methods:Genetic instruments for SLE were obtained from a public genome-wide association study (GWAS) with 4,036 patients with SLE and 6,959 controls. Summary statistical data for CVDs, including coronary artery disease (CAD), myocardial infarction (MI), atrial fibrillation (AF), ischemic stroke (IS), and its subtypes, were identified from other available GWAS meta-analyses. The inverse-variance weighted (IVW) method was used as the primary method to estimate the causal effect. The simple- and weighted-median method, MR-Egger method, and MR pleiotropy residual sum and outlier (MR-PRESSO) were provided as a supplement to the IVW method. Besides, we performed sensitivity analyses, including Cochran's Q test, MR-Egger intercept test, and leave-one-out analysis, to evaluate the robustness of the results. Results:A total of 15 single-nucleotide polymorphisms (SNPs) were identified after excluding linkage disequilibrium (LD) and potential confounding factors. According to the IVW results, our MR study indicated that genetically predicted SLE was not causally connected with the risk of CVDs [CAD: odds ratio (OR) = 1.005, 95% confidence interval (CI) = 0.986-1.024, -value = 0.619; MI: OR = 1.002, 95% CI = 0.982-1.023, -value = 0.854; AF: OR = 0.998, 95% CI = 0.982-1.014, -value = 0.795; IS: OR = 1.006, 95% CI = 0.984-1.028, -value = 0.621; cardioembolic stroke (CES): OR = 0.992, 95% CI = 0.949-1.036, -value = 0.707; small vessel stroke (SVS): OR = 1.014, 95% CI = 0.964-1.067, -value = 0.589; large artery stroke (LAS): OR = 1.030, 95% CI = 0.968-1.096, -value = 0.352]. Analogical findings could be observed in supplementary MR methods. Sensitivity analyses suggested that the causal estimates were robust. Conclusion:Our two-sample MR analysis provided no evidence that genetically determined SLE was causally associated with the risk of CVDs. 10.3389/fcvm.2022.896499
Mendelian randomization of blood lipids for coronary heart disease. European heart journal AIMS:To investigate the causal role of high-density lipoprotein cholesterol (HDL-C) and triglycerides in coronary heart disease (CHD) using multiple instrumental variables for Mendelian randomization. METHODS AND RESULTS:We developed weighted allele scores based on single nucleotide polymorphisms (SNPs) with established associations with HDL-C, triglycerides, and low-density lipoprotein cholesterol (LDL-C). For each trait, we constructed two scores. The first was unrestricted, including all independent SNPs associated with the lipid trait identified from a prior meta-analysis (threshold P < 2 × 10(-6)); and the second a restricted score, filtered to remove any SNPs also associated with either of the other two lipid traits at P ≤ 0.01. Mendelian randomization meta-analyses were conducted in 17 studies including 62,199 participants and 12,099 CHD events. Both the unrestricted and restricted allele scores for LDL-C (42 and 19 SNPs, respectively) associated with CHD. For HDL-C, the unrestricted allele score (48 SNPs) was associated with CHD (OR: 0.53; 95% CI: 0.40, 0.70), per 1 mmol/L higher HDL-C, but neither the restricted allele score (19 SNPs; OR: 0.91; 95% CI: 0.42, 1.98) nor the unrestricted HDL-C allele score adjusted for triglycerides, LDL-C, or statin use (OR: 0.81; 95% CI: 0.44, 1.46) showed a robust association. For triglycerides, the unrestricted allele score (67 SNPs) and the restricted allele score (27 SNPs) were both associated with CHD (OR: 1.62; 95% CI: 1.24, 2.11 and 1.61; 95% CI: 1.00, 2.59, respectively) per 1-log unit increment. However, the unrestricted triglyceride score adjusted for HDL-C, LDL-C, and statin use gave an OR for CHD of 1.01 (95% CI: 0.59, 1.75). CONCLUSION:The genetic findings support a causal effect of triglycerides on CHD risk, but a causal role for HDL-C, though possible, remains less certain. 10.1093/eurheartj/eht571
Genomics of hypertension: the road to precision medicine. Nature reviews. Cardiology The known genetic architecture of blood pressure now comprises >30 genes, with rare variants resulting in monogenic forms of hypertension or hypotension and >1,477 common single-nucleotide polymorphisms (SNPs) being associated with the blood pressure phenotype. Monogenic blood pressure syndromes predominantly involve the renin-angiotensin-aldosterone system and the adrenal glucocorticoid pathway, with a smaller fraction caused by neuroendocrine tumours of the sympathetic and parasympathetic nervous systems. The SNPs identified in genome-wide association studies (GWAS) as being associated with the blood pressure phenotype explain only approximately 27% of the 30-50% estimated heritability of blood pressure, and the effect of each SNP on the blood pressure phenotype is small. A paucity of SNPs from GWAS are mapped to known genes causing monogenic blood pressure syndromes. For example, a GWAS signal mapped to the gene encoding uromodulin has been shown to affect blood pressure by influencing sodium homeostasis, and the effects of another GWAS signal were mediated by endothelin. However, the majority of blood pressure-associated SNPs show pleiotropic associations. Unravelling these associations can potentially help us to understand the underlying biological pathways. In this Review, we appraise the current knowledge of blood pressure genomics, explore the causal pathways for hypertension identified in Mendelian randomization studies and highlight the opportunities for drug repurposing and pharmacogenomics for the treatment of hypertension. 10.1038/s41569-020-00466-4
Association of cannabis use disorder with cardiovascular diseases: A two-sample Mendelian randomization study. Frontiers in cardiovascular medicine Background:The use of cannabis has increased globally due to more regions decriminalizing marijuana use for therapeutic and recreational aims. Several observational studies have revealed that cannabis use is associated with an increased risk of adverse cardiovascular pathologies and diseases. Nevertheless, the causal associations between cannabis use and cardiovascular diseases remain unclear. Hence, we performed single-variable and multivariable Mendelian randomization (MR) to evaluate the association between cannabis use disorder and various cardiovascular diseases. Materials and methods:Summary statistics were collected from the largest-to-date genome-wide association studies (GWAS) of cannabis use disorder. The 12 SNPs for cannabis use disorder were used as instrumental variables in this study. MR estimates were pooled using a random-effects inverse-variance weighted (IVW) method. Simple median and weighted median methods were conducted as sensitivity analyses. Results:The genetic liability to cannabis use disorder was associated with an augmented risk of coronary artery disease, myocardial infarction, atrial fibrillation, heart failure, deep venous thrombosis, pulmonary embolism, and stroke. Except for stroke, the results were inconsistent in the sensitivity analyses. The overall patterns for the associations of cannabis use disorder with atrial fibrillation, heart failure, pulmonary embolism and stroke remained in multivariable MR analyses adjusting for potential mediators, including smoking, alcohol, body mass index, blood lipid, type 2 diabetes, hypertension, and depression. However, the association with coronary artery disease, myocardial infarction, and deep venous thrombosis did not persist in multivariable MR analyses. Mediation analysis demonstrated that smoking, body mass index, low-density lipoprotein, hypertension, and depression have more significant mediation effects, which suggests that these factors partly mediate the link from cannabis use disorder to coronary artery disease, myocardial infarction, and deep venous thrombosis. Conclusion:The genetic liability to cannabis use disorder was associated with a higher risk of atrial fibrillation, heart failure, pulmonary embolism, and stroke. The evidence for the association between cannabis use disorder, coronary artery disease, myocardial infarction, and deep venous thrombosis was weak. Hence, future use of cannabis for therapeutic and recreational aims should consider its potential impact on cardiovascular diseases. 10.3389/fcvm.2022.966707
The Association between Blood Lipids and Systemic Lupus Erythematosus: A Two-Sample Mendelian Randomization Research. Metabolites We evaluated the causal effects of blood lipid levels on systemic lupus erythematosus with a two-sample Mendelian randomization analysis. Independent single-nucleotide polymorphisms related to blood lipids levels (p < 5 × 10−8) were selected as instrumental variables (IVs) from a published genome-wide association study (GWAS). SLE GWAS analysis that included 4036 cases and 6959 controls of European ancestry provided the related roles between instrumental variables and result (SLE). The causal effects were evaluated with two-sample Mendelian randomization (MR) analyses. According to the inverse-variance weighted approaches, genes predictive of increased LDL cholesterol (OR: 1.131; 95% CI: 0.838, 1.528; p = 0.420), HDL cholesterol (OR: 1.093; 95% CI: 0.884, 1.352; p = 0.412), triglycerides (OR: 0.903; 95% CI: 0.716, 1.137; p = 0.384), Apolipoprotein A-I (OR: 0.854; 95% CI: 0.680, 1.074; p = 0.177), and Apolipoprotein B (OR: 0.933; 95% CI: 0.719, 1.211; p = 0.605) were not causally related to the risk of SLE, consistent with multivariate Mendelian randomization analysis. The reverse-MR analyses showed no massive causal roles between SLE and LDL cholesterol (OR: 0.998; 95% CI: 0.994, 1.001; p = 0.166) as well as Apolipoprotein B (OR: 0.998; 95% CI: 0.994, 1.001; p = 0.229). Nevertheless, a causal role of SLE in decreasing HDL cholesterol (OR: 0.993; 95% CI: 0.988, 0.997; p = 0.002), triglycerides (OR: 0.996; 95% CI: 0.993, 0.999; p = 0.010), and Apolipoprotein A-I (OR: 0.995; 95% CI: 0.990, 0.999; p = 0.026) was validated to some extent. Our study found no causal association between abnormal blood lipids and SLE nor a causal effect between SLE and LDL cholesterol as well as Apolipoprotein B. Nevertheless, some evidence showed that SLE exerted a causal effect on lowering HDL cholesterol, Apolipoprotein A-I, and triglyceride levels. 10.3390/metabo13010027
A putative causality of vitamin D in common diseases: A mendelian randomization study. Frontiers in nutrition Backgrounds:Vitamin D is considered as a nutrient protecting individuals against an array of diseases based on observational studies. Such a protective effect, however, has not been demonstrated by randomized controlled trials. This study aims to explore a putative causal role of vitamin D in common diseases through a two-sample Mendelian randomization (MR) framework. Methods:Circulating vitamin D was predicted by 41 genetic variants discovered in European populations. Common diseases were verified through two ways, using information from Japanese patients of Biobank Japan and using information from European patients of FinnGen project. We additionally validated the results by replacing vitamin D-associated instrumental variables (IVs) of European population with that of an independent Japanese population and of an independent Indian population. Inverse-variance weighted method was used as the primary analytical approach while a series of MR methods including MR-Egger regression, weighted median, maximum likelihood, MR-PRESSO and multivariate MR were adopted to guarantee MR model assumptions and to detect horizontal pleiotropy. Results:Genetically predicted vitamin D was significantly associated with an increased risk of Graves' disease (OR = 1.71, 95%CI: 1.25-2.33, = 0.001) and cataract (OR = 1.14, 95%CI: 1.03-1.28, = 0.016); while with a decreased risk of esophageal cancer (OR = 0.66, 95%CI: 0.46-0.93, = 0.019). This significant causal link between vitamin D and cataract was validated replacing IVs identified in the European population with those from Japanese population. No notable associations of vitamin D with other diseases were observed. Conclusions:Our findings indicate a potential causal role of vitamin D in common diseases, which needs further validation. 10.3389/fnut.2022.938356
Birthweight, BMI in adulthood and latent autoimmune diabetes in adults: a Mendelian randomisation study. Diabetologia AIMS/HYPOTHESIS:Observational studies have found an increased risk of latent autoimmune diabetes in adults (LADA) associated with low birthweight and adult overweight/obese status. We aimed to investigate whether these associations are causal, using a two-sample Mendelian randomisation (MR) design. In addition, we compared results for LADA and type 2 diabetes. METHODS:We identified 43 SNPs acting through the fetal genome as instrumental variables (IVs) for own birthweight from a genome-wide association study (GWAS) of the Early Growth Genetics Consortium (EGG) and the UK Biobank. We identified 820 SNPs as IVs for adult BMI from a GWAS of the UK Biobank and the Genetic Investigation of ANthropometric Traits consortium (GIANT). Summary statistics for the associations between IVs and LADA were extracted from the only GWAS involving 2634 cases and 5947 population controls. We used the inverse-variance weighted (IVW) estimator as our primary analysis, supplemented by a series of sensitivity analyses. RESULTS:Genetically determined own birthweight was inversely associated with LADA (OR per SD [~500 g] decrease in birthweight 1.68 [95% CI 1.01, 2.82]). In contrast, genetically predicted BMI in adulthood was positively associated with LADA (OR per SD [~4.8 kg/m] increase in BMI 1.40 [95% CI 1.14, 1.71]). Robust results were obtained in a range of sensitivity analyses using other MR estimators or excluding some IVs. With respect to type 2 diabetes, the association with birthweight was not stronger than in LADA while the association with adult BMI was stronger than in LADA. CONCLUSIONS/ INTERPRETATION:This study provides genetic support for a causal link between low birthweight, adult overweight/obese status and LADA. 10.1007/s00125-022-05725-2
Effect of Basal Metabolic Rate on Cancer: A Mendelian Randomization Study. Ng Jack C M,Schooling C Mary Frontiers in genetics Basal metabolic rate is associated with cancer, but these observations are open to confounding. Limited evidence from Mendelian randomization studies exists, with inconclusive results. Moreover, whether basal metabolic rate has a similar role in cancer for men and women independent of insulin-like growth factor 1 increasing cancer risk has not been investigated. We conducted a two-sample Mendelian randomization study using summary data from the UK Biobank to estimate the causal effect of basal metabolic rate on cancer. Overall and sex-specific analysis and multiple sensitivity analyses were performed including multivariable Mendelian randomization to control for insulin-like growth factor 1. We obtained 782 genetic variants strongly (-value < 5 × 10) and independently ( < 0.01) predicting basal metabolic rate. Genetically predicted higher basal metabolic rate was associated with an increase in cancer risk overall (odds ratio, 1.06; 95% confidence interval, 1.02-1.10) with similar estimates by sex (odds ratio for men, 1.07; 95% confidence interval, 1.002-1.14; odds ratio for women, 1.06; 95% confidence interval, 0.995-1.12). Sensitivity analyses including adjustment for insulin-like growth factor 1 showed directionally consistent results. Higher basal metabolic rate might increase cancer risk. Basal metabolic rate as a potential modifiable target of cancer prevention warrants further study. 10.3389/fgene.2021.735541
Causal associations of obstructive sleep apnea with cardiovascular disease: a Mendelian randomization study. Sleep STUDY OBJECTIVES:Obstructive sleep apnea (OSA) had been associated with various cardiovascular diseases (CVDs) in observational studies, but causal inferences have not been confirmed. We used the Mendelian randomization (MR) study to explore the potential causal association between OSA with CVDs in the general population. METHODS:We performed a two-sample MR analysis using five gene-wide significant single-nucleotide polymorphisms associated with OSA at genome-wide significance from the FinnGen study (N = 217 955) and 12 cardiovascular diseases from the UK Biobank and the genetic consortia. The inverse-variance weight was chosen as the primary analysis and was complemented by various sensitivity analyses. The study design applied univariable MR, multivariable MR, and mediation analysis. RESULTS:MR analyses provide evidence of genetically predicted OSA on the risk of heart failure (odds ratio [OR],1.26; 95% confidence interval [CI],1.08 to 1.47), hypertension (OR,1.24; 95%CI, 1.11 to 1.39) and atrial fibrillation (OR,1.21; 95%CI,1.12 to 1.31). Multivariable MR indicated the adverse effect of OSA on heart failure persisted after adjusting BMI, smoking, drinking, and education (IVW OR,1.13; 95%CI, 1.01 to 1.27). However, the significance of hypertension and atrial fibrillation was dampened. Mediation analyses suggest that the causal association between OSA and heart failure is mediated in part by Apolipoprotein B, with a mediated portion of 9%. CONCLUSIONS:This study suggested that genetically predicted OSA is a potential causal risk factor for heart failure based on a large-scale population. Nevertheless, further studies regarding ancestral diversity are needed to confirm the causal association between OSA and CVDs. 10.1093/sleep/zsac298
Inflammatory bowel disease and cardiovascular disease: A two-sample Mendelian randomization analysis. Frontiers in cardiovascular medicine Background:Although epidemiological studies have shown a positive relationship between inflammatory bowel disease (IBD) and risk of cardiovascular disease (CVD) outcomes, a solid causal relationship has not been established. Thus, a two-sample Mendelian randomization (MR) study was conducted to explore the potential causal effect between IBD and CVD outcomes. Methods:We performed a two-sample MR analysis to analyze the causal effect of the IBD on CVD outcome by using summary-level genome-wide association studies of European descent. The inverse-variance weighted (IVW) method was used as the main MR analysis, with complementary analyses of MR Egger, maximum likelihood, weighted median, penalized weighted media, simple mode, weighted mode, and MR-PRESSO methods. Multiple sensitivity analyses were used to evaluate the robustness of our results. Results:All -values were greater than 0.05 in the IVW method, showing no evidence of a causal association between circulating IBD and CVD. Similar results were observed by using other MR methods. No evidence of heterogeneity, pleiotropy, or outlier single-nucleotide polymorphisms was detected. Sensitivity analyses demonstrated the robustness of the results. Conclusion:The findings of this study provided no evidence to support that IBD has a large effect on risk of CVD outcomes, which is in contrast to many previous observational reports. Further studies are needed to determine the potential mechanism of association identified in observational studies. 10.3389/fcvm.2022.927120
COVID-19 is associated with the risk of cardiovascular disease death: A two-sample Mendelian randomization study. Frontiers in cardiovascular medicine Objective:This study aimed to estimate the causal effects of Coronavirus disease 2019 susceptibility and hospitalization on cardiovascular disease death using two-sample Mendelian randomization analysis. Methods:We used statistics from a genome-wide association study. A total of 2,568,698 participants were assessed in this study, including 1,299,010 in Coronavirus disease 2019 susceptibility databases, 908,494 in Coronavirus disease 2019 hospitalization database, and 361,194 in a cardiovascular disease death database. We performed two-sample Mendelian randomization analysis using the inverse variance weighted method. As sensitivity analysis techniques, Mendelian randomization-Egger regression, heterogeneity analyses, and Leave-one-out analysis were employed. Reverse Mendelian randomization analysis was used to detect reverse causality. Statistical significance was defined as < 0.05. Results:Coronavirus disease 2019 susceptibility may be a causal factor for cardiovascular disease death (β = 2.188 × 10, = 0.002), which involves five common single nucleotide polymorphisms. Similarly, Coronavirus disease 2019 hospitalization may also be a causal factor for cardiovascular disease death (β = 8.626 × 10, = 0.010), which involves nine common single nucleotide polymorphisms. Furthermore, sensitivity and reverse Mendelian randomization analysis suggested that no heterogeneity, horizontal pleiotropy or reverse causality was found between Coronavirus disease 2019 and cardiovascular disease death. Conclusion:Our bidirectional Mendelian randomization analysis showed a causal relationship between Coronavirus disease 2019 susceptibility and hospitalization associated with an increased risk of cardiovascular disease death. 10.3389/fcvm.2022.974944
Age at menarche and ischemic heart disease: An update mendelian randomization study. Frontiers in genetics Although earlier menarche age has been associated with ischemic heart disease in previous observational studies, the relationship's causation has not been shown. Through two-sample Mendelian randomization (MR), we were able to define the causal connection. We performed Mendelian Randomization (MR) analysis to explore the associations between genetically predicted AAM and IHD. Summary-level databases for exposure and outcome were selected from the MR-Base database (https://gwas.mrcieu.ac.uk/). Single-nucleotide polymorphisms (SNPs) connected to AAM at genome-wide significance level ( < 5 × 10) were considered as instrumental variables (IVs). We used four methods to pool MR estimates, including fixed-effects inverse variance weighting (fe-IVW), multiplicative random-effects inverse variance weighting (mre-IVW), weighted median (WM), and MR-Egger regression methods. Sensitivity analyses were performed to evaluate the robustness of the results. PhenoScanner searches and Multivariable Mendelian randomization (MVMR) analysis was used for assessing confounders. 117 SNPs significantly correlated with AAM were screened as instruments, the results of three main methods showed that genetically earlier AAM may have a causal effect on the higher risk of IHD (fe-IVW: OR = 0.80, 95% CI: 0.72-0.88, < 0.001; mre-IVW: OR = 0.80, 95% CI: 0.70-0.90, < 0.001; WE: OR = 0.79, 95% CI: 0.66-0.93, = 0.006). These results were consistent across sensitivity analyses. MR analysis revealed that there was still a relationship between AAM and IHD even when pleiotropic SNPs of confounders were removed employing PhenoScanner searches. In MVMR, the significant association remained after adjusting for biological sex, but it was attenuated with adjustment of body mass index including childhood and adult. Our MR analysis revealed a substantial genetically determined confounder-mediated relationship between an increase in genetically predicted AAM and a lower risk of IHD. By addressing the intervention of body mass index, the risk of IHD may be lowered. 10.3389/fgene.2022.942861
Telomere length and metabolic syndrome traits: A Mendelian randomisation study. Loh Nellie Y,Noordam Raymond,Christodoulides Constantinos Aging cell Observational studies have revealed associations between short leucocyte telomere length (LTL), a TL marker in somatic tissues and multiple Metabolic Syndrome (MetS) traits. Animal studies have supported these findings by showing that increased telomere attrition leads to adipose tissue dysfunction and insulin resistance. We investigated the associations between genetically instrumented LTL and MetS traits using Mendelian Randomisation (MR). Fifty-two independent variants identified at FDR<0.05 from a genome-wide association study (GWAS) including 78,592 Europeans and collectively accounting for 2.93% of LTL variance were selected as genetic instruments for LTL. Summary-level data for MetS traits and for the MetS as a binary phenotype were obtained from the largest publicly available GWAS and two-sample MR analyses were used to estimate the associations of LTL with these traits. The combined effect of the genetic instruments was modelled using inverse variance weighted regression and sensitivity analyses with MR-Egger, weighted-median and MR-PRESSO were performed to test for and correct horizonal pleiotropy. Genetically instrumented longer LTL was associated with higher waist-to-hip ratio adjusted for body mass index (β = 0.045 SD, SE = 0.018, p = 0.01), raised systolic (β = 1.529 mmHg, SE = 0.332, p = 4x10 ) and diastolic (β = 0.633 mmHg, SE = 0.222, p = 0.004) blood pressure, and increased MetS risk (OR = 1.133, 95% CI 1.057-1.215). Consistent results were obtained in sensitivity analyses, which provided no evidence of unbalanced horizontal pleiotropy. Telomere shortening might not be a major driver of cellular senescence and dysfunction in human adipose tissue. Future experimental studies should examine the mechanistic bases for the links between longer LTL and increased upper-body fat distribution and raised blood pressure. 10.1111/acel.13445
Bidirectional two-sample Mendelian randomization study of causality between rheumatoid arthritis and myocardial infarction. Frontiers in immunology Background:Epidemiological evidence suggests an association between rheumatoid arthritis (RA) and myocardial infarction (MI). However, causality remains uncertain. Therefore, this study aimed to explore the causal association between RA and MI. Methods:Using publicly available genome-wide association study summary datasets, bidirectional two-sample Mendelian randomization (TSMR) was performed using inverse-variance weighted (IVW), weighted median, MR-Egger regression, simple mode, and weighted mode methods. Results:The MR results for the causal effect of RA on MI (IVW, odds ratio [OR] = 1.041, 95% confidence interval [CI]: 1.007-1.076, = 0.017; weighted median, OR = 1.027, 95% CI: 1.006-1.049, = 0.012) supported a causal association between genetic susceptibility to RA and an increased risk of MI. MR results for the causal effect of MI on RA (IVW, OR = 1.012, 95% CI: 0.807-1.268, = 0.921; weighted median, OR = 1.069, 95% CI: 0.855-1.338, = 0.556) indicated that there was no causal association between genetic susceptibility to MI and an increased risk of RA. Conclusion:Bidirectional TSMR analysis supports a causal association between genetic susceptibility to RA and an increased risk of MI but does not support a causal association between genetic susceptibility to MI and an increased risk of RA. 10.3389/fimmu.2022.1017444
Inflammation and heart failure: a two-sample Mendelian randomization study. Journal of cardiovascular medicine (Hagerstown, Md.) BACKGROUND:It is hypothesized that inflammation leads to heart failure. Results from observational studies thus far have been inconsistent and it is unclear whether inflammation is causally associated with new-onset heart failure. Mendelian randomization analyses are less prone to biases common in observational studies such as reverse causation and unmeasured confounding. The aim of this study was to investigate the causal relation between various inflammatory biomarkers with risk of new-onset heart failure by using a two-sample Mendelian randomization approach. METHODS:Ten inflammatory biomarkers with available genome-wide association studies (GWAS) among individuals of European ancestry were identified and included C-reactive protein (CRP), immunoglobulin E, tumour necrosis factor (TNF), toll-like receptor 4, interleukin 1 receptor antagonist, interleukin 2 receptor subunit α, interleukin 6 receptor subunit α, interleukin 16, 17 and 18. For the associations between the identified SNPs and heart failure, we used the largest GWAS meta-analysis performed by the Heart Failure Molecular Epidemiology for Therapeutic Targets Consortium with 47 309 participants with heart failure and 930 014 controls. For our main analyses, we used the inverse-variance weighted method. RESULTS:We included 63 SNPs. CRP, TNF, interleukin 2, 16 and 18 were not associated with heart failure with odds ratios (ORs) of 1.01 [95% confidence interval (95% CI: 0.94-1.09), 1.11 (95% CI: 0.80-1.48), 0.97 (95% CI: 0.93-1.02), 0.99 (95% CI: 0.96-1.03) and 1.01 (95% CI: 0.97-1.06), respectively. The other biomarkers were also not associated with the risk of heart failure and suffered from weak instrument bias. CONCLUSION:This Mendelian randomization study could not determine a causal relationship between inflammation and risk of heart failure. However, some biomarkers suffered from weak instrument bias. 10.2459/JCM.0000000000001373
The relationship between processed meat, red meat, and risk of types of cancer: A Mendelian randomization study. Frontiers in nutrition Background:Observational studies have suggested processed and red meat may increase the risk of cancer. However, the causal effects and direction between them were still unclear. We conducted two-sample Mendelian randomization (MR) analysis to evaluate the causal effect of processed meat and red meat on the risk of nine common types of cancer, namely, lung, ovarian, endometrial, breast, kidney, gastric, prostate, skin, and oropharyngeal cancer. Methods:Genome-wide association studies (GWAS) for processed meat and red meat (pork, beef, and mutton) were obtained from the UK Biobank. GWAS of types of cancer in this study were extracted from the genetic consortia and the FinnGen consortium. The inverse variance weighted (IVW) was carried out as the main method for two-sample MR analysis. Sensitivity analyses were used to assess the robustness of the results. Results:Genetically predicted processed meat intake was causally associated with increased risk of lung cancer (OR [odds ratio] = 1.923, 95% CI = 1.084-3.409, = 0.025). There is no convincing evidence for the associations between genetically determined processed meat, red meat, and the risk of other cancers we studied. Conclusion:Our results suggested that intake of processed meat may increase the risk of lung cancer. These findings provided no evidence to support that consumption of processed and red meat has a large effect on the risk of other cancers we studied. Further research is needed to clarify the results. 10.3389/fnut.2022.942155
Assessment of causal association between thyroid function and lipid metabolism: a Mendelian randomization study. Wang Jing-Jia,Zhuang Zhen-Huang,Shao Chun-Li,Yu Can-Qing,Wang Wen-Yao,Zhang Kuo,Meng Xiang-Bin,Gao Jun,Tian Jian,Zheng Ji-Lin,Huang Tao,Tang Yi-Da Chinese medical journal BACKGROUND:Thyroid dysfunction is associated with cardiovascular diseases. However, the role of thyroid function in lipid metabolism remains partly unknown. The present study aimed to investigate the causal association between thyroid function and serum lipid metabolism via a genetic analysis termed Mendelian randomization (MR). METHODS:The MR approach uses a genetic variant as the instrumental variable in epidemiological studies to mimic a randomized controlled trial. A two-sample MR was performed to assess the causal association, using summary statistics from the Atrial Fibrillation Genetics Consortium (n = 537,409) and the Global Lipids Genetics Consortium (n = 188,577). The clinical measures of thyroid function include thyrotropin (TSH), free triiodothyronine (FT3) and free thyroxine (FT4) levels, FT3:FT4 ratio and concentration of thyroid peroxidase antibodies (TPOAb). The serum lipid metabolism traits include total cholesterol (TC) and triglycerides, high-density lipoprotein, and low-density lipoprotein (LDL) levels. The MR estimate and MR inverse variance-weighted method were used to assess the association between thyroid function and serum lipid metabolism. RESULTS:The results demonstrated that increased TSH levels were significantly associated with higher TC (β = 0.052, P = 0.002) and LDL (β = 0.041, P = 0.018) levels. In addition, the FT3:FT4 ratio was significantly associated with TC (β = 0.240, P = 0.033) and LDL (β = 0.025, P = 0.027) levels. However, no significant differences were observed between genetically predicted FT4 and TPOAb and serum lipids. CONCLUSION:Taken together, the results of the present study suggest an association between thyroid function and serum lipid metabolism, highlighting the importance of the pituitary-thyroid-cardiac axis in dyslipidemia susceptibility. 10.1097/CM9.0000000000001505
The Association of Hyperuricemia and Gout With the Risk of Cardiovascular Diseases: A Cohort and Mendelian Randomization Study in UK Biobank. Frontiers in medicine Background:The association between hyperuricemia/gout with cardiovascular diseases (CVD) have been investigated. However, whether the magnitude of associations differs between hyperuricemia and gout, and the causality of these associations, remains inconclusive. Methods:Based on UK Biobank, we conducted a cohort analysis including 431,967 participants, who were categorized as gout, hyperuricemia, and normal groups at recruitment, and followed up for CVD until December 2019. The phenotypic association of hyperuricemia/gout with CVD was estimated by Cox regression, adjusting for multiple confounders. Further exploration on the causality of such links was performed using Mendelian Randomization (MR) analysis, where we selected exclusive genetic variants for hyperuricemia and for gout based on summary GWAS data from independent populations. Results:During mean 10.20 years of follow-up, hyperuricemia patients were associated with increased CVD (HR = 1.33, 95% CI: 1.29-1.36), compared to individuals who were free of hyperuricemia/gout. The risk elevation was even higher for gout patients (HR = 1.54, 95% CI: 1.48-1.62). Furthermore, we found significantly positive association between genetic liability for hyperuricemia and CVD in both one-sample (OR = 1.06, 95% CI: 1.02-1.11) and two-sample (OR = 1.09, 95% CI: 1.03-1.16) MR analysis. However, genetic liability for gout was not associated with CVD (OR = 0.89, 95% CI: 0.79-1.01 in one-sample, and OR = 0.92, 95% CI: 0.82-1.21 in two-sample MR analysis). Conclusion:Individuals with hyperuricemia/gout were at increased risk of various types of CVD. As the MR analyses suggest a causal effect of hyperuricemia, but not gout, on CVD, these results indicate the possible effects of other gout-associated factors on the development of CVD, in addition to the uric acid pathway. 10.3389/fmed.2021.817150
Lung function and cardiovascular disease: a two-sample Mendelian randomisation study. Higbee Daniel H,Granell Raquel,Sanderson Eleanor,Davey Smith George,Dodd James W The European respiratory journal BACKGROUND:Observational studies suggest an association between reduced lung function and risk of coronary artery disease and ischaemic stroke, independent of shared cardiovascular risk factors such as cigarette smoking. We use the latest genetic epidemiological methods to determine whether impaired lung function is causally associated with an increased risk of cardiovascular disease. METHODS AND FINDINGS:Mendelian randomisation uses genetic variants as instrumental variables to investigate causation. Preliminary analysis used two-sample Mendelian randomisation with lung function single nucleotide polymorphisms. To avoid collider bias, the main analysis used single nucleotide polymorphisms for lung function identified from UKBiobank in a multivariable Mendelian randomisation model conditioning for height, body mass index and smoking.Multivariable Mendelian randomisation shows strong evidence that reduced forced vital capacity (FVC) causes increased risk of coronary artery disease (OR 1.32, 95% CI 1.19-1.46 per standard deviation). Reduced forced expiratory volume in 1 s (FEV) is unlikely to cause increased risk of coronary artery disease, as evidence of its effect becomes weak after conditioning for height (OR 1.08, 95% CI 0.89-1.30). There is weak evidence that reduced lung function increases risk of ischaemic stroke. CONCLUSION:There is strong evidence that reduced FVC is independently and causally associated with coronary artery disease. Although the mechanism remains unclear, FVC could be taken into consideration when assessing cardiovascular risk and considered a potential target for reducing cardiovascular events. FEV and airflow obstruction do not appear to cause increased cardiovascular events; confounding and collider bias may explain previous findings of a causal association. 10.1183/13993003.03196-2020
Lack of bidirectional association between age-related macular degeneration and Alzheimer's disease: A Mendelian randomization study. Alzheimer's & dementia : the journal of the Alzheimer's Association INTRODUCTION:Observational studies have reported inconsistent results on the relationship between age-related macular degeneration (AMD) and Alzheimer's disease (AD). Therefore, we aimed to determine whether there is a causal association between AMD and AD. METHODS:This two-sample bidirectional Mendelian randomization (MR) study evaluated causal associations between advanced AMD and AD using summary data from large genome-wide association studies. RESULTS:Genetic liability for advanced AMD showed no statistical causal association with AD risk (odds ratio [OR] = 0.999, 95% confidence interval [CI]: 0.955-1.044, P = .948). Reverse MR analysis provided little support for a causal effect of AD on advanced AMD (OR = 0.973, 95%CI: 0.938-1.008, P = .133). DISCUSSION:This MR study found no evidence to support a bidirectional causality between advanced AMD and AD. HIGHLIGHTS:We evaluated the bidirectional causal relationship between advanced AMD and AD. Advanced AMD showed no statistical causal association with risk of AD. We found no evidence to support a causal effect of AD on advanced AMD risk. The associations observed in epidemiological studies should not be considered causal. 10.1002/alz.12775
The relationship between lipoprotein(a) and risk of cardiovascular disease: a Mendelian randomization analysis. European journal of medical research BACKGROUND:Lipoprotein(a) [Lp(a)] is one of the residual risk factors for cardiovascular disease (CVD) in the setting of optimal low-density lipoprotein cholesterol (LDL-C). The association between Lp(a) and CVD is still in the exploratory phase, with few studies indicating a causal connection between Lp(a) and various CVD. METHODS:Lp(a) (n = 377,590) was a genome-wide association study (GWAS) based on European populations from Neale Lab. Large GWAS datasets for CVD, including aortic aneurysm(AA) (n = 209,366), atrial fibrillation(AF) (n = 1,030,836), coronary heart disease(CHD) (n = 361,194), secondary hypertension(HBP) (n = 164,147), heart failure(HF) (n = 208,178), ischemic stroke (IS) (n = 218,792), large artery atherosclerosis stroke(ISL) (n = 150, 765), small vessel stroke(ISS) (n = 198,048), lacunar stroke(LIS) (n = 225,419), and pulmonary embolism(PE) (n = 218,413) were also based on European populations. We performed separate univariate two-sample Mendelian randomization (MR) analysis for Lp(a) and CVD as described above. We evaluated this connection mainly using the random-effects inverse variance weighted technique(IVW1) with a 95% confidence interval (CI) for the odds ratio (OR). This was supplemented by MR-Egger, weighted median, maximum likelihood, penalized weighted median, and fixed-effects inverse variance weighted methods. MR-PRESSO offers another means of statistical detection. RESULTS:Our two-sample MR, which was predominately based on IVW1, revealed a causal relationship between Lp(a) and AA (OR = 1.005, 95%CI: 1.001-1.010, P = 0.009), CHD (OR = 1.003, 95%CI 1.001-1.004, P = 0.010), and ISL (OR = 1.003, 9 5%CI 1.002-1.004, P = 9.50E-11), in addition, there is no causal association with AF, HBP, HF, IS, ISS, LIS, or PE. Similar conclusions were reached by the MR-PRESSO method. CONCLUSION:This MR study suggested a causal relationship between Lp(a) and CHD, AA, and ISL, but not associated with AF, HF, IS, LIS, ISS, HBP, or PE. Our work further verifies the association between Lp(a) and various CVD, resulting in improved Lp(a) management and a reduction in the prevalence of CVD. 10.1186/s40001-022-00825-6
Circulating vitamin C and the risk of cardiovascular diseases: A Mendelian randomization study. Zhu Jiahao,Ling Yuxiao,Tse Lap A,Kinra Sanjay,Li Yingjun Nutrition, metabolism, and cardiovascular diseases : NMCD BACKGROUND AND AIMS:The impact of vitamin C supplementation on the risk of cardiovascular diseases (CVDs) remains uncertain with inconsistent evidence obtained from observational studies and randomized clinical trials (RCTs). We aimed to assess possible causal associations of vitamin C with major CVD events as well as their risk factors using Mendelian randomization (MR) design. METHODS AND RESULTS:Nine genetic variants associated with vitamin C at genome-wide significance (p < 5 × 10) were used as instrumental variables to predict plasma vitamin C levels. The primary outcomes were coronary artery disease (Ncase = 122,733 and Ncontrol = 424,528), atrial fibrillation (Ncase = 60,620 and Ncontrol = 970,216), heart failure (Ncase = 47,309 and Ncontrol = 930,014), and ischemic stroke (Ncase = 40,585 and Ncontrol = 406,111). Several CVD risk factors were also evaluated in secondary analyses. Two-sample MR analyses were performed using the inverse variance weighted method, with several sensitivity analyses. Genetically determined higher levels of plasma vitamin C were not significantly associated with any of the four examined CVD events. Likewise, there is no convincing evidence for the associations between genetically determined vitamin C and CVD risk factors, including higher blood lipids, higher blood pressure, and abnormal body composition. Sensitivity analyses using different analytical approaches yielded consistent results. Additionally, MR assumptions did not seem to be violated. CONCLUSION:This MR study does not support a causal protective role to circulate vitamin C levels on various types of CVD events. In combination with previous RCT results, our findings suggest that vitamin C supplementation to increase circulating vitamin C levels may not help in CVD prevention. 10.1016/j.numecd.2021.04.023
Relationship between NAFLD and coronary artery disease: A Mendelian randomization study. Hepatology (Baltimore, Md.) BACKGROUND AND AIMS:There is an ongoing debate on whether NAFLD is an active contributor or an innocent bystander in the pathogenesis of coronary artery disease (CAD). The aim of the present study was to assess the causal relationship between NAFLD and CAD. APPROACH AND RESULTS:We performed two-sample Mendelian randomization (MR) analyses using summary-level data to assess the association between genetically predicted NAFLD (i.e., chronically elevated serum alanine aminotransferase levels [cALT], imaging-based and biopsy-confirmed NAFLD) and risk of CAD. Analyses were repeated after exclusion of NAFLD susceptibility genes that are associated with impaired VLDL secretion.Inverse-variance weighted MR analyses showed a statistically significant association between genetically predicted cALT and risk of CAD (OR: 1.116, 95% CI: 1.039, 1.199), but not for the other NAFLD-related traits (OR: 1.046, 95% CI: 0.764, 1.433 and OR: 1.014, 95% CI: 0.968, 1.062 for imaging-based and biopsy-confirmed NAFLD, respectively). MR-Egger regression revealed a statistically significant intercept, indicative of directional pleiotropy, for all traits. Repeat analyses after exclusion of genes associated with impaired VLDL secretion showed consistent associations between genetically predicted NAFLD and CAD for all traits (i.e., cALT [OR: 1.203, 95% CI: 1.113, 1.300]), imaging-based (OR: 2.149, 95% CI: 1.276, 3.620) and biopsy-confirmed NAFLD (OR: 1.113, 95% CI: 1.041, 1.189), which persisted when more stringent biopsy-confirmed NAFLD criteria were used (OR: 1.154, 95% CI: 1.043, 1.278) or when more stringent MR methods were applied. MR-Egger regression did not show a statistically significant intercept. CONCLUSION:The two-sample MR analyses showed a robust association between genetically predicted NAFLD and CAD after exclusion of genetic variants that are implicated in impaired VLDL secretion. 10.1002/hep.32534
The association between depression and metabolic syndrome and its components: a bidirectional two-sample Mendelian randomization study. Translational psychiatry Observational studies suggested a bidirectional correlation between depression and metabolic syndrome (MetS) and its components. However, the causal associations between them remained unclear. We aimed to investigate whether genetically predicted depression is related to the risk of MetS and its components, and vice versa. We performed a bidirectional two-sample Mendelian randomization (MR) study using summary-level data from the most comprehensive genome-wide association studies (GWAS) of depression (n = 2,113,907), MetS (n = 291,107), waist circumference (n = 462,166), hypertension (n = 463,010) fasting blood glucose (FBG, n = 281,416), triglycerides (n = 441,016), high-density lipoprotein cholesterol (HDL-C, n = 403,943). The random-effects inverse-variance weighted (IVW) method was applied as the primary method. The results identified that genetically predicted depression was significantly positive associated with risk of MetS (OR: 1.224, 95% CI: 1.091-1.374, p = 5.58 × 10), waist circumference (OR: 1.083, 95% CI: 1.027-1.143, p = 0.003), hypertension (OR: 1.028, 95% CI: 1.016-1.039, p = 1.34 × 10) and triglycerides (OR: 1.111, 95% CI: 1.060-1.163, p = 9.35 × 10) while negative associated with HDL-C (OR: 0.932, 95% CI: 0.885-0.981, p = 0.007) but not FBG (OR: 1.010, 95% CI: 0.986-1.034, p = 1.34). No causal relationships were identified for MetS and its components on depression risk. The present MR analysis strength the evidence that depression is a risk factor for MetS and its components (waist circumference, hypertension, FBG, triglycerides, and HDL-C). Early diagnosis and prevention of depression are crucial in the management of MetS and its components. 10.1038/s41398-021-01759-z
Estimating the Effect of Liver and Pancreas Volume and Fat Content on Risk of Diabetes: A Mendelian Randomization Study. Martin Susan,Sorokin Elena P,Thomas E Louise,Sattar Naveed,Cule Madeleine,Bell Jimmy D,Yaghootkar Hanieh Diabetes care OBJECTIVE:Fat content and volume of liver and pancreas are associated with risk of diabetes in observational studies; whether these associations are causal is unknown. We conducted a Mendelian randomization (MR) study to examine causality of such associations. RESEARCH DESIGN AND METHODS:We used genetic variants associated (P < 5 × 10-8) with the exposures (liver and pancreas volume and fat content) using MRI scans of UK Biobank participants (n = 32,859). We obtained summary-level data for risk of type 1 (9,358 cases) and type 2 (55,005 cases) diabetes from the largest available genome-wide association studies. We performed inverse-variance weighted MR as main analysis and several sensitivity analyses to assess pleiotropy and to exclude variants with potential pleiotropic effects. RESULTS:Observationally, liver fat and volume were associated with type 2 diabetes (odds ratio per 1 SD higher exposure 2.16 [2.02, 2.31] and 2.11 [1.96, 2.27], respectively). Pancreatic fat was associated with type 2 diabetes (1.42 [1.34, 1.51]) but not type 1 diabetes, and pancreas volume was negatively associated with type 1 diabetes (0.42 [0.36, 0.48]) and type 2 diabetes (0.73 [0.68, 0.78]). MR analysis provided evidence only for a causal role of liver fat and pancreas volume in risk of type 2 diabetes (1.27 [1.08, 1.49] or 27% increased risk and 0.76 [0.62, 0.94] or 24% decreased risk per 1SD, respectively) and no causal associations with type 1 diabetes. CONCLUSIONS:Our findings assist in understanding the causal role of ectopic fat in the liver and pancreas and of organ volume in the pathophysiology of type 1 and type 2 diabetes. 10.2337/dc21-1262
Causal Graph Among Serum Lipids and Glycemic Traits: A Mendelian Randomization Study. Diabetes We systematically investigated the bidirectional causality among HDL cholesterol (HDL-C), LDL cholesterol (LDL-C), triglycerides (TGs), fasting insulin (FI), and glycated hemoglobin A1c (HbA1c) based on genome-wide association summary statistics of Europeans (n = 1,320,016 for lipids, 151,013 for FI, and 344,182 for HbA1c). We applied multivariable Mendelian randomization (MR) to account for the correlation among different traits and constructed a causal graph with 13 significant causal effects after adjusting for multiple testing (P < 0.0025). Remarkably, we found that the effects of lipids on glycemic traits were through FI from TGs (β = 0.06 [95% CI 0.03, 0.08] in units of 1 SD for each trait) and HDL-C (β = -0.02 [-0.03, -0.01]). On the other hand, FI had a strong negative effect on HDL-C (β = -0.15 [-0.21, -0.09]) and positive effects on TGs (β = 0.22 [0.14, 0.31]) and HbA1c (β = 0.15 [0.12, 0.19]), while HbA1c could raise LDL-C (β = 0.06 [0.03, 0.08]) and TGs (β = 0.08 [0.06, 0.10]). These estimates derived from inverse-variance weighting were robust when using different MR methods. Our results suggest that elevated FI was a strong causal factor of high TGs and low HDL-C, which in turn would further increase FI. Therefore, early control of insulin resistance is critical to reduce the risk of type 2 diabetes, dyslipidemia, and cardiovascular complications. 10.2337/db21-0734
MendelianRandomization: an R package for performing Mendelian randomization analyses using summarized data. International journal of epidemiology MendelianRandomization is a software package for the R open-source software environment that performs Mendelian randomization analyses using summarized data. The core functionality is to implement the inverse-variance weighted, MR-Egger and weighted median methods for multiple genetic variants. Several options are available to the user, such as the use of robust regression, fixed- or random-effects models and the penalization of weights for genetic variants with heterogeneous causal estimates. Extensions to these methods, such as allowing for variants to be correlated, can be chosen if appropriate. Graphical commands allow summarized data to be displayed in an interactive graph, or the plotting of causal estimates from multiple methods, for comparison. Although the main method of data entry is directly by the user, there is also an option for allowing summarized data to be incorporated from the PhenoScanner database of genotype-phenotype associations. We hope to develop this feature in future versions of the package. The R software environment is available for download from [https://www.r-project.org/]. The MendelianRandomization package can be downloaded from the Comprehensive R Archive Network (CRAN) within R, or directly from [https://cran.r-project.org/web/packages/MendelianRandomization/]. Both R and the MendelianRandomization package are released under GNU General Public Licenses (GPL-2|GPL-3). 10.1093/ije/dyx034
Polycystic Ovary Syndrome and Risk of Type 2 Diabetes, Coronary Heart Disease, and Stroke. Zhu Tiantian,Cui Jinrui,Goodarzi Mark O Diabetes Polycystic ovary syndrome (PCOS) has been associated with diabetes and cardiovascular disease; however, whether the relationship is causal is uncertain. We conducted a two-sample Mendelian randomization study to investigate the associations of PCOS with type 2 diabetes, coronary heart disease (CHD), and stroke. Association between PCOS and diabetes risk was examined in European and Asian cohorts, both sex specific and sex combined. Causal effects of PCOS on risks of CHD and stroke were evaluated in European cohorts. Stroke was analyzed as any stroke as well as four subtypes of stroke (ischemic, large artery, cardioembolic, small vessel). We found no association of genetically predicted PCOS with risk of diabetes, CHD, or stroke. This suggests that PCOS in and of itself does not increase the risk of these outcomes. Other features of PCOS (obesity, elevated testosterone, low sex hormone binding globulin) may explain the association between PCOS and cardiometabolic diseases. In light of these results, efforts to prevent cardiometabolic complications in PCOS should focus on women with high-risk features rather than all women with PCOS. 10.2337/db20-0800