Evaluate the Relationship Between Obstructive Sleep Apnea and Metabolic Syndrome in Real-World Data.
Nature and science of sleep
Objective:Obstructive sleep apnea (OSA) is a disorder characterized by disruption in breathing and hypoventilation. In parallel, metabolic syndrome (MetS) mainly co-occur with OSA, however, their association has not been fully elucidated. Therefore, this study aimed to reveal the relationship between OSA and MetS using data from the National Health And Nutrition Examination Survey (NHANES) database and pooled data from Genome-Wide Association Studies (GWAS). Material and Methods:Data from the National Health and Nutrition Examination Survey and pooled data from genome-wide association analysis (GWAS) were used univariate and multivariate logistic regression analyses were carried out to evaluate the correlation between OSA and MetS, and multivariate logistic regression models were utilized for adjusting for potential confounders. Two-sample Mendelian randomization (MR) was used to assess the causal relationship between OSA and MetS. The variance-weighted inverse method was employed as the main method of analysis. Results:A positive relationship of OSA with Mets was evidenced by multivariate logistic regression analysis, and OSA was associated with higher incidence rates of all-cause and cardiovascular mortality. OSA is strongly associated with abdominal obesity, hypertension, hyperglycemia, high triglycerides, and low HDL. Furthermore, except for hypertriglyceridemia, MR analysis indicated that genetically driven OSA was causally associated with a higher risk of MetS. Conclusion:The positive relationship of OSA with Mets was revealed, and higher incidence rates of all-cause mortality and cardiovascular mortality were noted to be correlated with OSA. MR analysis further confirmed the causal relationship of OSA with MetS and cardiovascular disease.
10.2147/NSS.S433514
Multi-stage metabolomics and genetic analyses identified metabolite biomarkers of metabolic syndrome and their genetic determinants.
Wu Qiong,Li Jiankang,Sun Xiaohui,He Di,Cheng Zongxue,Li Jun,Zhang Xuhui,Xie Yongming,Zhu Yimin,Lai Maode
EBioMedicine
BACKGROUND:Metabolic syndrome (MetS) is a cluster of multiple cardiometabolic risk factors that increase the risk of type 2 diabetes and cardiovascular diseases. Identifying novel biomarkers of MetS and their genetic associations could provide insights into the mechanisms of cardiometabolic diseases. METHODS:Potential MetS-associated metabolites were screened and internally validated by untargeted metabolomics analyses among 693 patients with MetS and 705 controls. External validation was conducted using two well-established targeted metabolomic methods among 149 patients with MetS and 253 controls. The genetic associations of metabolites were determined by linear regression using our previous genome-wide SNP data. Causal relationships were assessed using a one-sample Mendelian Randomization (MR) approach. FINDINGS:Nine metabolites were ultimately found to be associated with MetS or its components. Five metabolites, including LysoPC(14:0), LysoPC(15:0), propionyl carnitine, phenylalanine, and docosapentaenoic acid (DPA) were selected to construct a metabolite risk score (MRS), which was found to have a dose-response relationship with MetS and metabolic abnormalities. Moreover, MRS displayed a good ability to differentiate MetS and metabolic abnormalities. Three SNPs (rs11635491, rs7067822, and rs1952458) were associated with LysoPC(15:0). Two SNPs, rs1952458 and rs11635491 were found to be marginally correlated with several MetS components. MR analyses showed that a higher LysoPC(15:0) level was causally associated with the risk of overweight/obesity, dyslipidaemia, high uric acid, high insulin and high HOMA-IR. INTERPRETATION:We identified five metabolite biomarkers of MetS and three SNPs associated with LysoPC(15:0). MR analyses revealed that abnormal LysoPC metabolism may be causally linked the metabolic risk. FUNDING:This work was supported by grants from the National Key Research and Development Program of China (2017YFC0907004).
10.1016/j.ebiom.2021.103707
Genetic evidence for the causal relations between metabolic syndrome and psychiatric disorders: a Mendelian randomization study.
Translational psychiatry
Emerging evidence reveals associations between metabolic syndrome (MetS) and psychiatric disorders (PDs), although causality remains uncertain. Consequently, we conducted Mendelian randomization (MR) to systematically evaluate the causality between MetS and PDs. Linkage disequilibrium score regression estimated the heritability of PDs and their genetic correlations with MetS. In primary analyses, the main model employed inverse variance weighting method, with sensitivity analyses using various MR models to ensure robustness. Replication MR analyses, involving cohorts distinct from those in the primary analyses, were performed to validate the generalizability of the findings. Multivariable MR analyses were carried out to account for genetically predicted body mass index (BMI). As a result, genetic correlations of MetS with attention-deficit/hyperactivity disorder(ADHD), anorexia nervosa(ANO), major depressive disorder(MDD), and schizophrenia were identified. Causal effects of MetS on ADHD (OR: 1.59 [95% CI:1.45-1.74]), ANO (OR: 1.42 [95% CI:1.25-1.61]), MDD(OR: 1.23 [95% CI: 1.13-1.33]), and the effects of ADHD (OR: 1.03 [95% CI: 1.02-1.04]) and ANO (OR: 1.01 [95% CI: 1.01-1.02]) on MetS were observed in primary analyses. Results from sensitivity analyses and replication analyses were generally consistent with the primary analyses, confirming the robustness and generalizability of the findings. Associations between MetS and ADHD, as well as ANO persisted after adjusting for BMI, whereas the statistical significance of the association between MetS and MDD was no longer observable. These results contribute to a deeper understanding of the mechanisms underlying PDs, suggesting potential modifiable targets for public prevention and clinical intervention in specific PDs related to metabolic pathways.
10.1038/s41398-024-02759-5
Adiposity impacts cognitive function in Asian populations: an epidemiological and Mendelian Randomization study.
The Lancet regional health. Western Pacific
Background:Obesity and related metabolic disturbances including diabetes, hypertension and hyperlipidemia predict future cognitive decline. Asia has a high prevalence of both obesity and metabolic disease, potentially amplifying the future burden of dementia in the region. We aimed to investigate the impact of adiposity and metabolic risk on cognitive function in Asian populations, using an epidemiological analysis and a two-sample Mendelian Randomization (MR) study. Methods:The Health for Life in Singapore (HELIOS) Study is a population-based cohort of South-East-Asian men and women in Singapore, aged 30-84 years. We analyzed 8769 participants with metabolic and cognitive data collected between 2018 and 2021. Whole-body fat mass was quantified with Dual X-Ray Absorptiometry (DEXA). Cognition was assessed using a computerized cognitive battery. An index of general cognition ' ' was derived through factor analysis. We tested the relationship of fat mass indices and metabolic measures with ' ' using regression approaches. We then performed inverse-variance-weighted MR of adiposity and metabolic risk factors on ' ', using summary statistics for genome-wide association studies of BMI, visceral adipose tissue (VAT), waist-hip-ratio (WHR), blood pressure, HDL cholesterol, triglycerides, fasting glucose, HbA1c, and general cognition. Findings:Participants were 58.9% female, and aged 51.4 (11.3) years. In univariate analysis, all 29 adiposity and metabolic measures assessed were associated with ' ' at P < 0.05. In multivariable analyses, reduced ' ' was consistently associated with increased visceral fat mass index and lower HDL cholesterol (P < 0.001), but not with blood pressure, triglycerides, or glycemic indices. The reduction in associated with 1SD higher visceral fat, or 1SD lower HDL cholesterol, was equivalent to a 0.7 and 0.9-year increase in chronological age respectively (P < 0.001). Inverse variance MR analyses showed that reduced ' ' is associated with genetically determined elevation of VAT, BMI and WHR (all P < 0.001). In contrast, MR did not support a causal role for blood pressure, lipid, or glycemic indices on cognition. Interpretation:We show an independent relationship between adiposity and cognition in a multi-ethnic Asian population. MR analyses suggest that both visceral adiposity and raised BMI are likely to be causally linked to cognition. Our findings have important implications for preservation of cognitive health, including further motivation for action to reverse the rising burden of obesity in the Asia-Pacific region. Funding:The Nanyang Technological University-the Lee Kong Chian School of Medicine, National Healthcare Group, National Medical Research Council, Ministry of Education, Singapore.
10.1016/j.lanwpc.2023.100710
The association of metabolic syndrome with rotator cuff tendinopathy: a two-sample Mendelian randomization study.
Diabetology & metabolic syndrome
BACKGROUND:Observational research reported the underlying correlation of metabolic syndrome (MetS) and its components with rotator cuff tendinopathy (RCT), but their causality remained unclear. This study aimed to investigate whether genetically predicted MetS was related to the risk of RCT. METHODS:Both univariable and multivariable Mendelian randomization (MR) analysis was applied using summary-level data from the most comprehensive genome-wide association studies to estimate the associations of MetS and its component with RCT, with the inverse variance weighted (IVW) as the primary method, and the method of Causal Analysis Using Summary Effect Estimates (CAUSE) as a supplement for false positives detection. The mediation analysis was furtherly used for the assessment of direct and indirect effects. RESULTS:Univariable analysis revealed that genetically predicted MetS (OR: 1.0793; 95% CI 1.0311 to 1.1297), body mass index (BMI) (OR 1.2239; 95% CI 1.1357 to 1.3189), and waist circumference (WAC) (OR 1.3177; 95% CI 1.2015 to 1.4451) had a significant positive association with the risk of RCT. Triglycerides and systolic blood pressure were suggestively associated with RCT risk. These associations were also identified by CAUSE. There was independent causality of BMI (OR: 1.1806; 95% CI 1.0788 to 1.2920) and WAC (OR 1.3716; 95% CI 1.2076 to 1.5580) on RCT after adjustment for confounders. No mediator was found in the causal associations. CONCLUSION:Our study revealed the genetic causality of MetS and its components, especially BMI and WAC, with RCT risk. Early prevention and diagnosis of excess central adiposity contributing to MetS are significant in the RCT risk management.
10.1186/s13098-023-01189-5
Association between genetically determined telomere length and health-related outcomes: A systematic review and meta-analysis of Mendelian randomization studies.
Aging cell
Emerging evidence has shown that leukocyte telomere length (LTL) is associated with various health-related outcomes, while the causality of these associations remains unclear. We performed a systematic review and meta-analysis of current evidence from Mendelian randomization (MR) studies on the association between LTL and health-related outcomes. We searched PubMed, Embase, and Web of Science up to April 2022 to identify eligible MR studies. We graded the evidence level of each MR association based on the results of the main analysis and four sensitive MR methods, MR-Egger, weighted median, MR-PRESSO, and multivariate MR. Meta-analyses of published MR studies were also performed. A total of 62 studies with 310 outcomes and 396 MR associations were included. Robust evidence level was observed for the association between longer LTL and increased risk of 24 neoplasms (the strongest magnitude for osteosarcoma, GBM, glioma, thyroid cancer, and non-GBM glioma), six genitourinary and digestive system outcomes of excessive or abnormal growth, hypertension, metabolic syndrome, multiple sclerosis, and clonal hematopoiesis of indeterminate potential. Robust inverse association was observed for coronary heart disease, chronic kidney disease, rheumatoid arthritis, juvenile idiopathic arthritis, idiopathic pulmonary fibrosis, and facial aging. Meta-analyses of MR studies suggested that genetically determined LTL was associated with 12 neoplasms and 9 nonneoplasm outcomes. Evidence from published MR studies supports that LTL plays a causal role in various neoplastic and nonneoplastic diseases. Further research is required to elucidate the underlying mechanisms and to bring insight into the potential prediction, prevention, and therapeutic applications of telomere length.
10.1111/acel.13874
Thyroid Function and Metabolic Syndrome: A Two-Sample Bidirectional Mendelian Randomization Study.
The Journal of clinical endocrinology and metabolism
CONTEXT:Thyroid function has been associated with metabolic syndrome (MetS) in a number of observational studies but the direction of effects and the exact causal mechanism of this relationship is still unknown. OBJECTIVE:To examine genetically predicted effects of thyroid function on MetS risk and its components, and vice versa, using large-scale summary genetic association data. METHODS:We performed a two-sample bidirectional Mendelian randomization (MR) study using summary statistics from the most comprehensive genome-wide association studies (GWAS) of thyroid-stimulating hormone (TSH, n = 119 715), free thyroxine (fT4, n = 49 269), MetS (n = 291 107), and components of MetS: waist circumference (n = 462 166), fasting blood glucose (n = 281 416), hypertension (n = 463 010), triglycerides (TG, n = 441 016) and high-density lipoprotein cholesterol (HDL-C, n = 403 943). We chose the multiplicative random effects inverse variance weighted (IVW) method as the main analysis. Sensitivity analysis included weighted median and mode analysis, as well as MR-Egger and Causal Analysis Using Summary Effect estimates (CAUSE). RESULTS:Our results suggest that higher fT4 levels lower the risk of developing MetS (OR = 0.96, P = .037). Genetically predicted fT4 was also positively associated with HDL-C (β = 0.02, P = .008), while genetically predicted TSH was positively associated with TG (β = 0.01, P = .044). These effects were consistent across different MR analyses and confirmed with the CAUSE analysis. In the reverse direction MR analysis, genetically predicted HDL-C was negatively associated with TSH (β = -0.03, P = .046) in the main IVW analysis. CONCLUSION:Our study suggests that variations in normal-range thyroid function are causally associated with the diagnosis of MetS and with lipid profile, while in the reverse direction, HDL-C has a plausible causal effect on reference-range TSH levels.
10.1210/clinem/dgad371
Association between sleep duration and metabolic syndrome: linear and nonlinear Mendelian randomization analyses.
Journal of translational medicine
BACKGROUND:Observational studies have found that both short and long sleep duration are associated with increased risk of metabolic syndrome (MetS). This study aimed to examine the associations of genetically determined sleep durations with MetS and its five components (i.e., central obesity, high blood pressure, dyslipidemia, hypertriglyceridemia, and hyperglycemia) among a group of elderly population. METHODS:In 335,727 participants of White British from the UK Biobank, linear Mendelian randomization (MR) methods were first employed to examine the causal association of genetically predicted continuous sleep duration with MetS and its each component. Nonlinear MR analyses were performed to determine the nonlinearity of these associations. The causal associations of short and long sleep duration with MetS and its components were further assessed by using genetic variants that associated with short (≤ 6 h) and long sleep (≥ 9 h) durations. RESULTS:Linear MR analyses demonstrated that genetically predicted 1-h longer sleep duration was associated with a 13% lower risk of MetS, a 30% lower risk of central obesity, and a 26% lower risk of hyperglycemia. Non-linear MR analyses provided evidence for non-linear associations of genetically predicted sleep duration with MetS and its five components (all P values < 0.008). Genetically predicted short sleep duration was moderately associated with MetS and its four components, including central obesity, dyslipidemia, hypertriglyceridemia, and hyperglycemia (all P values < 0.002), whereas genetically long sleep duration was not associated with MetS and any of its components. CONCLUSIONS:Genetically predicted short sleep duration, but not genetically predicted long sleep duration, is a potentially causal risk factor for MetS.
10.1186/s12967-023-03920-2
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
Lean mass, grip strength and risk of type 2 diabetes: a bi-directional Mendelian randomisation study.
Yeung Chris Ho Ching,Au Yeung Shiu Lun,Fong Shirley Siu Ming,Schooling C Mary
Diabetologia
AIMS/HYPOTHESIS:Muscle mass and strength may protect against type 2 diabetes as a sink for glucose disposal. In randomised controlled trials, resistance training improves glucose metabolism in people with the metabolic syndrome. Whether increasing muscle mass and strength protects against diabetes in the general population is unknown. We assessed the effect of markers of muscle mass and strength on diabetes and glycaemic traits using bi-directional Mendelian randomisation. METHODS:Inverse variance weighting estimates were obtained by applying genetic variants that predict male lean mass, female lean mass and grip strength, obtained from the UK Biobank GWAS, to the largest available case-control study of diabetes (DIAbetes Genetics Replication And Meta-analysis [DIAGRAM]; n = 74,124 cases and 824,006 controls) and to a study of glycaemic traits (Meta-Analyses of Glucose and Insulin-related traits Consortium [MAGIC]). Conversely, we also applied genetic variants that predict diabetes, HbA, fasting glucose, fasting insulin and HOMA-B to UK Biobank summary statistics for genetic association with lean mass and grip strength. As sensitivity analyses we used weighted median, Mendelian randomisation (MR)-Egger and Mendelian Randomization Pleiotropy RESidual Sum and Outlier (MR-PRESSO) and removed pleiotropic SNPs. RESULTS:Grip strength was not significantly associated with diabetes using inverse variance weighting (OR 0.72 per SD increase in grip strength, 95% CI 0.51, 1.01, p = 0.06) and including pleiotropic SNPs but was significantly associated with diabetes using MR-PRESSO (OR 0.77, 95% CI 0.62, 0.95, p = 0.02) after removing pleiotropic SNPs. Female lean mass was significantly associated with diabetes (OR 0.91, 95% CI 0.84, 0.99, p = 0.02) while male lean mass was not significant but directionally similar (OR 0.94, 95% CI 0.88, 1.01, p = 0.09). Conversely, diabetes was inversely and significantly associated with male lean mass (β -0.02 SD change in lean mass, 95% CI -0.04, -0.00, p = 0.04) and grip strength (β -0.01, 95% CI -0.02, -0.00, p = 0.01). CONCLUSIONS/INTERPRETATION:Increased muscle mass and strength may be related to lower diabetes risk. Diabetes may also be associated with grip strength and lean mass. Muscle strength could warrant further investigation as a possible target of intervention for diabetes prevention.
10.1007/s00125-019-4826-0
The role of adiposity in cardiometabolic traits: a Mendelian randomization analysis.
Fall Tove,Hägg Sara,Mägi Reedik,Ploner Alexander,Fischer Krista,Horikoshi Momoko,Sarin Antti-Pekka,Thorleifsson Gudmar,Ladenvall Claes,Kals Mart,Kuningas Maris,Draisma Harmen H M,Ried Janina S,van Zuydam Natalie R,Huikari Ville,Mangino Massimo,Sonestedt Emily,Benyamin Beben,Nelson Christopher P,Rivera Natalia V,Kristiansson Kati,Shen Huei-Yi,Havulinna Aki S,Dehghan Abbas,Donnelly Louise A,Kaakinen Marika,Nuotio Marja-Liisa,Robertson Neil,de Bruijn Renée F A G,Ikram M Arfan,Amin Najaf,Balmforth Anthony J,Braund Peter S,Doney Alexander S F,Döring Angela,Elliott Paul,Esko Tõnu,Franco Oscar H,Gretarsdottir Solveig,Hartikainen Anna-Liisa,Heikkilä Kauko,Herzig Karl-Heinz,Holm Hilma,Hottenga Jouke Jan,Hyppönen Elina,Illig Thomas,Isaacs Aaron,Isomaa Bo,Karssen Lennart C,Kettunen Johannes,Koenig Wolfgang,Kuulasmaa Kari,Laatikainen Tiina,Laitinen Jaana,Lindgren Cecilia,Lyssenko Valeriya,Läärä Esa,Rayner Nigel W,Männistö Satu,Pouta Anneli,Rathmann Wolfgang,Rivadeneira Fernando,Ruokonen Aimo,Savolainen Markku J,Sijbrands Eric J G,Small Kerrin S,Smit Jan H,Steinthorsdottir Valgerdur,Syvänen Ann-Christine,Taanila Anja,Tobin Martin D,Uitterlinden Andre G,Willems Sara M,Willemsen Gonneke,Witteman Jacqueline,Perola Markus,Evans Alun,Ferrières Jean,Virtamo Jarmo,Kee Frank,Tregouet David-Alexandre,Arveiler Dominique,Amouyel Philippe,Ferrario Marco M,Brambilla Paolo,Hall Alistair S,Heath Andrew C,Madden Pamela A F,Martin Nicholas G,Montgomery Grant W,Whitfield John B,Jula Antti,Knekt Paul,Oostra Ben,van Duijn Cornelia M,Penninx Brenda W J H,Smith George Davey,Kaprio Jaakko,Samani Nilesh J,Gieger Christian,Peters Annette,Wichmann H Erich,Boomsma Dorret I,de Geus Eco J C,Tuomi TiinaMaija,Power Chris,Hammond Christopher J,Spector Tim D,Lind Lars,Orho-Melander Marju,Palmer Colin Neil Alexander,Morris Andrew D,Groop Leif,Järvelin Marjo-Riitta,Salomaa Veikko,Vartiainen Erkki,Hofman Albert,Ripatti Samuli,Metspalu Andres,Thorsteinsdottir Unnur,Stefansson Kari,Pedersen Nancy L,McCarthy Mark I,Ingelsson Erik,Prokopenko Inga,
PLoS medicine
BACKGROUND:The association between adiposity and cardiometabolic traits is well known from epidemiological studies. Whilst the causal relationship is clear for some of these traits, for others it is not. We aimed to determine whether adiposity is causally related to various cardiometabolic traits using the Mendelian randomization approach. METHODS AND FINDINGS:We used the adiposity-associated variant rs9939609 at the FTO locus as an instrumental variable (IV) for body mass index (BMI) in a Mendelian randomization design. Thirty-six population-based studies of individuals of European descent contributed to the analyses. Age- and sex-adjusted regression models were fitted to test for association between (i) rs9939609 and BMI (n = 198,502), (ii) rs9939609 and 24 traits, and (iii) BMI and 24 traits. The causal effect of BMI on the outcome measures was quantified by IV estimators. The estimators were compared to the BMI-trait associations derived from the same individuals. In the IV analysis, we demonstrated novel evidence for a causal relationship between adiposity and incident heart failure (hazard ratio, 1.19 per BMI-unit increase; 95% CI, 1.03-1.39) and replicated earlier reports of a causal association with type 2 diabetes, metabolic syndrome, dyslipidemia, and hypertension (odds ratio for IV estimator, 1.1-1.4; all p < 0.05). For quantitative traits, our results provide novel evidence for a causal effect of adiposity on the liver enzymes alanine aminotransferase and gamma-glutamyl transferase and confirm previous reports of a causal effect of adiposity on systolic and diastolic blood pressure, fasting insulin, 2-h post-load glucose from the oral glucose tolerance test, C-reactive protein, triglycerides, and high-density lipoprotein cholesterol levels (all p < 0.05). The estimated causal effects were in agreement with traditional observational measures in all instances except for type 2 diabetes, where the causal estimate was larger than the observational estimate (p = 0.001). CONCLUSIONS:We provide novel evidence for a causal relationship between adiposity and heart failure as well as between adiposity and increased liver enzymes.
10.1371/journal.pmed.1001474
Mitochondrial genome copy number measured by DNA sequencing in human blood is strongly associated with metabolic traits via cell-type composition differences.
Human genomics
BACKGROUND:Mitochondrial genome copy number (MT-CN) varies among humans and across tissues and is highly heritable, but its causes and consequences are not well understood. When measured by bulk DNA sequencing in blood, MT-CN may reflect a combination of the number of mitochondria per cell and cell-type composition. Here, we studied MT-CN variation in blood-derived DNA from 19184 Finnish individuals using a combination of genome (N = 4163) and exome sequencing (N = 19034) data as well as imputed genotypes (N = 17718). RESULTS:We identified two loci significantly associated with MT-CN variation: a common variant at the MYB-HBS1L locus (P = 1.6 × 10), which has previously been associated with numerous hematological parameters; and a burden of rare variants in the TMBIM1 gene (P = 3.0 × 10), which has been reported to protect against non-alcoholic fatty liver disease. We also found that MT-CN is strongly associated with insulin levels (P = 2.0 × 10) and other metabolic syndrome (metS)-related traits. Using a Mendelian randomization framework, we show evidence that MT-CN measured in blood is causally related to insulin levels. We then applied an MT-CN polygenic risk score (PRS) derived from Finnish data to the UK Biobank, where the association between the PRS and metS traits was replicated. Adjusting for cell counts largely eliminated these signals, suggesting that MT-CN affects metS via cell-type composition. CONCLUSION:These results suggest that measurements of MT-CN in blood-derived DNA partially reflect differences in cell-type composition and that these differences are causally linked to insulin and related traits.
10.1186/s40246-021-00335-2
Distinct causal effects of body fat distribution on cardiometabolic traits among children: Findings from the BCAMS study.
Nutrition, metabolism, and cardiovascular diseases : NMCD
BACKGROUND AND AIMS:Observational studies reveal that different body fat measures are associated with cardiometabolic disease with different effects. However, causality is not reflected by such observations. To explore and compare the causal relationships of general obesity (measured by body mass index (BMI)), adipose obesity (measured by fat mass percentage (FMP)) and central obesity (measured by waist-to-height ratio (WHtR)) with cardiometabolic traits among children. METHODS AND RESULTS:We conducted one sample Mendelian randomization (MR) analysis in 3266 children from Beijing Children and Adolescents Metabolic Syndrome Study. Genetic instruments based on 28 SNPs were performed to explore and compare the causal associations of genetically BMI, FMP and WHtR with cardiometabolic traits. The genetic instruments were robustly correlated with observed BMI, FMP and WHtR. Each genetically 1-SD increment in BMI, FMP and WHtR were causally associated with increment in systolic blood pressure (SBP), diastolic blood pressure (DBP), log-transformed fasting plasma glucose (FPG), log-transformed HOMA-β, and decrease in log-transformed high-density lipoprotein cholesterol (HDL), respectively (all P < 0.05 after Bonferroni correction). The receiver operating characteristic curve indicated that BMI and FMP showed stronger effects on SBP, DBP, HOMA-β and HDL than WHtR (all P < 0.05). We also observed causal associations of BMI and FMP with log-transformed fasting insulin and HOMA-IR. CONCLUSIONS:The MR analysis based on population-based cohort indicated a causal relationship of adiposity and body fat distribution with cardiometabolic traits. When compared with central obesity, general obesity and adipose obesity might own stronger effects on blood pressure and blood lipids among children.
10.1016/j.numecd.2022.03.030
Gamma-glutamyl-leucine levels are causally associated with elevated cardio-metabolic risks.
Frontiers in nutrition
Objective:Gamma-glutamyl dipeptides are bioactive peptides involved in inflammation, oxidative stress, and glucose regulation. Gamma-glutamyl-leucine (Gamma-Glu-Leu) has been extensively reported to be associated with the risk of cardio-metabolic diseases, such as obesity, metabolic syndrome, and type 2 diabetes. However, the causality remains to be uncovered. The aim of this study was to explore the causal-effect relationships between Gamma-Glu-Leu and metabolic risk. Materials and methods:In this study, 1,289 subjects were included from a cross-sectional survey on metabolic syndrome (MetS) in eastern China. Serum Gamma-Glu-Leu levels were measured by untargeted metabolomics. Using linear regressions, a two-stage genome-wide association study (GWAS) for Gamma-Glu-Leu was conducted to seek its instrumental single nucleotide polymorphisms (SNPs). One-sample Mendelian randomization (MR) analyses were performed to evaluate the causality between Gamma-Glu-Leu and the metabolic risk. Results:Four SNPs are associated with serum Gamma-Glu-Leu levels, including rs12476238, rs56146133, rs2479714, and rs12229654. Out of them, rs12476238 exhibits the strongest association (Beta = -0.38, S.E. = 0.07 in discovery stage, Beta = -0.29, S.E. = 0.14 in validation stage, combined -value = 1.04 × 10). Each of the four SNPs has a nominal association with at least one metabolic risk factor. Both rs12229654 and rs56146133 are associated with body mass index, waist circumference (WC), the ratio of WC to hip circumference, blood pressure, and triglyceride (5 × 10 < < 0.05). rs56146133 also has nominal associations with fasting insulin, glucose, and insulin resistance index (5 × 10 < < 0.05). Using the four SNPs serving as the instrumental SNPs of Gamma-Glu-Leu, the MR analyses revealed that higher Gamma-Glu-Leu levels are causally associated with elevated risks of multiple cardio-metabolic factors except for high-density lipoprotein cholesterol and low-density lipoprotein cholesterol ( > 0.05). Conclusion:Four SNPs (rs12476238, rs56146133, rs2479714, and rs12229654) may regulate the levels of serum Gamma-Glu-Leu. Higher Gamma-Glu-Leu levels are causally linked to cardio-metabolic risks. Future prospective studies on Gamma-Glu-Leu are required to explain its role in metabolic disorders.
10.3389/fnut.2022.936220
Proteins associated with incident metabolic syndrome in population-based cohorts.
Lind Lars,Sundström Johan,Ärnlöv Johan
Diabetology & metabolic syndrome
BACKGROUND:The metabolic syndrome (MetS) identifies persons with clustering of multiple cardiometabolic risk factors. The underlying pathology inducing this clustering is not fully known. We used a targeted proteomics assay to identify associations of circulating proteins with MetS and its components, cross-sectionally and longitudinally. METHODS:We explored and validated associations of 86 cardiovascular proteins, assessed using a proximity extension assay, with the MetS in two independent cohorts; the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS, n = 996) and Uppsala Longitudinal Study of Adult Men (ULSAM, n = 785). The analyses were adjusted for smoking, exercise habits, education, and energy and alcohol intake. RESULTS:Nine proteins were associated with all five components of the MetS in PIVUS using FDR < 0.05 in a cross-sectional analysis. Of those nine proteins, only Interleukin-1 receptor antagonist protein (IL-1RA) was associated with all five components of the MetS in ULSAM using p < 0.05. IL-1RA levels were associated with incident MetS (n = 109) in PIVUS during a 5-year follow-up (HR 1.76 for a 1 SD change (95% CI 1.38, 2.24), p = 4.3*10). IL-1RA was however not causally related to MetS in a two-sample Mendelian randomization analysis using published data. CONCLUSION:Circulating IL-1RA was related to all five components of the MetS in a cross-sectional analysis in two independent samples, as well as to incident MetS in a longitudinal analysis. However, Mendelian randomization analyses did not provide support for a causal role for IL-1RA in the development of MetS.
10.1186/s13098-021-00752-2
Pleiotropic Effects of Variants on Lipid Profiles, Metabolic Syndrome, and the Risk of Diabetes Mellitus.
International journal of molecular sciences
Apolipoprotein B (ApoB) plays a crucial role in lipid and lipoprotein metabolism. The effects of locus variants on lipid profiles, metabolic syndrome, and the risk of diabetes mellitus (DM) in Asian populations are unclear. We included 1478 Taiwan Biobank participants with whole-genome sequence (WGS) data and 115,088 TWB participants with Axiom genome-wide CHB array data and subjected them to genotype-phenotype analyses using locus variants. Five nonsynonymous mutations, including Asian-specific rs144467873 and rs13306194 variants, were selected from participants with the WGS data. Using a combination of regional association studies, a linkage disequilibrium map, and multivariate analysis, we revealed that the locus variants rs144467873, rs13306194, and rs1367117 were independently associated with total, low-density lipoprotein (LDL), and non-high-density lipoprotein (non-HDL) cholesterol levels; rs1318006 was associated with HDL cholesterol levels; rs13306194 and rs35131127 were associated with serum triglyceride levels; rs144467873, rs13306194, rs56213756, and rs679899 were associated with remnant cholesterol levels; and rs144467873 and rs4665709 were associated with metabolic syndrome. Mendelian randomization (MR) analyses conducted using weighted genetic risk scores from three or two LDL-cholesterol-level-associated variants revealed significant association with prevalent DM ( = 0.0029 and 8.2 × 10, respectively), which became insignificant after adjustment for LDL-C levels. In conclusion, these results indicate that common and rare variants are independently associated with various lipid levels and metabolic syndrome in Taiwanese individuals. MR analyses supported variants associated with the risk of DM through their associations with LDL cholesterol levels.
10.3390/ijms232314963
Adiponectin and cardiometabolic trait and mortality: where do we go?
Cardiovascular research
Adiponectin is an adipocyte-derived cytokine known for its cardioprotective effects in preclinical studies. Early epidemiologic studies replicated these findings and drew great interest. Subsequent large-scale prospective cohorts, however, showed that adiponectin levels seemed not to relate to incident coronary artery disease (CAD). Even more surprisingly, a paradoxical increase of all-cause and cardiovascular (CV) mortality with increased adiponectin levels was reported. The adiponectin-mortality paradox has been explained by some groups asserting that adiponectin secretion is promoted by elevated natriuretic peptides (NP). Other groups have proposed that adiponectin is elevated due to adiponectin resistance in subjects with metabolic syndrome or heart failure (HF). However, there is no unifying theory that can clearly explain this paradox. In patients with HF with reduced ejection fraction (HFrEF), stretched cardiomyocytes secrete NPs, which further promote release of adiponectin from adipose tissue, leading to adiponectin resistance. On the other hand, adiponectin biology may differ in patients with heart failure with preserved ejection fraction (HFpEF), which constitutes 50% of all of HF. Most HFpEF patients are obese, which exerts inflammation and myocardial stiffness, i.e. likely to prevent myocardial stretch and subsequent NP release. This segment of the patient population may display different adiponectin biology from its HFrEF counterpart. Dissecting the adiponectin-mortality relationship in terms of different HF subtypes may help to comprehensively understand this paradox. Mendelian randomization (MR) analyses claimed that adiponectin levels are not causally related to CAD or metabolic syndrome. Results from MR studies, however, should be interpreted with great caution because the underlying history of CAD or CHF was not taken into account in these analyses, an issue that may substantially confound the results. Here, we discuss many aspects of adiponectin; cardiometabolic traits, therapeutic interventions, and the ongoing debate about the adiponectin paradox, which were recently described in basic, epidemiologic, and clinical studies.
10.1093/cvr/cvab199
Association of 25-hydroxyvitamin D with cardiometabolic risk factors and metabolic syndrome: a mendelian randomization study.
Chen Chi,Chen Yi,Weng Pan,Xia Fangzhen,Li Qin,Zhai Hualing,Wang Ningjian,Lu Yingli
Nutrition journal
BACKGROUND:Low circulating vitamin D levels have been associated with increased risk of metabolic syndrome (MS) and cardiometabolic risk factors in multiple epidemiology studies. However, whether this association is causal is still unclear. We aimed to test whether genetically lowered vitamin D levels were associated with MS and its metabolic traits, using mendelian randomization (MR) methodology. METHODS:Ten thousand six hundred fifty-five participants were enrolled from the SPECT-China study, which was performed in 23 sites in East China during 2014 to 2016. Using four single-nucleotide polymorphisms (SNPs) in the DHCR7, CYP2R1, GC and CYP24A1 genes with known effects on 25(OH) D concentrations, we created a genetic risk score (GRS) as instrumental variable (IV) to estimate the effect of genetically lowered 25(OH) D on MS and cardiometabolic risk factors. MS was defined according to the International Diabetes Federation criteria. RESULTS:Lower measured 25(OH)D levels were associated with MS (OR 0.921, 95% CI 0.888, 0.954) after multivariable adjustment. However, the MR-derived odds ratio of genetically determined 25(OH) D for risk of MS was 0.977 (95% CI 0.966, 1.030). The MR-derived estimates for raised fasting plasma glucose was 0.578 (95% CI 0.321, 0.980) per 10 nmol/L GRS determined increase of 25(OH) D levels. CONCLUSIONS:We found no evidence that genetically determined reduction in 25(OH)D conferred an increased risk of MS and its metabolic traits. However, we created our GRS only on the basis of common variants, which represent limited amount of variance in 25(OH)D. MR studies using rare variants, and large-scale well-designed RCTs about the effect of vitamin D supplementation on MS are warranted to further validate the findings.
10.1186/s12937-019-0494-7
Association of serum 25-hydroxyvitamin D with metabolic syndrome and type 2 diabetes: a one sample Mendelian randomization study.
Xiao Jing,Lv Jingyi,Wang Shiyu,Zhou Yang,Chen Lunwen,Lu Juying,Zhang Xiaoyi,Wang Xiaojian,Gu Yunjuan,Lu Qingyun
BMC geriatrics
BACKGROUND:Vitamin D deficiency has been associated with type 2 diabetes (T2D) and metabolic syndrome (MS) and its components. However, it is unclear whether a low concentration of vitamin D is the cause or consequence of these health conditions. Thus, this study aimed to evaluate the association of vitamin D concentrations and its genetic risk scores (GRSs) with MS and its component diseases, such as T2D, in middle-aged and elderly participants from rural eastern China. METHODS:A subset of 2393 middle-aged and elderly individuals were selected from 70,458 participants of the Nantong Chronic Diseases Study of 2017-2018 in China. We used two 25-hydroxyvitamin D (25[OH]D) synthesis single-nucleotide polymorphisms (SNPs) (DHCR7-rs12785878 and CYP2R1-rs10741657) and two 25(OH) D metabolism SNPs (GC-rs2282679 and CYP24A1-rs6013897) for creating GRSs, which were used as instrumental variables to assess the effect of genetically lowered 25(OH) D concentrations on MS and T2D based on the Wald ratio. F statistics were used to validate that the four SNPs genetically determined 25(OH) D concentrations. RESULTS:Compared to vitamin D sufficient individuals, individuals with vitamin D insufficiency had an odds ratio (OR [95% confidence interval {CI}]) of MS of 1.30 (1.06-1.61) and of T2D of 1.32 (1.08-1.64), individuals with vitamin D deficiency had an ORs (95% CI) of MS of 1.50 (1.24-1.79) and of T2D of 1.47 (1.12-1.80), and those with vitamin D severe deficiency had an ORs (95% CI) of MS of 1.52 (1.29-1.85) and of T2D of 1.54 (1.27-1.85). Mendelian randomization analysis showed a 25-nmol/L decrease in genetically instrumented serum 25(OH) D concentrations using the two synthesis SNPs (DHCR7 and CYP2R1 genes) associated with the risk of T2D and abnormal diastolic blood pressure (DBP) with ORs of 1.10 (95%CI: 1.02-1.45) for T2D and 1.14 (95%CI: 1.03-1.43) for DBP. CONCLUSIONS:This one sample Mendelian randomization analysis shows genetic evidence for a causal role of lower 25(OH) D concentrations in promoting of T2D and abnormal DBP in middle-aged and elderly participants from rural China.
10.1186/s12877-021-02307-6
Components of the Metabolic Syndrome and Risk of Type 2 Diabetes.
Marott Sarah C W,Nordestgaard Børge G,Tybjærg-Hansen Anne,Benn Marianne
The Journal of clinical endocrinology and metabolism
CONTEXT:The metabolic syndrome (MetS) is associated with type 2 diabetes (T2D). However, whether each of the 5 components of the MetS individually is causally associated with T2D is unknown. OBJECTIVE:We tested the hypothesis that each component is causally associated with T2D. DESIGN:Mendelian randomization using genetic variations that alter levels of the MetS components are randomly assorted at gamete formation and free of confounding and reverse causation, which allows us to infer causality. SETTING:General community. STUDY PARTICIPANTS:A total of 95 756 individuals from the prospective Copenhagen General Population Study. MAIN OUTCOME MEASURE:Type 2 diabetes. RESULTS:A 1-cm larger waist circumference was associated with an observational 5% (95% confidence interval, 4%-5%) and a causal genetic 5% (1%-10%) higher risk of T2D. In contrast, although a 1-unit higher level of triglycerides and blood pressure and a 1-unit lower level of high-density lipoprotein cholesterol were associated with higher observational T2D risk, the corresponding causal genetic risks were not. As expected, a 1 mmol/L higher glucose level was associated with an observational 32% (30%-34%) and a causal genetic 82% (21%-173%) higher T2D risk. CONCLUSIONS:In conclusion, larger waist circumference and higher glucose levels were each causally associated with higher risk of T2D. Findings like these may change clinical thinking so that waist circumference control will be prioritized to the same extend as control of blood pressure, lipids, and glucose levels in T2D prevention.
10.1210/jc.2015-3777
Causal Effects of Metabolic Syndrome on Gastric Disorders: Univariable and Multivariable Mendelian Randomization.
The Journal of clinical endocrinology and metabolism
OBJECTIVES:This study aimed to investigate the causal effects of metabolic syndrome (MetS) components, including fasting blood glucose (FBG), HDL cholesterol (HDL-C), triglycerides (TG), waist circumference (WC), and hypertension, on the risks of chronic gastritis, benign gastric tumors, and gastric cancer using Mendelian randomization (MR) analyses. METHODS:Univariable two-sample Mendelian randomization (TSMR) and multivariable Mendelian randomization (MVMR) analyses were employed to evaluate the independent and combined effects of MetS components on gastric disorders. The primary MR method used was the random effects inverse variance weighted (IVW) approach. RESULTS:Univariable TSMR analysis identified significant associations between elevated TG (OR = 1.223, 95% CI: 1.011-1.480, p = 0.0386) and reduced HDL-C (OR = 0.833, 95% CI: 0.701-0.989, p = 0.037) with an increased risk of benign gastric tumors. However, these associations were not confirmed by MVMR for TG (OR = 1.187, 95% CI: 0.891-1.581, p = 0.2408) or HDL-C (OR = 0.989, 95% CI: 0.758-1.289, p = 0.932). Both TSMR (OR = 0.585, 95% CI: 0.411-0.831, p = 0.003) and MVMR (OR = 0.558, 95% CI: 0.334-0.930, p = 0.025) indicated that hypertension is associated with a reduced risk of gastric cancer. No significant associations were found for other MetS components and gastric disorders. CONCLUSIONS:The findings suggest that specific MetS components, such as TG and HDL-C, may affect the risk of benign gastric tumors, while hypertension might reduce the risk of gastric cancer. This study highlights the need for further research to understand the underlying mechanisms and potential indirect effects between MetS components and gastric disorders.
10.1210/clinem/dgae843
Exploring the causal relationship between asthma in the metabolic syndrome: a Mendelian randomization study.
The Journal of asthma : official journal of the Association for the Care of Asthma
BACKGROUND:Previous observational studies have indicated a potential association between metabolic syndrome (MetS) and asthma, though the causal nature of this connection is still uncertain. Our study used Mendelian randomization (MR) to examine the causal relationship between metabolic syndrome (MetS) and its components with asthma. METHODS:This study utilized single nucleotide polymorphisms (SNPs) related to MetS and its components, sourced from publicly available genome-wide association studies (GWAS) data, in combination with asthma data from the FinnGen database. Statistical analyses were conducted using the inverse variance weighted method (IVW), MR-Egger, and weighted median method. The robustness of the findings was confirmed through various sensitivity analyses. RESULTS:The IVW analysis indicated that MetS was associated with an increased risk of asthma (OR = 1.0781, 95% CI = 1.0255-1.1333, = 0.0032). Among the components of MetS, waist circumference (WC) showed a strong association with asthma (OR = 1.4777, 95% CI = 1.3412-1.6281, = 2.8707 × 10). Conversely, high-density lipoprotein cholesterol (HDL-C) was found to be inversely related to the risk of asthma (OR = 0.9186, 95% CI = 0.8669-0.9734, = 0.0041). CONCLUSION:The findings of this study support that MetS and its specific components, particularly abdominal obesity, are linked to a higher risk of asthma, while HDL-C might offer protective effects against asthma. These findings provide a foundation both for further research and possible therapeutic interventions.
10.1080/02770903.2024.2394143
Integrative multi-omics analysis of Crohn's disease and metabolic syndrome: Unveiling the underlying molecular mechanisms of comorbidity.
Computers in biology and medicine
OBJECTIVES:The focus of this study is on identifying a potential association between Crohn's disease (CD), a chronic inflammatory bowel condition, and metabolic syndrome (Mets), characterized by a cluster of metabolic abnormalities, including high blood pressure, abnormal lipid levels, and overweight. While the link between CD and MetS has been suggested in the medical community, the underlying molecular mechanisms remain largely unexplored. METHODS:Using microarray data from the Gene Expression Omnibus (GEO) database, we conducted a differential gene expression analysis and applied Weighted Gene Co-expression Network Analysis (WGCNA) to identify genes shared between CD and MetS. To further elucidate the functions of these shared genes, we performed Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses and constructed protein-protein interaction (PPI) networks. For key gene screening, we used Random Forest and Least Absolute Shrinkage and Selection Operator (LASSO) regression and constructed a diagnostic prediction model with the Extreme Gradient Boosting (XGBoost) algorithm. Additionally, CIBERSORT and Gene Set Variation Analysis (GSVA) were employed to examine the relationships between these genes and immune cell infiltration, as well as metabolic pathways. Mendelian randomization and colocalization analyses were also conducted to explore causal links between genes and disease. Lastly, single-cell RNA sequencing (scRNA-seq) was used to validate the functionality of these key genes. RESULTS:Through the use of the limma R package and WGCNA, we identified 1767 co-expressed genes common to both CD and MetS, which are notably enriched in pathways related to immune responses and metabolic regulation. After thorough analysis, 34 key genes were highlighted, demonstrating their potential utility in prognostic models. These genes were closely linked to tissue immune responses and metabolic functions. Subsequent scRNA-seq analysis confirmed the strong diagnostic potential of PIM2 and PBX2, with especially prominent expression in T and B cells. CONCLUSION:This study identifies shared regulatory genes between CD and MetS, advancing the development of precise diagnostic tools. In particular, PIM2 and PBX2 were found to be positively associated with hypoxia and hemoglobin metabolism pathways, suggesting their involvement in the modulation of cellular processes. These findings improve our understanding of the molecular mechanisms underlying the comorbidity of CD and MetS, offering novel targets for integrated therapeutic interventions.
10.1016/j.compbiomed.2024.109365
Multivariate genomic analysis of 5 million people elucidates the genetic architecture of shared components of the metabolic syndrome.
Nature genetics
Metabolic syndrome (MetS) is a complex hereditary condition comprising various metabolic traits as risk factors. Although the genetics of individual MetS components have been investigated actively through large-scale genome-wide association studies, the conjoint genetic architecture has not been fully elucidated. Here, we performed the largest multivariate genome-wide association study of MetS in Europe (n = 4,947,860) by leveraging genetic correlation between MetS components. We identified 1,307 genetic loci associated with MetS that were enriched primarily in brain tissues. Using transcriptomic data, we identified 11 genes associated strongly with MetS. Our phenome-wide association and Mendelian randomization analyses highlighted associations of MetS with diverse diseases beyond cardiometabolic diseases. Polygenic risk score analysis demonstrated better discrimination of MetS and predictive power in European and East Asian populations. Altogether, our findings will guide future studies aimed at elucidating the genetic architecture of MetS.
10.1038/s41588-024-01933-1
Causal effect between gut microbiota and metabolic syndrome in European population: a bidirectional mendelian randomization study.
Cell & bioscience
BACKGROUND:Observational studies have reported that gut microbiota composition is associated with metabolic syndrome. However, the causal effect of gut microbiota on metabolic syndrome has yet to be confirmed. METHODS:We performed a bidirectional Mendelian randomization study to investigate the causal effect between gut microbiota and metabolic syndrome in European population. Summary statistics of gut microbiota were from the largest available genome-wide association study meta-analysis (n = 13,266) conducted by the MiBioGen consortium. The summary statistics of outcome were obtained from the most comprehensive genome-wide association studies of metabolic syndrome (n = 291,107). The inverse-variance weighted method was applied as the primary method, and the robustness of the results was assessed by a series of sensitivity analyses. RESULTS:In the primary causal estimates, Actinobacteria (OR = 0.935, 95% CI = 0.878-0.996, P = 0.037), Bifidobacteriales (OR = 0.928, 95% CI = 0.868-0.992, P = 0.028), Bifidobacteriaceae (OR = 0.928, 95% CI = 0.868-0.992, P = 0.028), Desulfovibrio (OR = 0.920, 95% CI = 0.869-0.975, P = 0.005), and RuminococcaceaeUCG010 (OR = 0.882, 95% CI = 0.803-0.969, P = 0.009) may be associated with a lower risk of metabolic syndrome, while Lachnospiraceae (OR = 1.130, 95% CI = 1.016-1.257, P = 0.025), Veillonellaceae (OR = 1.055, 95% CI = 1.004-1.108, P = 0.034) and Olsenella (OR = 1.046, 95% CI = 1.009-1.085, P = 0.015) may be linked to a higher risk for metabolic syndrome. Reverse MR analysis demonstrated that abundance of RuminococcaceaeUCG010 (OR = 0.938, 95% CI = 0.886-0.994, P = 0.030) may be downregulated by metabolic syndrome. Sensitivity analyses indicated no heterogeneity or horizontal pleiotropy. CONCLUSIONS:Our Mendelian randomization study provided causal relationship between specific gut microbiota and metabolic syndrome, which might provide new insights into the potential pathogenic mechanisms of gut microbiota in metabolic syndrome and the assignment of effective therapeutic strategies.
10.1186/s13578-024-01232-6
Causal link between metabolic related factors and osteoarthritis: a Mendelian randomization investigation.
Li Kai, Leng Yan, Lei Di, Zhang Haojie, Ding Minghui, Lo Wai Leung Ambrose
INTRODUCTION: Metabolic syndrome (MetS) is significantly associated with osteoarthritis (OA), especially in MetS patients with blood glucose abnormalities, such as elevated fasting blood glucose (FG), which may increase OA risk. Dietary modifications, especially the intake of polyunsaturated fatty acids (PUFAs), are regarded as a potential means of preventing MetS and its complications. However, regarding the effects of FG, Omega-3s, and Omega-6s on OA, the research conclusions are conflicting, which is attributed to the complexity of the pathogenesis of OA. Therefore, it is imperative to thoroughly evaluate multiple factors to fully understand their role in OA, which needs further exploration and clarification. METHODS: Two-sample univariable Mendelian randomization (UVMR) and multivariable Mendelian randomization (MVMR) were employed to examine the causal effect of metabolic related factors on hip OA (HOA) or knee OA (KOA). The exposure and outcome datasets were obtained from Open GWAS IEU. All cases were independent European ancestry data. Three MR methods were performed to estimate the causal effect: inverse-variance weighting (IVW), weighted median method (WMM), and MR-Egger regression. Additionally, the intercept analysis in MR-Egger regression is used to estimate pleiotropy, and the IVW method and MR-Egger regression are used to test the heterogeneity. RESULTS: The UVMR analysis revealed a causal relationship between FG and HOA. By MVMR analysis, the study discovered a significant link between FG (OR = 0.79, 95%CI: 0.64∼0.99, p = 0.036) and KOA after accounting for body mass index (BMI), age, and sex hormone-binding globulin (SHBG). However, no causal effects of FG on HOA were seen. Omega-3s and Omega-6s did not have a causal influence on HOA or KOA. No significant evidence of pleiotropy was identified. DISCUSSION: The MR investigation showed a protective effect of FG on KOA development but no causal relationship between FG and HOA. No causal effect of Omega-3s and Omega-6s on HOA and KOA was observed. Shared genetic overlaps might also exist between BMI and age, SHBG and PUFAs for OA development. This finding offers a novel insight into the treatment and prevention of KOA from glucose metabolism perspective. The FG cutoff value should be explored in the future, and consideration should be given to demonstrating the study in populations other than Europeans.
10.3389/fnut.2024.1424286
The causal relationship between metabolic syndrome and its components and cardiovascular disease: A mendelian randomization study.
Diabetes research and clinical practice
AIM:To investigate the causal relationship between metabolic syndrome (MetS) and its components and 14 cardiovascular diseases using Mendelian randomization (MR). METHODS:We used summary statistics from large-scale genome-wide association studies of MetS, its components, and cardiovascular diseases. We performed a two-sample MR analysis using the inverse-variance weighted method and other sensitivity methods. We also performed multivariate MR to adjust for potential risk factors. RESULTS:Our study found that MetS was causally associated with an increased risk of ischemic stroke, abdominal aortic aneurysm, pulmonary embolism, coronary heart disease, heart failure, and peripheral artery disease. Waist circumference was causally associated with an increased risk of 6 cardiovascular diseases. Type 2 diabetes mellitus, diastolic blood pressure, systolic blood pressure, triglycerides, and high-density lipoprotein cholesterol were all causally associated with coronary heart disease, with varying causal relationships with the remaining 5 cardiovascular diseases. Multivariate MR showed that, except for ischaemic stroke, waist circumference remained causally associated with the remaining five cardiovascular diseases after adjusting for potential confounders. CONCLUSION:Our study provides evidence that metabolic syndrome is causally associated with 6 cardiovascular diseases. Waist circumference is the most important component of these relationships. These findings have implications for the prevention and management of metabolic syndrome and cardiovascular diseases.
10.1016/j.diabres.2024.111679
Genetic Links Between Metabolic Syndrome and Osteoarthritis: Insights From Cross-Trait Analysis.
The Journal of clinical endocrinology and metabolism
CONTEXT:Previous observational studies have indicated a bidirectional association between metabolic syndrome (MetS) and osteoarthritis (OA). However, it remains unclear whether these bidirectional associations reflect causal relationships or shared genetic factors, and the underlying biological mechanisms of this association are not fully understood. OBJECTIVE:We aimed to explore the genetic connection between MetS and OA using genome-wide association study (GWAS) summary data. METHODS:Leveraging summary statistics from GWAS conducted by the UK Biobank and the Glucose and Insulin-related Traits Consortium (MAGIC), we performed global genetic correlation analyses, genome-wide cross-trait meta-analyses, and a bidirectional two-sample Mendelian randomization analyses using summary statistics from GWAS to comprehensively assess the relationship of MetS and OA. RESULTS:We first detected an extensive genetic correlation between MetS and OA (rg = 0.393, P = 1.52 × 10-18), which was consistent in 4 MetS components, including waist circumference, triglycerides, hypertension, and high-density lipoprotein cholesterol and OA with rg ranging from -0.229 to 0.490. We then discovered 32 variants jointly associated with MetS and OA through Multi-Trait Analysis of GWAS (MTAG). Co-localization analysis found 12 genes shared between MetS and OA, with functional implications in several biological pathways. Finally, Mendelian randomization analysis suggested genetic liability to MetS significantly increased the risk of OA, but no reverse causality was found. CONCLUSION:Our results illustrate a common genetic architecture, pleiotropic loci, as well as causality between MetS and OA, potentially enhancing our knowledge of high comorbidity and genetic processes that overlap between the 2 disorders.
10.1210/clinem/dgae169
Metabolic syndrome and the plasma proteome: from association to causation.
Elhadad Mohamed A,Wilson Rory,Zaghlool Shaza B,Huth Cornelia,Gieger Christian,Grallert Harald,Graumann Johannes,Rathmann Wolfgang,Koenig Wolfgang,Sinner Moritz F,Hveem Kristian,Suhre Karsten,Thorand Barbara,Jonasson Christian,Waldenberger Melanie,Peters Annette
Cardiovascular diabetology
BACKGROUND:The metabolic syndrome (MetS), defined by the simultaneous clustering of cardio-metabolic risk factors, is a significant worldwide public health burden with an estimated 25% prevalence worldwide. The pathogenesis of MetS is not entirely clear and the use of molecular level data could help uncover common pathogenic pathways behind the observed clustering. METHODS:Using a highly multiplexed aptamer-based affinity proteomics platform, we examined associations between plasma proteins and prevalent and incident MetS in the KORA cohort (n = 998) and replicated our results for prevalent MetS in the HUNT3 study (n = 923). We applied logistic regression models adjusted for age, sex, smoking status, and physical activity. We used the bootstrap ranking algorithm of least absolute shrinkage and selection operator (LASSO) to select a predictive model from the incident MetS associated proteins and used area under the curve (AUC) to assess its performance. Finally, we investigated the causal effect of the replicated proteins on MetS using two-sample Mendelian randomization. RESULTS:Prevalent MetS was associated with 116 proteins, of which 53 replicated in HUNT. These included previously reported proteins like leptin, and new proteins like NTR domain-containing protein 2 and endoplasmic reticulum protein 29. Incident MetS was associated with 14 proteins in KORA, of which 13 overlap the prevalent MetS associated proteins with soluble advanced glycosylation end product-specific receptor (sRAGE) being unique to incident MetS. The LASSO selected an eight-protein predictive model with an (AUC = 0.75; 95% CI = 0.71-0.79) in KORA. Mendelian randomization suggested causal effects of three proteins on MetS, namely apolipoprotein E2 (APOE2) (Wald-Ratio = - 0.12, Wald-p = 3.63e-13), apolipoprotein B (APOB) (Wald-Ratio = - 0.09, Wald-p = 2.54e-04) and proto-oncogene tyrosine-protein kinase receptor (RET) (Wald-Ratio = 0.10, Wald-p = 5.40e-04). CONCLUSIONS:Our findings offer new insights into the plasma proteome underlying MetS and identify new protein associations. We reveal possible casual effects of APOE2, APOB and RET on MetS. Our results highlight protein candidates that could potentially serve as targets for prevention and therapy.
10.1186/s12933-021-01299-2
Education and metabolic syndrome: a Mendelian randomization study.
Frontiers in nutrition
Aims:The metabolic syndrome (MetS), a collection of conditions that heighten the risk of disease development and impose economic burdens on patients. However, the causal relationship between education and MetS was uncertain. In this study, the Mendelian randomization (MR) method was employed to elucidate the potential causal link between education and the MetS and its components. Method:Single nucleotide polymorphisms (SNPs) associated with education, MetS, and its components were sourced from a public database, with the inverse variance-weighted (IVW) method utilized for analysis. Results:Education demonstrated a significant negative correlation with the risk of MetS (OR = 0.55, 95% CI = 0.48-0.63, = 2.18E-51), waist circumference(OR = 0.80, 95% CI = 0.76-0.83, = 4.98E-33), hypertension (OR = 0.96, 95% CI = 0.95-0.97; = 4.54E-10), Fasting blood glucose (OR = 0.94, 95% CI = 0.91-0.97, = 7.58E-6) and triglycerides (OR = 0.83, 95% CI = 0.79-0.87, = 7.87E-18) while showing a positive association with high-density lipoprotein cholesterol (OR = 1.22, 95% CI = 1.18-1.25, = 1.45E-31). Conclusion:The findings of this study suggest that education can decrease the incidence of MetS.
10.3389/fnut.2024.1477537
Mendelian Randomization Analysis Identifies Inverse Causal Relationship between External Eating and Metabolic Phenotypes.
Nutrients
Disordered eating contributes to weight gain, obesity, and type 2 diabetes (T2D), but the precise mechanisms underlying the development of different eating patterns and connecting them to specific metabolic phenotypes remain unclear. We aimed to identify genetic variants linked to eating behaviour and investigate its causal relationships with metabolic traits using Mendelian randomization (MR). We tested associations between 30 genetic variants and eating patterns in individuals with T2D from the Volga-Ural region and investigated causal relationships between variants associated with eating patterns and various metabolic and anthropometric traits using data from the Volga-Ural population and large international consortia. We detected associations between and and external eating; between and emotional eating; between , , , , , , and T2D. Further analyses in a separate group revealed significant associations between metabolic syndrome (MetS) and the loci in , , , , , , , , and genes. MR results demonstrated an inverse causal relationship between external eating and glycated haemoglobin levels in the Volga-Ural sample. External eating influenced anthropometric traits such as body mass index, height, hip circumference, waist circumference, and weight in GWAS cohorts. Our findings suggest that eating patterns impact both anthropometric and metabolic traits.
10.3390/nu16081166
Relationships between body fat distribution and metabolic syndrome traits and outcomes: A mendelian randomization study.
PloS one
BACKGROUND:Obesity is a complex, multifactorial disease associated with substantial morbidity and mortality worldwide. Although it is frequently assessed using BMI, many epidemiological studies have shown links between body fat distribution and obesity-related outcomes. This study examined the relationships between body fat distribution and metabolic syndrome traits using Mendelian Randomization (MR). METHODS/FINDINGS:Genetic variants associated with visceral adipose tissue (VAT), abdominal subcutaneous adipose tissue (ASAT), and gluteofemoral adipose tissue (GFAT), as well as their relative ratios, were identified from a genome wide association study (GWAS) performed with the United Kingdom BioBank. GWAS summary statistics for traits and outcomes related to metabolic syndrome were obtained from the IEU Open GWAS Project. Two-sample MR and BMI-controlled multivariable MR (MVMR) were performed to examine relationships between each body fat measure and ratio with the outcomes. Increases in absolute GFAT were associated with a protective cardiometabolic profile, including lower low density lipoprotein cholesterol (β: -0.19, [95% CI: -0.28, -0.10], p < 0.001), higher high density lipoprotein cholesterol (β: 0.23, [95% CI: 0.03, 0.43], p = 0.025), lower triglycerides (β: -0.28, [95% CI: -0.45, -0.10], p = 0.0021), and decreased systolic (β: -1.65, [95% CI: -2.69, -0.61], p = 0.0019) and diastolic blood pressures (β: -0.95, [95% CI: -1.65, -0.25], p = 0.0075). These relationships were largely maintained in BMI-controlled MVMR analyses. Decreases in relative GFAT were linked with a worse cardiometabolic profile, with higher levels of detrimental lipids and increases in systolic and diastolic blood pressures. CONCLUSION:A MR analysis of ASAT, GFAT, and VAT depots and their relative ratios with metabolic syndrome related traits and outcomes revealed that increased absolute and relative GFAT were associated with a favorable cardiometabolic profile independently of BMI. These associations highlight the importance of body fat distribution in obesity and more precise means to categorize obesity beyond BMI.
10.1371/journal.pone.0293017
Genome-wide association study of self-reported walking pace suggests beneficial effects of brisk walking on health and survival.
Communications biology
Walking is a simple form of exercise, widely promoted for its health benefits. Self-reported walking pace has been associated with a range of cardiorespiratory and cancer outcomes, and is a strong predictor of mortality. Here we perform a genome-wide association study of self-reported walking pace in 450,967 European ancestry UK Biobank participants. We identify 70 independent associated loci (P < 5 × 10), 11 of which are novel. We estimate the SNP-based heritability as 13.2% (s.e. = 0.21%), reducing to 8.9% (s.e. = 0.17%) with adjustment for body mass index. Significant genetic correlations are observed with cardiometabolic, respiratory and psychiatric traits, educational attainment and all-cause mortality. Mendelian randomization analyses suggest a potential causal link of increasing walking pace with a lower cardiometabolic risk profile. Given its low heritability and simple measurement, these findings suggest that self-reported walking pace is a pragmatic target for interventions aiming for general benefits on health.
10.1038/s42003-020-01357-7
Linking Physical Activity to Breast Cancer Risk via Insulin/Insulin-Like Growth Factor Signaling System, Part 1: The Effect of Physical Activity on the Insulin/Insulin-Like Growth Factor Signaling System.
Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology
Physical activity may reduce the risk of developing breast cancer via its effect on the insulin/insulin-like growth factor (IGF) signaling system. A systematic review searched for randomized controlled trials (RCT), Mendelian randomization and prospective cohort studies that examined the effects of physical activity on insulin/IGF signaling [IGFs, their binding proteins (IGFBP), and markers of insulin resistance] in adult women. Meta-analyses were performed to generate effect estimates. Risk of bias was assessed, and the Grading of Recommendations Assessment, Development, and Evaluation system used to determine the overall quality of the evidence. Fifty-eight RCTs met our inclusion criteria, no observational or Mendelian randomization studies met the criteria for inclusion. Meta-analyses indicated that physical activity interventions (vs. control) reduced fasting insulin, the Homeostatic Model Assessment for Insulin Resistance and fasting glucose. Physical activity increased IGF-1, but there was no clear effect on IGFBP-3 or the ratio of IGF-1:IGFBP-3. Strong evidence was only established for fasting insulin and insulin resistance. Further research is needed to examine the effect of physical activity on C-peptide and HBA1c in women. Reductions in fasting insulin and insulin resistance following exercise suggest some biological plausibility of the first part of the physical activity-insulin/IGF signaling-breast cancer pathway. See related article by Drummond et al., p. 2116.
10.1158/1055-9965.EPI-22-0504
Linking Physical Activity to Breast Cancer Risk via Inflammation, Part 1: The Effect of Physical Activity on Inflammation.
Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology
The protective effect of physical activity on breast cancer incidence may partially be mediated by inflammation. Systematic searches of Medline, EMBASE, and SPORTDiscus were performed to identify intervention studies, Mendelian randomization studies, and prospective cohort studies that examined the effects of physical activity on circulating inflammatory biomarkers in adult women. Meta-analyses were performed to generate effect estimates. Risk of bias was assessed, and the Grading of Recommendations Assessment, Development, and Evaluation system was used to determine the overall quality of the evidence. Thirty-five intervention studies and one observational study met the criteria for inclusion. Meta-analyses of randomized controlled trials (RCT) indicated that, compared with control groups, exercise interventions reduced levels of C-reactive protein (CRP) [standardized mean difference (SMD) = -0.27, 95% confidence interval (CI) = -0.62 to 0.08), tumor necrosis factor alpha (TNFα, SMD = -0.63, 95% CI = -1.04 to -0.22), interleukin-6 (IL6, SMD = -0.55, 95% CI = -0.97 to -0.13) and leptin (SMD = -0.50, 95% CI = -1.10 to 0.09). Owing to heterogeneity in effect estimates and imprecision, evidence strength was graded as low (CRP, leptin) or moderate (TNFα and IL6). High-quality evidence indicated that exercise did not change adiponectin levels (SMD = 0.01, 95% CI = -0.14 to 0.17). These findings provide support for the biological plausibility of the first part of the physical activity-inflammation-breast cancer pathway.
10.1158/1055-9965.EPI-22-0928
Causal effects of various types of physical activities on psychiatric disorders: a Mendelian randomization study.
Frontiers in sports and active living
Background:Psychiatric disorders (PD) pose a significant burden, with vast prevalence and mortality, inflicting substantial costs on individuals and society. Despite its widespread prevalence, the complex pathogenesis of PD remains elusive, leading to limited and challenging therapeutic development. An emerging risk factor for chronic diseases, prolonged sedentary behavior, contrasts with the therapeutic potential of exercise, regardless of its intensity, for various ailments, including PD. Yet, the diversity in exercise modalities and intensities may offer varied impacts on health. This study, leveraging Mendelian Randomization (MR), seeks to investigate the causal relationship between exercise and PD, aiming to elucidate the optimal exercise modality and intensity for PD mitigation while addressing potential confounders. Methods:This study employed a Mendelian randomization analysis using the genome-wide association study (GWAS) database to investigate the causal relationship between types of physical activity and psychiatric disorders. Sensitivity analysis was conducted to demonstrate the reliability and robustness of the results. Results:In the past 4 weeks, engaging in a substantial amount of DIY physical activity was found to have a causal relationship with psychiatric disorders (IVW: OR = 0.228, 95% CI: 0.113-0.461, = 0.000038). As for the types of exercises, there may be a potential causal association between aerobic training (including swimming, cycling, fitness, and bowling) and psychiatric disorders (IVW: OR = 0.322, 95% CI = 0.148-0.704, = 0.004). However, there was no causal relationship found between mild DIY physical activity and psychiatric disorders (IVW: OR = 0.918, 95% CI = 0.417-2.021, = 0.831). Furthermore, it seems that there is no causal relationship between vigorous exercise and psychiatric disorders (IVW: OR = 2.705, 95% CI = 0.081-3.419, = 0.578). Conclusion:Our study confirms that only a certain level of training activity can have a protective effect on psychiatric disorders, while mild physical activity or vigorous training does not have an impact on psychiatric disorders.
10.3389/fspor.2024.1331586
A mendelian randomisation study of the causal effect of exercise intensity on the development of type 2 diabetes.
Frontiers in physiology
Objective:This study examines the causal effects of varying exercise intensities on type 2 diabetes mellitus (T2D) through Mendelian randomization (MR) analysis, using genetic variants as instrumental variables. Methods:A two-sample MR analysis was performed, employing Inverse Variance Weighted (IVW) as the primary method, supported by weighted median, MR-Egger regression, MR-PRESSO, and MR robustness-adjusted contour scores. Data were obtained from the International Exercise Genetics Database (IEGD) and the Global Diabetes Research Consortium (GRC), encompassing over 150,000 individuals for exercise intensity and around 200,000 T2D patients and controls. SNPs linked to exercise intensity were selected based on genome-wide significance ( < 5 × 10^-8) and linkage disequilibrium criteria (distance >10,000 kb, r^2 < 0.001). Results:The IVW analysis suggested that high-intensity exercise might reduce T2D risk, but the association was not statistically significant (OR = 0.667, 95% CI = 0.104-4.255, = 0.667). The wide confidence interval indicates uncertainty in the effect estimate. Low-intensity exercise showed no significant effect on T2D risk (OR ∼ 1.0). Sensitivity analyses, including weighted median and MR-Egger regression, confirmed no significant association between high-intensity exercise and T2D risk. The MR-PRESSO analysis found no significant outliers, and the global test for pleiotropy was non-significant ( = 0.455). Cochran's Q test for heterogeneity in the IVW analysis was non-significant (Q = 12.45, = 0.234), indicating consistency among SNP-derived estimates. Conclusion:High-intensity exercise potentially reduces T2D risk, but the association is not statistically significant. Further research is needed to understand the complex relationship between exercise intensity and T2D.
10.3389/fphys.2024.1378329
Dose response of running on blood biomarkers of wellness in generally healthy individuals.
PloS one
Exercise is effective toward delaying or preventing chronic disease, with a large body of evidence supporting its effectiveness. However, less is known about the specific healthspan-promoting effects of exercise on blood biomarkers in the disease-free population. In this work, we examine 23,237 generally healthy individuals who self-report varying weekly running volumes and compare them to 4,428 generally healthy sedentary individuals, as well as 82 professional endurance runners. We estimate the significance of differences among blood biomarkers for groups of increasing running levels using analysis of variance (ANOVA), adjusting for age, gender, and BMI. We attempt and add insight to our observational dataset analysis via two-sample Mendelian randomization (2S-MR) using large independent datasets. We find that self-reported running volume associates with biomarker signatures of improved wellness, with some serum markers apparently being principally modified by BMI, whereas others show a dose-effect with respect to running volume. We further detect hints of sexually dimorphic serum responses in oxygen transport and hormonal traits, and we also observe a tendency toward pronounced modifications in magnesium status in professional endurance athletes. Thus, our results further characterize blood biomarkers of exercise and metabolic health, particularly regarding dose-effect relationships, and better inform personalized advice for training and performance.
10.1371/journal.pone.0293631
Walking pace is a protective factor for rheumatoid arthritis: a mendelian randomization study.
Scientific reports
Walking pace is a simple and functional form of exercise and a strong predictor of health, but little is known about its causal association with rheumatoid arthritis. This study aimed to investigate the causal effect of WP on the developing RA using Mendelian randomization analysis. The genetic variation associated with WP was selected as an instrumental variable from the latest genome-wide association studies. Summary-level data for the outcomes were obtained from the corresponding GWAS. The inverse-variance weighted method was used as the primary MR analysis. The results were further tested using a multivariable MR approach based on Bayesian model averaging. Confounders (BMI, SMK, HBP, TD) with close associations with RA were included in the analysis. An observational study with individual data from UK Biobank was performed to reinforce our findings. The MR results indicated the significant inverse associations of WP with the risk of RA (odds ratio (OR), 0.31; 95% confidence interval (CI), 0.15, 0.62; p = 1.05 × 10 -3). After adjusting for the risk factors, the associations for WP and RA did not change substantially. Observational study results demonstrated the same effect of WP on reducing the risk of RA. The Mendelian randomization analysis and observational study provide evidence suggesting that walking pace is a protective factor for rheumatoid arthritis. Given its simple measurement, walking pace may be a pragmatic target for interventions.
10.1038/s41598-024-76666-6
Serum proteomic profiling of physical activity reveals CD300LG as a novel exerkine with a potential causal link to glucose homeostasis.
eLife
Background:Physical activity has been associated with preventing the development of type 2 diabetes and atherosclerotic cardiovascular disease. However, our understanding of the precise molecular mechanisms underlying these effects remains incomplete and good biomarkers to objectively assess physical activity are lacking. Methods:We analyzed 3072 serum proteins in 26 men, normal weight or overweight, undergoing 12 weeks of a combined strength and endurance exercise intervention. We estimated insulin sensitivity with hyperinsulinemic euglycemic clamp, maximum oxygen uptake, muscle strength, and used MRI/MRS to evaluate body composition and organ fat depots. Muscle and subcutaneous adipose tissue biopsies were used for mRNA sequencing. Additional association analyses were performed in samples from up to 47,747 individuals in the UK Biobank, as well as using two-sample Mendelian randomization and mice models. Results:Following 12 weeks of exercise intervention, we observed significant changes in 283 serum proteins. Notably, 66 of these proteins were elevated in overweight men and positively associated with liver fat before the exercise regimen, but were normalized after exercise. Furthermore, for 19.7 and 12.1% of the exercise-responsive proteins, corresponding changes in mRNA expression levels in muscle and fat, respectively, were shown. The protein CD300LG displayed consistent alterations in blood, muscle, and fat. Serum CD300LG exhibited positive associations with insulin sensitivity, and to angiogenesis-related gene expression in both muscle and fat. Furthermore, serum CD300LG was positively associated with physical activity and negatively associated with glucose levels in the UK Biobank. In this sample, the association between serum CD300LG and physical activity was significantly stronger in men than in women. Mendelian randomization analysis suggested potential causal relationships between levels of serum CD300LG and fasting glucose, 2 hr glucose after an oral glucose tolerance test, and HbA1c. Additionally, Cd300lg responded to exercise in a mouse model, and we observed signs of impaired glucose tolerance in male, but not female, knockout mice. Conclusions:Our study identified several novel proteins in serum whose levels change in response to prolonged exercise and were significantly associated with body composition, liver fat, and glucose homeostasis. Serum CD300LG increased with physical activity and is a potential causal link to improved glucose levels. CD300LG may be a promising exercise biomarker and a therapeutic target in type 2 diabetes. Funding:South-Eastern Norway Regional Health Authority, Simon Fougners Fund, Diabetesforbundet, Johan Selmer Kvanes' legat til forskning og bekjempelse av sukkersyke. The UK Biobank resource reference 53641. Australian National Health and Medical Research Council Investigator Grant (APP2017942). Australian Research Council Discovery Early Career Award (DE220101226). Research Council of Norway (Project grant: 325640 and Mobility grant: 287198). The Medical Student Research Program at the University of Oslo. Novo Nordisk Fonden Excellence Emerging Grant in Endocrinology and Metabolism 2023 (NNF23OC0082123). Clinical trial number:clinicaltrials.gov: NCT01803568.
10.7554/eLife.96535
Investigating the Causal Effects of Exercise-Induced Genes on Sarcopenia.
International journal of molecular sciences
Exercise is increasingly recognized as an effective strategy to counteract skeletal muscle aging and conditions such as sarcopenia. However, the specific exercise-induced genes responsible for these protective effects remain unclear. To address this, we conducted an eight-week aerobic exercise regimen on late-middle-aged mice and developed an integrated approach that combines mouse exercise-induced genes with human GWAS datasets to identify causal genes for sarcopenia. This approach led to significant improvements in the skeletal muscle phenotype of the mice and the identification of exercise-induced genes and miRNAs. By constructing a miRNA regulatory network enriched with transcription factors and GWAS signals related to muscle function and traits, we focused on 896 exercise-induced genes. Using human skeletal muscle -eQTLs as instrumental variables, 250 of these exercise-induced genes underwent two-sample Mendelian randomization analysis, identifying 40, 68, and 62 causal genes associated with sarcopenia and its clinical indicators-appendicular lean mass (ALM) and hand grip strength (HGS), respectively. Sensitivity analyses and cross-phenotype validation confirmed the robustness of our findings. Consistently across the three outcomes, , , , , and were identified as risk factors, while , , , , and were identified as protective factors, all with potential as biomarkers for sarcopenia progression. Biological activity and disease association analyses suggested that exercise exerts its anti-sarcopenia effects primarily through the regulation of fatty acid oxidation. Based on available drug-gene interaction data, 21 of the causal genes are druggable, offering potential therapeutic targets. Our findings highlight key genes and molecular pathways potentially responsible for the anti-sarcopenia benefits of exercise, offering insights into future therapeutic strategies that could mimic the safe and mild protective effects of exercise on age-related skeletal muscle degeneration.
10.3390/ijms251910773
Impact of exercise training on gut microbiome imbalance in obese individuals: a study based on Mendelian randomization analysis.
Frontiers in physiology
The aim of this study was to investigate the relationship between exercise and gut Microbiome and to assess its possible causality. Using Mendelian randomization (MR) research methods, we collected genetic data from different populations, including genetic variants associated with relative abundance or presence of microbial taxa as instrumental variables. At the same time, we extracted results related to obesity and gut Microbiome from existing relevant studies and used inverse variance weighting (IVW), weighted median, and MR-Egger regression to assess the causal relationship between obesity and gut Microbiome. We plotted forest plots and scatter plots of the association between obesity and gut Microbiome. Gut Microbiome was positively associated with obesity, and four bacterial genera (Akkermansia, RuminococcaceaeUCG011, Holdemania, and Intestinimonas) were associated with obesity according to inverse variance-weighted estimation in at least one MR method. Inverse variance weighted estimation showed that obesity was associated with obesity in Akkermansia (OR = 0.810, 95% CI 0.608-1.079, = 0.04), RuminococcaceaeUCG011 (OR = 1.238, 95% CI 0. 511-2.999, = 0.04), Holdemania Intestinimonas (OR = 1.214, 95% CI 1.002-1.470, = 0.03), and Intestinimonas (OR = 0.747, 95% CI 0.514-1.086, = 0.01) had a relevant effect. Obesity decreased the abundance of Akkermansia, Intestinimonas microbiome and increased the abundance of RuminococcaceaeUCG011, Holdemania microbiome. The results of this study, conducted using a two-sample Mendelian randomization method, suggest a causal relationship between obesity and intestinal microbiome. Obesity decreased the abundance of Akkermansia, Intestinimonas microbiome and increased the abundance of RuminococcaceaeUCG011, Holdemania microbiome. More randomized controlled trials are necessary to elucidate the protective effects of exercise on gut Microbiome and its unique protective mechanisms.
10.3389/fphys.2023.1264931
Association of Physical Activity with Asthma and Chronic Obstructive Pulmonary Disease and Mediation of Frailty: Mendelian Randomization Analyses.
International journal of chronic obstructive pulmonary disease
Background:The existence of an association between physical activity (PA) and asthma and chronic obstructive pulmonary disease (COPD) has been confirmed in observational studies. Therefore, it is necessary to reveal whether there is a risk-effect relationship between physical activity and asthma and COPD through Mendelian randomization (MR) analysis. Materials and Methods:Univariate Mendelian randomization (UVMR) analyses were performed to examine the associations between moderate to vigorous physical activity (MVPA), vigorous physical activity (VPA), accelerometer-assessed physical activity (AA), and strenuous exercise or other exercise (SSOE) with asthma and COPD. The methods of analysis were dominated by Inverse Variance-Weighted (IVW), Weighted median (WM), and MR-Egger methods. In addition, multivariate Mendelian randomization (MVMR) analyses were performed to correct the effects of four types of physical activity on asthma and COPD. Finally, potential mediating effect relationships were identified through mediation analyses. Results:The results of Univariate Mendelian randomization analysis showed that SSOE could reduce the risk of asthma and COPD(asthma: =0.15,95% CI=0.04-0.58, =0.006; COPD: =0.05, 95% CI=0.01-0.33, =0.002). The results of the Multivariate Mendelian randomization analysis showed that SSOE was still able to reduce the risk of asthma and COPD after adjusting for the effects of different types of physical activity(asthma: 95% CI=-2.77--0.31, =0.014; COPD: 95% CI=-4.00--0.50, =0.012). Mediation analyses showed that frailty intervened in the causal relationship between physical activity and asthma and chronic obstructive pulmonary disease. Conclusion:SSOE is a protective factor for asthma and COPD in the European population, while frailty plays a mediating role.
10.2147/COPD.S475714
Cycling and heart failure: A 2-sample Mendelian randomization.
Medicine
Heart failure (HF) is a major cause of mortality worldwide. Cycling, an aerobic exercise, is believed to have a more effective rehabilitative impact on patients with heart failure. Previous studies have demonstrated the benefits of exercise in patients with HF. However, a precise causal relationship remains unknown. Two-sample Mendelian randomization (MR) was used to investigate the potential causal relationship between regular cardiac cycling and heart failure (HF) development. Data from the IEU OpenGWAS project, an extensive genetic study involving a diverse group of European males and females was used to determine how choices related to physical activity, such as cycling, impact cardiovascular well-being. To ensure reliability and robustness, the MR-Egger regression, weighted median, and random effects with inverse variance weighting methods were used. The key findings were summarized using odds ratio (OR) and 95% confidence intervals (CI). The MR-Egger, weighted mean, and inverse variance weighted (IVW) estimated superiority ratios were 0.960 (95% CI: 0.909-1.013), 0.985 (95% CI: 0.962-1.009), and 0.982 (95% CI: 0.966-0.998), respectively, indicating a significant association between cycling and a decreased risk of heart failure. These findings suggest that cycling, a form of moderate and easily accessible physical activity, may be a protective factor against HF. These findings correlate with those of previous studies regarding the crucial role of regular physical activity for the prevention and management of cardiovascular disease. The outcomes of this MR analysis can be used in the development of public health policies and aid individuals making lifestyle choices that promote heart health.
10.1097/MD.0000000000037619
Genetically predicted effects of physical activity and sedentary behavior on myasthenia gravis: evidence from mendelian randomization study.
BMC neurology
BACKGROUND:Myasthenia gravis (MG) is an autoimmune disorder affecting the neuromuscular junction. Despite the potential benefits of higher physical activity and lower sedentary behavior in MG patients, evidence from observational studies for the effect of physical activity on the risk of MG is limited and inconclusive. METHODS:We employed linkage disequilibrium score (LDSC) regression, two-sample Mendelian randomization (MR), and its multivariable extension analyses (MVMR) to assess the relationship between leisure screen time (LST), moderate-to-vigorous intensity physical activity during leisure time (MVPA) and the risk of MG using genome-wide association studies (GWAS) summary datasets. MR analyses were performed using the inverse-variance-weighted (IVW), weighted-median, and MR-Egger regression. Sensitivity analyses were further performed using alternative instruments to test the robustness of our findings. RESULTS:We found evidence of genetic overlap between LST (rg = 0.113, P = 0.023) and MG, as well as between MVPA (rg=-0.220, P = 0.0001) and MG, using LDSC method. The results of the MR suggested an association between genetic liability to LST and increased risk of MG (IVW OR = 1.609, 95% CI = 1.153 to 2.244; P = 0.005). This association was particularly notable for late-onset MG (IVW OR = 1.698, 95% CI = 1.145 to 2.518; P = 0.008), but not for early-onset MG. Consistent findings were obtained in the MVMR analysis using BMI as covariate (IVW OR = 1.593, 95% CI 1.167 to 2.173, P = 0.003). However, the MR analysis does not support a substantial causal effect of MVPA on the risk of MG. CONCLUSION:Our findings support a causal effect of sedentary behavior as measured by LST on MG, indicating that lack of exercise may play a role in the development of MG. Longitudinal and interventional studies of this association are warranted.
10.1186/s12883-023-03343-y
Physical activity, sedentary behavior, and the risk of functional gastrointestinal disorders: A two-sample Mendelian randomization study.
Journal of digestive diseases
OBJECTIVES:Functional dyspepsia (FD) and irritable bowel syndrome (IBS) are prevalent functional gastrointestinal disorders (FGIDs). In this study we aimed to explore the causal association between physical activity or sedentary behavior and the risk of FD and IBS. METHODS:Mendelian randomization (MR) analysis was employed. Candidate genetic instruments for physical activity and sedentary behavior were retrieved from the latest published Genome-Wide Association Study (GWAS), which included up to 703 901 participants. Summary-level GWAS data for FD (8 875 cases and 320 387 controls) and IBS (9 323 cases and 301 931 controls) were obtained from the FinnGen study. The causal effects were mainly estimated by inverse variance weighted (IVW) method. Sensitivity analyses were implemented with Cochran's Q test, MR-Egger intercept test, leave-one-out analysis, and the funnel plot. RESULTS:No significant association of moderate-to-vigorous intensity physical activity (MVPA), leisure screen time (LST), sedentary behavior at work (SDW), and sedentary commuting (SDC) with the risk of FD was found. However, there was a suggestive correlation between MVPA and the decreased risk of FD (odds ratio [OR] 0.63, 95% confidence interval [CI] 0.39-0.99, P = 0.047). Genetically predicted MVPA decreased the risk of IBS (OR 0.58, 95% CI 0.40-0.84, P = 0.004), while increased LST was positively associated with IBS risk (OR 1.33, 95% CI 1.15-1.53, P < 0.001). No causal effects of SDW or SDC on IBS risk were observed. CONCLUSION:MVPA and LST are causally linked to the development of IBS, which will facilitate primary prevention of IBS.
10.1111/1751-2980.13274
Causal links between sedentary behavior, physical activity, and psychiatric disorders: a Mendelian randomization study.
Annals of general psychiatry
BACKGROUND:Studies suggest a correlation between excessive sedentary behavior, insufficient physical activity, and an elevated likelihood of experiencing psychiatric disorder. Nonetheless, the precise influence of sedentary behavior and physical activity on psychiatric disorder remains uncertain. Hence, the objective of this research was to investigate the possible causal relationship between sedentary behavior, physical activity, and the susceptibility to psychiatric disorder (depression, schizophrenia and bipolar disorder), utilizing a two-sample Mendelian randomization (MR) approach. METHODS:Potential genetic instruments related to sedentary leisure behaviors were identified from the UK Biobank database, specifically a summary-level genome-wide association study (GWAS) involving 422,218 individuals of European descent. The UK Biobank database also provided the GWAS data for physical activity. Primary analysis was performed using inverse variance weighting (IVW) to assess the causal relationship between sedentary behavior, physical activity, and the risk of psychiatric disorder (depression, schizophrenia and bipolar disorder). Sensitivity analysis was conducted using Cochran's Q test, the MR-Egger intercept test, the MR-pleiotropy RESidual sum and outlier test, leave-one-out analysis, and funnel plot analysis. RESULTS:According to the IVW analysis, there was a significant association between genetically predicted leisure television watching and an increased risk of depression (odds ratio [OR] = 1.027, 95% confidence interval [CI]: 1.001-1.053; P = 0.04). The IVW analysis also indicated that there was a decreased risk of depression associated with fraction accelerations of > 425 milligravities, as measured by accelerometers (OR = 0.951, 95%CI: 0.914-0.989; P = 0.013). The other MR methods obtained consistent but non-significant results in the same direction. However, there was no evidence of a causal association between genetic liability for moderate-to-vigorous physical activity, accelerometer-assessed physical activity, computer use, or driving and the risk of depression. Furthermore, IVW analysis has also found that driving has a slight effect in reducing the risk of schizophrenia (OR = 0.092, 95%CI: 0.010-0.827; P = 0.033), while leisure television viewing has a significant protective effect against the onset of bipolar disorder (OR = 0.719, 95%CI: 0.567-0.912; P = 0.006). CONCLUSION:The study provides compelling evidence of a link between depression, bipolar disorder, and excessive TV watching. Furthermore, it suggests that higher accelerometer-assessed fraction accelerations of > 425 milligravities can serve as a genetic protective factor against depression. To mitigate the risk of developing depression, it is advisable to reduce sedentary activities, particularly television watching, and prioritize engaging in vigorous physical exercise.
10.1186/s12991-024-00495-0
Association between strenuous sports or other exercises and lung cancer risk: a mendelian randomization study.
Translational lung cancer research
Background:Studying the relationship between strenuous sports or other exercises (SSOE) and lung cancer risk remains underexplored. Traditional observational studies face challenges like confounders and inverse causation. However, Mendelian randomization (MR) provides a promising approach in epidemiology and genetics, using genetic variants as instrumental variables to investigate causal relationships. By leveraging MR, we have scrutinized the causal link between SSOE and lung cancer development. Methods:Twelve single-nucleotide polymorphisms (SNPs) associated with SSOE, as identified in previously published genome-wide association studies, were utilized as instrumental variables in our investigation. Summary genetic data at the individual level were obtained from relevant studies and cancer consortia. The study encompassed a total of 11,348 cases and 15,861 controls. The statistical technique of inverse variance-weighting (IVW), commonly employed in meta-analyses and MR studies, was employed to assess the causal relationship between SSOE and lung cancer risk. Results:The MR risk analysis indicated a causal relationship between SSOE and the incidence of lung cancer, with evidence of a reduced risk for overall lung cancer [odds ratio (OR) =0.129; 95% confidence interval (CI): 0.021-0.779; P=0.03], lung adenocarcinoma (OR =0.161; 95% CI: 0.012-2.102; P=0.16) and squamous cell lung cancer (OR =0.045; 95% CI: 0.003-0.677; P=0.03). The combined OR for lung cancer from SSOE (controlling for waist circumference and smoking status) was 0.054 (95% CI: 0.010-0.302, P<0.001). Conclusions:Our MR analysis findings indicate a potential correlation between SSOE and a protective effect against lung cancer development. Further investigation is imperative to uncover the precise mechanistic link between them.
10.21037/tlcr-23-810
Causal relationships of physical activity and leisure sedentary behaviors with COPD: A Mendelian randomization study.
Archives of gerontology and geriatrics
BACKGROUND:Chronic diseases such as chronic obstructive pulmonary disease (COPD) have been linked to low levels of physical activity (PA) and higher frequency of leisure sedentary behavior (LSB). The main causes of COPD include respiratory and peripheral muscle dysfunction, low levels of PA, and LSB which are associated with a higher risk of developing COPD. The attribution relationship between PA or LSB and COPD risk or COPD respiratory insufficiency is unclear. To explore this further, we conducted a Mendelian randomization (MR) study using a genotype-simulated randomized trial group to systematically evaluate the causal relationships of PA/LSB on COPD risk and respiratory insufficiency. METHODS:The exposure data were obtained from large-scale genome-wide association studies (GWAS), including the PA dataset (N = 729,373) and LSB dataset (N = 1,109,337). The outcome data were derived from the Finn-Gen COPD dataset (N = 381,392). The causal effects were estimated with IVW, MR-Egger, and WM. Sensitivity analysis was conducted using Cochran's Q test, MR-Egger intercept test, MR-PRESSO, leave-one-out analysis, and funnel plot to estimate the robustness of our findings. RESULTS:Genetically predicted leisure television (TV) watching significantly increased the risk of COPD (OR = 2.4895, 95 % CI: 1.85259 to 3.34536; P = 1.44 × 10) and COPD respiratory insufficiency (OR = 2.55, 95 % CI: 1.53 to 4.27; P = 3.54 × 10). No casual effect of other PA or LSB phenotypes on COPD risk or respiratory insufficiency was observed. CONCLUSION:Our study provides evidence that TV watching may increase the risk of COPD and its related respiratory insufficiency. These findings emphasized the importance of promoting regular physical exercise and reducing leisure sedentary behavior to prevent COPD.
10.1016/j.archger.2024.105364
Mendelian randomization analysis reveals the impact of physical and occupational activities on the risk of gastroesophageal reflux disease and Barrett's esophagus.
Scandinavian journal of gastroenterology
BACKGROUND:Recent studies have indicated that participating in physical activity may provide a safeguard against gastroesophageal reflux disease (GERD). Nevertheless, the precise links between physical and occupational activity and the occurrence of GERD and Barrett's esophagus (BE) are still uncertain. METHODS:Conducting univariate and multivariate Mendelian randomization investigations to examine the causal relationship between exposures and outcomes. Genetic variation simulation was used in randomized experiments. Data on physical and occupational activity were obtained from the UK Biobank and GWAS catalog. In the meantime, data on GERD and BE were extracted from a high quality meta-analysis. RESULTS:The results of univariate Mendelian randomization analysis using multiple methods suggest a causal relationship between strenuous sports or other forms of exercise (as a protective factor) and GERD/BE. At the same time, three types of occupational related physical activities, including heavy manual or physical work, shift work and walking or standing work, are risk factors for GERD/BE and have a causal relationship with them. These results were reconfirmed through multivariate Mendelian randomization analysis, which excluding the influence of other potential confounding factors. CONCLUSIONS:The findings indicated that strenuous sports or other forms of exercise could lower the likelihood of GERD/BE, while excessive physical strain in the workplace, prolonged periods of standing or walking, and shift work could raise the risk of GERD/BE. Acknowledging this risk and implementing suitable measures can contribute to the prevention of GERD and BE, thus mitigating the associated health burden.
10.1080/00365521.2023.2287416
Physical activity and the osteoarthritis of the knee: A Mendelian randomization study.
Medicine
Previous studies have reported an association between physical activity and the occurrence and progression of knee osteoarthritis (KOA). However, the existing evidence remains limited and of low-quality. This study aimed to examine the causal relationship between different levels of physical activity and KOA. Instrumental variables, represented by single nucleotide polymorphisms (SNPs), were utilized to capture sedentary behavior, appropriate physical exercise, and excessive physical activity. Aggregated statistics from the UK Biobank genome-wide association study dataset were used to assess the impact of these SNPs on KOA. Causality was estimated using inverse variance weighting (IVW), MR Egger, simple model, weighted median, and weighted model approaches. The stability of the results was assessed through heterogeneity and sensitivity analyses. Mendelian randomization (MR) analysis revealed a strong association between sedentary behavior and KOA, with an odds ratio (OR) of 2.096 (95% CI: 1.506-2.917) and a P value of 1.14 × 10-5. Appropriate physical exercise behavior exhibited a strong negative association with KOA, with an OR of 0.147 (95% CI: 0.037-0.582) and a P value of 0.006. Conversely, excessive physical activity behavior showed a significant positive association with KOA, with an OR of 2.162 (95% CI: 1.327-3.521) and a P value of .002. Our findings indicate that sedentary behavior and excessive physical activity are identified as risk factors for KOA, whereas engaging in appropriate physical exercise emerges as a protective factor against the development of KOA.
10.1097/MD.0000000000038650
Genome-wide association analyses of physical activity and sedentary behavior provide insights into underlying mechanisms and roles in disease prevention.
Nature genetics
Although physical activity and sedentary behavior are moderately heritable, little is known about the mechanisms that influence these traits. Combining data for up to 703,901 individuals from 51 studies in a multi-ancestry meta-analysis of genome-wide association studies yields 99 loci that associate with self-reported moderate-to-vigorous intensity physical activity during leisure time (MVPA), leisure screen time (LST) and/or sedentary behavior at work. Loci associated with LST are enriched for genes whose expression in skeletal muscle is altered by resistance training. A missense variant in ACTN3 makes the alpha-actinin-3 filaments more flexible, resulting in lower maximal force in isolated type II muscle fibers, and possibly protection from exercise-induced muscle damage. Finally, Mendelian randomization analyses show that beneficial effects of lower LST and higher MVPA on several risk factors and diseases are mediated or confounded by body mass index (BMI). Our results provide insights into physical activity mechanisms and its role in disease prevention.
10.1038/s41588-022-01165-1
Causal Associations Between Lifestyle Habits and Risk of Benign Prostatic Hyperplasia: A Two-Sample Mendelian Randomization Study.
The journals of gerontology. Series A, Biological sciences and medical sciences
BACKGROUND:Benign prostatic hyperplasia (BPH) most often occurs in older men; previous studies and clinical experience suggest a potential link between lifestyle habits such as sleep habits, sedentary behavior, exercise levels, and BPH, but whether they have a clear causal relationship and the direction of that causality is unclear. We aimed to investigate the causal relationship between lifestyle habits and BPH using 2-sample Mendelian randomization (MR) analysis. METHODS:Instrumental genetic independent variables strongly associated with the selected exposure factors were filtered from published genome-wide association studies (GWAS) consisting primarily of European ancestry samples. GWAS from BPH was analyzed as an MR outcome with the inverse-variance weighted method, maximum likelihood, weighted median method, MR-Egger regression, and several sensitivity analyses, including Cochran's Q test, intercept of MR-Egger, and MR pleiotropy residual sum and outlier test. RESULTS:MR analysis showed a significant causal risk relationship between sleep duration and BPH, with an odds ratio of 0.42 (95% confidence interval, 0.25-0.69, p = .001) for BPH when sleep duration was increased by 1 standard deviation, but we did not find a causal relationship between the 2 when we performed a reverse analysis. However, sedentary behavior and different levels of exercise did not significantly affect the risk of BPH. CONCLUSIONS:This study showed a strong causal relationship between sleep levels and BPH, with adequate sleep duration being a protective factor for BPH.
10.1093/gerona/glad187
Association between appendicular lean mass and chronic obstructive pulmonary disease: epidemiological cross-sectional study and bidirectional Mendelian randomization analysis.
Frontiers in nutrition
Background:The association of BMI with COPD, and sarcopenia in COPD have been both confirmed by several studies, but research on the relationship and causality of body lean mass and the risk of chronic obstructive pulmonary disease (COPD) remains to be discovered. The purpose of this study was to explore the association between lean mass and COPD risk as well as to further examine the causal relationship in the findings. Methods:Three thousand four hundred fifty-nine participants from NHANES 2013-2018 were included in the epidemiological cross-sectional study to assess the association between relative lean mass and COPD by restricted spline analysis (RCS) and weighted multiple logistic regression. Furthermore, to verify the causality between lean mass and COPD, a two-sample Mendelian randomization (MR) with inverse variance weighting (IVW) method was used to analyze GWAS data from European ancestry. Genetic data from the United Kindom Biobank for appendicular lean mass (450,243 cases) and lung function (FEV/FVC) (400,102 cases) together with the FinnGen platform for COPD (6,915 cases and 186,723 controls) were used for MR. Results:Weighted multiple logistic regression showed a significant correlation between relative appendicular lean mass and COPD after adjusting for confounders (OR = 0.985, 95% CI: 0.975-0.995). Compared to the lower mass (155.3-254.7) g/kg, the high mass (317.0-408.5) g/kg of appendicular lean apparently decreases the risk of COPD (OR = 0.214, 95% CI: 0.060-0.767). Besides, in the analysis of MR, there was a forward causality between appendicular lean mass and COPD (IVW: OR = 0.803; 95%CI: 0.680-0.949; = 0.01), with a weak trend of causality to lung function. Conclusion:Our study not only found an inverse association between appendicular lean mass and COPD but also supported a unidirectional causality. This provided possible evidence for further identification of people at risk for COPD and prevention of COPD based on limb muscle exercise and nutritional supplementation to maintain skeletal muscle mass.
10.3389/fnut.2023.1159949
A meta-review of "lifestyle psychiatry": the role of exercise, smoking, diet and sleep in the prevention and treatment of mental disorders.
World psychiatry : official journal of the World Psychiatric Association (WPA)
There is increasing academic and clinical interest in how "lifestyle factors" traditionally associated with physical health may also relate to mental health and psychological well-being. In response, international and national health bodies are producing guidelines to address health behaviors in the prevention and treatment of mental illness. However, the current evidence for the causal role of lifestyle factors in the onset and prognosis of mental disorders is unclear. We performed a systematic meta-review of the top-tier evidence examining how physical activity, sleep, dietary patterns and tobacco smoking impact on the risk and treatment outcomes across a range of mental disorders. Results from 29 meta-analyses of prospective/cohort studies, 12 Mendelian randomization studies, two meta-reviews, and two meta-analyses of randomized controlled trials were synthesized to generate overviews of the evidence for targeting each of the specific lifestyle factors in the prevention and treatment of depression, anxiety and stress-related disorders, schizophrenia, bipolar disorder, and attention-deficit/hyperactivity disorder. Standout findings include: a) convergent evidence indicating the use of physical activity in primary prevention and clinical treatment across a spectrum of mental disorders; b) emerging evidence implicating tobacco smoking as a causal factor in onset of both common and severe mental illness; c) the need to clearly establish causal relations between dietary patterns and risk of mental illness, and how diet should be best addressed within mental health care; and d) poor sleep as a risk factor for mental illness, although with further research required to understand the complex, bidirectional relations and the benefits of non-pharmacological sleep-focused interventions. The potentially shared neurobiological pathways between multiple lifestyle factors and mental health are discussed, along with directions for future research, and recommendations for the implementation of these findings at public health and clinical service levels.
10.1002/wps.20773
A review of Mendelian randomization in amyotrophic lateral sclerosis.
Brain : a journal of neurology
Amyotrophic lateral sclerosis is a relatively common and rapidly progressive neurodegenerative disease that, in the majority of cases, is thought to be determined by a complex gene-environment interaction. Exponential growth in the number of performed genome-wide association studies combined with the advent of Mendelian randomization is opening significant new opportunities to identify environmental exposures that increase or decrease the risk of amyotrophic lateral sclerosis. Each of these discoveries has the potential to shape new therapeutic interventions. However, to do so, rigorous methodological standards must be applied in the performance of Mendelian randomization. We have reviewed Mendelian randomization studies performed in amyotrophic lateral sclerosis to date. We identified 20 Mendelian randomization studies, including evaluation of physical exercise, adiposity, cognitive performance, immune function, blood lipids, sleep behaviours, educational attainment, alcohol consumption, smoking and type 2 diabetes mellitus. We have evaluated each study using gold standard methodology supported by the Mendelian randomization literature and the STROBE-Mendelian randomization checklist. Where discrepancies exist between Mendelian randomization studies, we suggest the underlying reasons. A number of studies conclude that there is a causal link between blood lipids and risk of amyotrophic lateral sclerosis; replication across different datasets and even different populations adds confidence. For other putative risk factors, such as smoking and immune function, Mendelian randomization studies have provided cause for doubt. We highlight the use of positive control analyses in choosing exposure single nucleotide polymorphisms (SNPs) to make up the Mendelian randomization instrument, use of SNP clumping to avoid false positive results due to SNPs in linkage and the importance of multiple testing correction. We discuss the implications of survival bias for study of late age of onset diseases such as amyotrophic lateral sclerosis and make recommendations to mitigate this potentially important confounder. For Mendelian randomization to be useful to the amyotrophic lateral sclerosis field, high methodological standards must be applied to ensure reproducibility. Mendelian randomization is already an impactful tool, but poor-quality studies will lead to incorrect interpretations by a field that includes non-statisticians, wasted resources and missed opportunities.
10.1093/brain/awab420
Association of physical activity, sedentary behaviours and sleep duration with cardiovascular diseases and lipid profiles: a Mendelian randomization analysis.
Zhuang Zhenhuang,Gao Meng,Yang Ruotong,Li Nan,Liu Zhonghua,Cao Weihua,Huang Tao
Lipids in health and disease
BACKGROUND:Observational studies have shown that moderate-to-vigorous physical activity (MVPA), vigorous physical activity (VPA), sedentary behaviours, and sleep duration were associated with cardiovascular diseases (CVDs) and lipid levels. However, whether such observations reflect causality remain largely unknown. We aimed to investigate the causal associations of physical activity, sedentary behaviours, and sleep duration with coronary artery disease (CAD), myocardial infarction (MI), stroke and lipid levels. METHODS:We conducted a Mendelian randomization (MR) study using genetic variants as instruments which are associated with physical activity, sedentary behaviours, and sleep duration to examine the causal effects on CVDs and lipid levels. This study included analyses of 4 potentially modifiable factors and 7 outcomes. Thus, the threshold of statistical significance is P = 1.8 × 10 (0.05/4 × 7) after Bonferroni correction. RESULTS:In the present study, there was suggestive evidence for associations of genetically predicted VPA with CAD (odds ratio, 0.65; 95% confidence intervals, 0.47-0.90; P = 0.009) and MI (0.74; 0.59-0.93; P = 0.010). However, genetically predicted VPA, MVPA, sleep duration and sedentary behaviours did not show significant associations with stroke and any lipid levels. CONCLUSIONS:Our findings from the MR approach provided suggestive evidence that vigorous exercise decreased risk of CAD and MI, but not stroke. However, there was no evidence to support causal associations of MVPA,sleep duration or sedentary behaviours with cardiovascular risk and lipid levels. TRANSLATIONAL PERSPECTIVE:The findings of this study did not point out specific recommendations on increasing physical activity required to deliver significant health benefits. Nevertheless, the findings allowed clinicians and public health practitioners to provide advice about increasing the total amount of excising time by demonstrating that such advice can be effective. Reliable assessment of the association of physical activity levels with different subtypes of CVDs is needed to provide the basis for a comprehensive clinical approach on CVDs prevention, which can be achieved through lifestyle interventions in addition to drug therapy.
10.1186/s12944-020-01257-z
An Exposure-Wide and Mendelian Randomization Approach to Identifying Modifiable Factors for the Prevention of Depression.
The American journal of psychiatry
OBJECTIVE:Efforts to prevent depression, the leading cause of disability worldwide, have focused on a limited number of candidate factors. Using phenotypic and genomic data from over 100,000 UK Biobank participants, the authors sought to systematically screen and validate a wide range of potential modifiable factors for depression. METHODS:Baseline data were extracted for 106 modifiable factors, including lifestyle (e.g., exercise, sleep, media, diet), social (e.g., support, engagement), and environmental (e.g., green space, pollution) variables. Incident depression was defined as minimal depressive symptoms at baseline and clinically significant depression at follow-up. At-risk individuals for incident depression were identified by polygenic risk scores or by reported traumatic life events. An exposure-wide association scan was conducted to identify factors associated with incident depression in the full sample and among at-risk individuals. Two-sample Mendelian randomization was then used to validate potentially causal relationships between identified factors and depression. RESULTS:Numerous factors across social, sleep, media, dietary, and exercise-related domains were prospectively associated with depression, even among at-risk individuals. However, only a subset of factors was supported by Mendelian randomization evidence, including confiding in others (odds ratio=0.76, 95% CI=0.67, 0.86), television watching time (odds ratio=1.09, 95% CI=1.05, 1.13), and daytime napping (odds ratio=1.34, 95% CI=1.17, 1.53). CONCLUSIONS:Using a two-stage approach, this study validates several actionable targets for preventing depression. It also demonstrates that not all factors associated with depression in observational research may translate into robust targets for prevention. A large-scale exposure-wide approach combined with genetically informed methods for causal inference may help prioritize strategies for multimodal prevention in psychiatry.
10.1176/appi.ajp.2020.19111158
Metabolic Signature of Healthy Lifestyle and Risk of Rheumatoid Arthritis: Observational and Mendelian Randomization Study.
The American journal of clinical nutrition
BACKGROUND:Although substantial evidence reveals that healthy lifestyle behaviors are associated with a lower risk of rheumatoid arthritis (RA), the underlying metabolic mechanisms remain unclear. OBJECTIVES:This study aimed to identify the metabolic signature reflecting a healthy lifestyle and investigate its observational and genetic linkage with RA risk. METHODS:This study included 87,258 UK Biobank participants (557 cases with incident RA) aged 37-73 y with complete lifestyle, genotyping, and nuclear magnetic resonance (NMR) metabolomics data. A healthy lifestyle was assessed based on 5 factors: healthy diet, regular exercise, not smoking, moderate alcohol consumption, and normal body mass index. The metabolic signature was developed by summing the selected metabolites' concentrations weighted by the coefficients using elastic net regression. We used the multivariate Cox model to assess the associations between metabolic signatures and RA risk, and examined the mediating role of the metabolic signature in the impact of a healthy lifestyle on RA. We performed genome-wide association analysis (GWAS) to obtain genetic variants associated with the metabolic signature and then conducted Mendelian randomization (MR) analyses to detect causality. RESULTS:The metabolic signature comprised 81 metabolites, robustly correlated with a healthy lifestyle (r = 0.45, P = 4.2 × 10). The metabolic signature was inversely associated with RA risk (HR per standard deviation (SD) increment: 0.76; 95% CI: 0.70-0.83), and largely explained the protective effects of healthy lifestyle on RA with 64% (95% CI: 50.4-83.3) mediation proportion. 1- and 2-sample MR analyses also consistently showed the associations of genetically inferred per SD increment in metabolic signature with a reduction in RA risk (HR: 0.84; 95% CI: 0.75-0.94; and P = 0.002 and OR: 0.84; 95% CI: 0.73-0.97; and P = 0.02, respectively). CONCLUSIONS:Our findings implicate that the metabolic signature reflecting healthy lifestyle is a potential causal mediator in the development of RA, highlighting the importance of early lifestyle intervention and metabolic status tracking for precise prevention of RA.
10.1016/j.ajcnut.2023.04.034
Causal relationship between physical activity, leisure sedentary behaviors and COVID-19 risk: a Mendelian randomization study.
Journal of translational medicine
BACKGROUND:The 2019 coronavirus disease pandemic (COVID-19) poses an enormous threat to public health worldwide, and the ensuing management of social isolation has greatly decreased opportunities for physical activity (PA) and increased opportunities for leisure sedentary behaviors (LSB). Given that both PA and LSB have been established as major influencing factors for obesity, diabetes and cardiometabolic syndrome, whether PA/LSB in turn affects the susceptibility to COVID-19 by disrupting metabolic homeostasis remains to be explored. In this study, we aimed to systematically evaluate the causal relationship between PA/LSB and COVID-19 susceptibility, hospitalization and severity using a Mendelian randomization study. METHODS:Data were obtained from a large-scale PA dataset (N = 377,000), LSB dataset (N = 422,218) and COVID-19 Host Genetics Initiative (N = 2,586,691). The causal effects were estimated with inverse variance weighted, MR-Egger, weighted median and MR-PRESSO. Sensitivity analyses were implemented with Cochran's Q test, MR-Egger intercept test, MR-PRESSO, leave-one-out analysis and the funnel plot. Risk factor analyses were further conducted to investigate the potential mediators. RESULTS:Genetically predicted accelerometer-assessed PA decreased the risk for COVID-19 hospitalization (OR = 0.93, 95% CI 0.88-0.97; P = 0.002), while leisure television watching significantly increased the risk of COVID-19 hospitalization (OR = 1.55, 95% CI 1.29-1.88; P = 4.68 × 10) and disease severity (OR = 1.85, 95% CI 1.33-2.56; P = 0.0002) after Bonferroni correction. No causal effects of self-reported moderate to vigorous physical activity (MVPA), accelerometer fraction of accelerations > 425 milligravities, computer use or driving on COVID-19 progression were observed. Risk factor analyses indicated that the above causal associations might be mediated by several metabolic risk factors, including smoking, high body mass index, elevated serum triglyceride levels, insulin resistance and the occurrence of type 2 diabetes. CONCLUSION:Our findings supported a causal effect of accelerometer-assessed PA on the reduced risk of COVID-19 hospitalization as well as television watching on the increased risk of COVID-19 hospitalization and severity, which was potentially mediated by smoking, obesity and type 2 diabetes-related phenotypes. Particular attention should be given to reducing leisure sedentary behaviors and encouraging proper exercise during isolation and quarantine for COVID-19.
10.1186/s12967-022-03407-6
Mood instability and risk of gastrointestinal diseases - a univariable and multivariable mendelian randomization study.
Annals of general psychiatry
BACKGROUND:Mood instability, characterized by sudden and unpredictable mood shifts, is prevalent in psychiatric disorders and as a personality trait. Its association with gastrointestinal diseases has been recognized but remains poorly understood in terms of causality. METHODS:This study aims to investigate the causal relationship between mood instability and a spectrum of gastrointestinal diseases by univariable and multivariable mendelian randomization analysis. The exposure and outcome data were retrieved from the IEU open GWAS database, the UK biobank and the FinnGen study. Instrumental variables were selected to meet relevance, independence, and exclusion restriction criteria. GWAS datasets for mood instability and 28 gastrointestinal diseases were utilized, incorporating diverse populations and genders. Univariable and multivariable Mendelian randomization analyses were conducted using R software. MR statistics from different datasets for the same disease were meta-analyzed to maximize the study population. RESULTS:In univariable MR analysis, genetic predisposition to mood instability showed significant associations with increased risk for several gastrointestinal diseases, including: gastroesophageal reflux disease, gastric ulcer, acute gastritis, irritable bowel syndrome, internal hemorrhoids, cirrhosis, cholecystitis, cholelithiasis, acute pancreatitis, chronic pancreatitis. In multivariable MR analysis, after adjusting for major depression, bipolar disorder, anxiety disorder, and schizophrenia, associations with the following gastrointestinal diseases remained statistically significant: internal hemorrhoids, cirrhosis, acute pancreatitis, chronic pancreatitis. CONCLUSION:This study provides compelling evidence for a potential causal relationship between mood instability and certain gastrointestinal diseases underscoring the importance of considering mood instability as a potential risk factor for gastrointestinal diseases as well as the positive role of maintaining mood stability in the prevention of gastrointestinal disorders.
10.1186/s12991-024-00537-7
Integration of observational and causal evidence for the association between adiposity and 17 gastrointestinal outcomes: An umbrella review and meta-analysis.
Obesity reviews : an official journal of the International Association for the Study of Obesity
We systematically reviewed observational and Mendelian randomization (MR) articles that evaluated the association between obesity and 17 gastrointestinal (GI) diseases to integrate causal and observational evidence. A total of 594 observational studies from 26 systematic reviews and meta-analyses and nine MR articles were included. For every 5 kg/m increase in body mass index (BMI), there was an increased risk of GI diseases ranging from 2% for rectal cancer (relative risk [RR]: 1.02, 95% confidence interval [CI]: 1.01 to 1.03) to 63% for gallbladder disease (RR: 1.63, 95% CI: 1.50 to 1.77). MR articles indicated that risks of developing GI diseases elevated with each 1 standard deviation increase in genetically predicted BMI, ranging from 11% for Crohn's disease to 189% for nonalcoholic fatty liver disease. Moreover, upper GI conditions were less susceptible, whereas hepatobiliary organs were more vulnerable to increased adiposity. Among the associations between obesity and the 17 GI conditions, causal relationships were inferred from only approximately half (10/17, 59%). This study reveals a substantial gap between observational and causal evidence, indicating that a combined approach is necessary to effectively inform public health policies and guide epidemiological research on obesity and GI diseases.
10.1111/obr.13823
Genetic evidence for the causal impact of insomnia on gastrointestinal diseases and the mediating effects of adiposity traits.
Journal of gastroenterology and hepatology
BACKGROUND AND AIM:Insomnia has been implicated in gastrointestinal diseases (GIs), but the causal effect between insomnia and GIs and underlying mechanisms remain unknown. METHODS:By using the released summary-level data, we conducted a two-step Mendelian randomization (MR) analysis to examine the relationship between insomnia and four GIs and estimate the mediating role of candidate mediators. The first step was to investigate the causal association between insomnia and GIs using univariable MR analysis. The second step was to estimate the mediation proportion of selected mediators in these associations using multivariable MR analysis. Subsequently, results from different datasets were combined using the fixed-effect meta-analysis. RESULTS:Univariable MR analysis provided strong evidence for the causal effects of insomnia on four GIs after Bonferroni correction for multiple comparisons, including peptic ulcer disease (PUD) (odds ratio [OR] = 1.15, 95% interval confidence [CI] = 1.10-1.20, P = 1.83 × 10), gastroesophageal reflux (GORD) (OR = 1.19, 95% CI = 1.16-1.22, P = 5.95 × 10), irritable bowel syndrome (IBS) (OR = 1.18, 95% CI = 1.15-1.22, P = 8.69 × 10), and inflammatory bowel disease (IBD) (OR = 1.09, 95% CI = 1.03-1.05, P = 3.46 × 10). In the mediation analysis, body mass index (BMI) and waist-to-hip ratio (WHR) were selected as mediators in the association between insomnia and PUD (BMI: mediation proportion [95% CI]: 13.61% [7.64%-20.70%]; WHR: 8.74% [5.50%-12.44%]) and GORD (BMI: 11.82% [5.94%-18.74%]; WHR: 7.68% [4.73%-11.12%]). CONCLUSIONS:Our findings suggest that genetically instrumented insomnia has causal effects on PUD, GORD, IBS, and IBD, respectively. Adiposity traits partially mediated the associations between insomnia and GIs. Further clinical studies are warranted to evaluate the protective effect of insomnia treatment on GIs.
10.1111/jgh.16678
Investigating the causal relationship of gut microbiota with GERD and BE: a bidirectional mendelian randomization.
BMC genomics
BACKGROUND:Gut microbiota(GM) have been proven associated with lots of gastrointestinal diseases, but its causal relationship with Gastroesophageal reflux disease(GERD) and Barrett's esophagus(BE) hasn't been explored. We aimed to uncover the causal relation between GM and GERD/BE and potential mediators by utilizing Mendelian Randomization(MR) analysis. METHODS:Summary statistics of GM(comprising 301 bacteria taxa and 205 metabolism pathways) were extracted from MiBioGen Consortium(N = 18,340) and Dutch Microbiome Project(N = 7,738), GERD and BE from a multitrait meta-analysis(N=602,604, N=56,429). Bidirectional two-sample MR analysis and linkage disequilibrium score regression(LDSC) were used to explore the genetic correlation between GM and GERD/BE. Mediation MR analysis was performed for the risk factors of GERD/BE, including Body mass index(BMI), weight, type 2 diabetes, major depressive disorder(MDD), smoking initiation, alcohol consumption, and dietary intake(including carbohydrate, sugar, fat, protein intake), to detect the potential mediators between GM and GERD/BE. RESULTS:11 bacterial taxa and 13 metabolism pathways were found associated with GERD, and 18 taxa and 5 pathways exhibited causal relationship with BE. Mediation MR analysis suggested weight and BMI played a crucial role in these relationships. LDSC identified 1 taxon and 4 metabolism pathways related to GERD, and 1 taxon related to BE. Specie Faecalibacterium prausnitzii had a suggestive impact on both GERD(OR = 1.087, 95%CI = 1.01-1.17) and BE(OR = 1.388, 95%CI = 1.03-1.86) and LDSC had determined their correlation. Reverse MR indicated that BE impacted 10 taxa and 4 pathways. CONCLUSIONS:This study established a causal link between gut microbiota and GERD/BE, and identified the probable mediators. It offers new insights into the role of gut microbiota in the development and progression of GERD and BE in the host.
10.1186/s12864-024-10377-0
Causal association between gastrointestinal diseases and coronary artery disease: a bidirectional Mendelian randomization study.
Frontiers in endocrinology
Background:Coronary artery disease (CAD) has been a dominating reason of mortality globally due to its complexity of etiology. A variety of gastrointestinal disorders (GDs) have been accounted to be related to CAD. Thus, this study aims to determine their causal relationship by two-sample Mendelian randomization (MR) analysis. Methods:Single-nucleotide polymorphisms (SNPs) relevant to 22 GDs were employed as instrumental variables from the genome-wide association summary (GWAS) datasets. Genetic associations with CAD and HF were acquired from UK Biobank, FinnGen, and other GWAS studies. We conducted a univariable MR (UVMR) analysis followed by a meta-analysis. A multivariable MR (MVMR) analysis was then performed with smoking and body mass index (BMI) as justifications. Also, a bi-directional MR analysis was leveraged to verify the reverse causal correlations. Results:Generally, UVMR analyses separately observed the causal effects of GDs on CAD and HF. Genetic liability to gastroesophageal reflux disease displayed a positive association with both CAD (OR=1.19; 95%CI: 1.01-1.41) and HF (OR=1.22; 95%CI: 1.00-1.49) risk; genetic liability to celiac disease separately attributed to CAD (OR=1.02; 95%CI: 1.01-1.03) and HF (OR=1.01; 95%CI: 1.00-1.02), which also maintained after MVMR analysis. Besides, we observed mutually causal associations between CAD and celiac disease. Conclusion:Our work suggested that genetic susceptibility to some GDs might causally increase the risk of CAD and HF, emphasizing the importance of preventing CAD in patients with GDs.
10.3389/fendo.2024.1458196
Sarcopenia-related traits and 10 digestive system disorders: insight from genetic correlation and Mendelian randomization.
Frontiers in public health
Introduction:Despite observational studies suggest hypotheses indicating a potential link, the precise causal connection between sarcopenia and digestive system illnesses has not been clearly defined. Methods:We first use Linkage Disequilibrium Score Regression (LDSC) testing to determine the genetic correlation of traits associated with sarcopenia and 10 specific gastrointestinal diseases. Subsequently, we performed a set of bidirectional Mendelian Randomization (MR) analyses to gauge the genetic inclination towards sarcopenia-related traits in relation to each gastrointestinal condition, individually, across the FinnGen, UK Biobank, and other extensive collaborative consortia. The analytical outcomes were synthesized using a fixed-effects meta-analytic model. For outcomes indicating substantial causal impacts, mediation MR analyses were executed. Additionally, a battery of sensitivity analyses was conducted to evaluate the study's strength and dependability. Results:Our findings established a strong causal link between appendicular lean mass and gastroesophageal reflux disease (OR = 0.8607; 95% CI: 0.8345-0.8877; < 0.0001) and a noteworthy correlation with nonalcoholic fatty liver disease (OR = 0.7981; 95% CI: 0.7281-0.8749; < 0.0001), as per the meta-analysis data. We also evaluated the intermediary role of metabolic disorders in the association between appendicular lean mass and the aforementioned diseases. The intermediary effect towards gastroesophageal reflux disease is quantified as 0.0087 (95% CI, 8e-04, 0.0183), accounting for 5.9398% (95% CI, 0.5462, 12.4940%) of the overall effect. For non-alcoholic fatty liver, the intermediary impact is 0.0150 (95% CI, 0.0050, 0.0270), representing 19.7808% (95% CI, 6.5936, 35.6055%) of the total effect. Conclusion:The findings posit that augmenting muscle mass may serve as a preventative strategy against gastroesophageal reflux disease and non-alcoholic fatty liver, highlighting the critical role of metabolic disorder management in reducing the risks of these sarcopenia-related conditions.
10.3389/fpubh.2024.1412842
Impact of negative emotions on upper gastrointestinal diseases: A Mendel randomization study.
PloS one
Mendelian randomization method is a powerful tool in epidemiological research. The core idea is to use genetic variation as a tool to assess the causal relationship between risk factors and specific diseases. Confounding factors are important interference factors for causal inference in epidemiological studies, and genetic variation in Mendelian randomization studies follows the principle of random distribution of alleles to offspring, which is similar to randomized controlled trials. Mendel 's randomization method can effectively avoid the confounding factors, reverse causality in observational studies and the representativeness and feasibility of randomized controlled trials. Previous observational studies have reported a relationship between negative emotions and upper gastrointestinal disease. However, whether this relationship is causal remains unclear. We aimed to evaluate the causal relationship between negative emotions and upper gastrointestinal diseases using two-sample Mendelian randomization (MR). Three sets of genetic instruments from the database were obtained for analysis, including 12 anxiety-related single nucleotide polymorphisms (SNPs), 46 depression-related SNPs, and 58 nervous-related SNPs. SNPs were filtered using the Phenoscanner website, and the inverse variance weighted method, weighted median method, MR-Egger regression, MR pleiotropy residual sum, and outlier test were used for analysis. In inverse variance weighted analysis, anxiety and depression had an effect on gastroduodenal ulcer (p = 2.849×10-3, β = 4.908, 95% CI = 1.684-8.132; and p = 6.457×10-4, β = 1.767, 95% CI = 0.752-2.782, respectively). Additionally, depression had an effect on diseases of the esophagus, stomach, and duodenum (p = 3.498×10-5, β = 0.926, 95% CI = 0.487-1.364). Cochran's Q-derived p-values were 0.457, 0.603, and 0.643, and MR-Egger intercept-derived p-values were 0.697, 0.294, and 0.362, respectively. Here, we show that anxiety and depression have a causal relationship with gastroduodenal ulcers, and depression has a causal relationship with diseases of the esophagus, stomach, and duodenum.
10.1371/journal.pone.0304121
Investigating the causal links between obstructive sleep apnea and gastrointestinal diseases mediated by metabolic syndrome through mendelian randomization.
Scientific reports
Previous studies have pointed to a potential link between Obstructive Sleep Apnea (OSA) and gastrointestinal diseases, suggesting that this relationship might be influenced by the presence of Metabolic Syndrome. However, the exact role of these factors in determining gastrointestinal diseases has not been thoroughly explored. In our study, we utilized data from the Genome-wide Association Studies (GWAS) database, focusing on OSA, metabolic syndrome characteristics such as Body Mass Index (BMI), waist circumference, triglycerides, cholesterol, hypertension, type 2 diabetes, and common gastrointestinal diseases including chronic gastritis, gastric ulcers, irritable bowel syndrome, colorectal cancer, inflammatory bowel disease, cholecystitis, nonalcoholic fatty liver, and dyspepsia. By applying Single-variable and Multi-variable Mendelian randomization methods, we aimed to assess the correlation between OSA and gastrointestinal diseases and investigate whether this correlation is influenced by metabolic syndrome. Our findings revealed a strong association between OSA and an increased risk of chronic gastritis, gastric ulcers, inflammatory bowel disease, and nonalcoholic fatty liver disease. No significant connections were found with irritable bowel syndrome, colorectal cancer, cholecystitis, or dyspepsia. Additionally, OSA was linked to metabolic syndrome traits like BMI, waist circumference, triglycerides, hypertension, and type 2 diabetes. Further analysis showed that BMI, triglycerides, and hypertension were causally related to inflammatory bowel disease; BMI, waist circumference, hypertension, and type 2 diabetes to nonalcoholic fatty liver disease; and triglycerides, hypertension, and type 2 diabetes to chronic gastritis. The multivariable analysis indicated that hypertension mediates the relationship between OSA and chronic gastritis; BMI, triglycerides, and hypertension mediate the link between OSA and inflammatory bowel disease; and waist circumference mediates the connection between OSA and nonalcoholic fatty liver disease. To wrap up, this finding helps us understand how these issues might be related and stresses the role of metabolic syndrome in preventing them, which could lessen their effect on health.
10.1038/s41598-024-77471-x
Independent associations of education, intelligence, and cognition with gastrointestinal diseases and the mediating effects of risk factors: a Mendelian randomization study.
Frontiers in medicine
Background:Education, intelligence and cognition affect occupational performance and socioeconomic status and may influence virous diseases development. However, the impact of these factors on gastrointestinal diseases and their mediating risk factors remains unclear. Methods:We utilized genome-wide association studies from European ancestry populations to perform two-sample Mendelian randomization analyses, aiming to estimate genetic instruments associated with education, intelligence, or cognition in relation to 24 gastrointestinal diseases Subsequently, we evaluated 14 potential mediators of this association and calculated the corresponding mediated proportions through two-step Mendelian randomization analyses. Result:As the dominant factor in gastrointestinal diseases, education had a statistically significant association with 2 gastrointestinal diseases (acute pancreatitis, gastroesophageal reflux) and a suggestive association with 6 diseases (cirrhosis, alcoholic liver disease, cholecystitis, cholelithiasis, chronic gastritis and gastric ulcer). Of the 14 mediators, smoking and adiposity traits played a major role in mediating the effects. Conclusion:The study demonstrated the causal, independent impact of education on specific gastrointestinal diseases. Smoking and adiposity traits emerged as primary mediators, illuminating potential avenues for targeted interventions for prevention of them.
10.3389/fmed.2024.1342358
Causal relationships of Helicobacter pylori and related gastrointestinal diseases on Type 2 diabetes: Univariable and Multivariable Mendelian randomization.
PloS one
BACKGROUND:Previous observational studies have demonstrated a connection between the risk of Type 2 diabetes mellitus (T2DM) and gastrointestinal problems brought on by Helicobacter pylori (H. pylori) infection. However, little is understood about how these factors impact on T2DM. METHOD:This study used data from the GWAS database on H. pylori antibodies, gastroduodenal ulcers, chronic gastritis, gastric cancer, T2DM and information on potential mediators: obesity, glycosylated hemoglobin (HbA1c) and blood glucose levels. Using univariate Mendelian randomization (MR) and multivariate MR (MVMR) analyses to evaluate the relationship between H. pylori and associated gastrointestinal diseases with the risk of developing of T2DM and explore the presence of mediators to ascertain the probable mechanisms. RESULTS:Genetic evidence suggests that H. pylori IgG antibody (P = 0.006, b = 0.0945, OR = 1.0995, 95% CI = 1.023-1.176), H. pylori GroEL antibody (P = 0.028, OR = 1.033, 95% CI = 1.004-1.064), gastroduodenal ulcers (P = 0.019, OR = 1.036, 95% CI = 1.006-1.068) and chronic gastritis (P = 0.005, OR = 1.042, 95% CI = 1.012-1.074) are all linked to an increased risk of T2DM, additionally, H. pylori IgG antibody is associated with obesity (P = 0.034, OR = 1.03, 95% CI = 1.002-1.055). The results of MVMR showed that the pathogenic relationship between H. pylori GroEL antibody and gastroduodenal ulcer in T2DM is mediated by blood glucose level and obesity, respectively. CONCLUSION:Our study found that H. pylori IgG antibody, H. pylori GroEL antibody, gastroduodenal ulcer and chronic gastritis are all related to t T2DM, and blood glucose level and obesity mediate the development of H. pylori GroEL antibody and gastroduodenal ulcer on T2DM, respectively. These findings may inform new prevention and intervention strategies for T2DM.
10.1371/journal.pone.0300835
Gut microbiota and common gastrointestinal diseases: a bidirectional two-sample Mendelian randomized study.
Frontiers in microbiology
Background:Several recent studies have shown an association between gut microbiota and gastrointestinal diseases. However, the causal relationship between gut microbiota and gastrointestinal disorders is unclear. Methods:We assessed causal relationships between gut microbiota and eight common gastrointestinal diseases using Mendelian randomization (MR) analyses. IVW results were considered primary results. Cochrane's Q and MR-Egger tests were used to test for heterogeneity and pleiotropy. Leave-one-out was used to test the stability of the MR results, and Bonferroni correction was used to test the strength of the causal relationship between exposure and outcome. Results:MR analyses of 196 gut microbiota and eight common gastrointestinal disease phenotypes showed 62 flora and common gastrointestinal diseases with potential causal relationships. Among these potential causal relationships, after the Bonferroni-corrected test, significant causal relationships remained between Genus Oxalobacter and CD (OR = 1.29, 95% CI: 1.13-1.48, = 2.5 × 10-4, = 4.20 × 10-4), and between Family Clostridiaceae1 and IBS (OR = 0.9967, 95% CI: 0.9944-0.9991, = 1.3 × 10-3, = 1.56 × 10-3). Cochrane's -test showed no significant heterogeneity among the various single nucleotide polymorphisms (SNPs). In addition, no significant level of pleiotropy was found according to the MR-Egger. Conclusion:This study provides new insights into the mechanisms of gut microbiota-mediated gastrointestinal disorders and some guidance for targeting specific gut microbiota for treating gastrointestinal disorders.
10.3389/fmicb.2023.1273269
Birth weight, childhood obesity, adulthood obesity and body composition, and gastrointestinal diseases: a Mendelian randomization study.
Obesity (Silver Spring, Md.)
OBJECTIVE:This Mendelian randomization study aimed to investigate the associations of birth weight, childhood BMI, and adulthood BMI, waist-hip ratio, and body composition with the risk of 24 gastrointestinal diseases. METHODS:Independent genetic instruments associated with the exposures at the genome-wide significance level (p < 5 × 10 ) were selected from corresponding large-scale genome-wide association studies. Summary-level data for gastrointestinal diseases were obtained from the UK Biobank, the FinnGen study, and large consortia of European ancestry. RESULTS:Genetically predicted higher levels of birth weight were associated with a lower risk of gastroesophageal reflux. Genetically predicted higher childhood BMI was associated with an increased risk of duodenal ulcer, nonalcoholic fatty liver disease, and cholelithiasis. However, the associations did not persist after adjusting for genetically predicted adulthood BMI. Genetically predicted higher adulthood BMI and waist-hip ratio were associated with 19 and 17 gastrointestinal diseases, respectively. Genetically predicted greater visceral adiposity was associated with an increased risk of 17 gastrointestinal diseases. There were no strong associations among genetically predicted whole-body fat and fat-free mass indices with gastrointestinal diseases. CONCLUSIONS:This study suggests that greater adulthood adiposity, measured as either BMI, waist-hip ratio, or visceral adipose tissue, is causally associated with an increased risk of a broad range of gastrointestinal diseases in the European population.
10.1002/oby.23857
Causal effect of adiposity on the risk of 19 gastrointestinal diseases: a Mendelian randomization study.
Obesity (Silver Spring, Md.)
OBJECTIVE:Although the association between adiposity and gastrointestinal (GI) diseases has been explored, the causal effects of adiposity on GI diseases are largely unknown. METHODS:Mendelian randomization was conducted using single-nucleotide polymorphisms associated with BMI and waist circumference (WC) as instrumental variables, and the causal associations of BMI or WC with GI conditions were estimated among >400,000 UK Biobank participants, >170,000 Finnish-descent participants, and numerous consortia participants of predominantly European ancestry. RESULTS:Genetically predicted BMI was robustly associated with increased risk of nonalcoholic fatty liver disease (NAFLD), cholecystitis, cholelithiasis, and primary biliary cholangitis. For the diseases, the odds ratio per 1-SD increase in genetically predicted BMI (4.77 kg/m ) ranged from 1.22 (95% CI: 1.12-1.34; p < 0.0001) for NAFLD to 1.65 (95% CI: 1.31-2.06; p < 0.0001) for cholecystitis. Genetically predicted WC was robustly associated with increased risk of NAFLD, alcoholic liver disease, cholecystitis, cholelithiasis, colon cancer, and gastric cancer. Alcoholic liver disease was consistently associated with WC even after adjusting for alcohol consumption in a multivariable Mendelian randomization analysis. The odds ratio per 1-SD increase in genetically predicted WC (12.52 cm) for such associations ranged from 1.41 (95% CI: 1.17-1.70; p = 0.0015) for gastric cancer to 1.74 (95% CI: 1.21-1.78; p < 0.0001) for cholelithiasis. CONCLUSIONS:High genetically predicted adiposity was causally associated with an increased risk of GI abnormalities, particularly of hepatobiliary organs (liver, biliary tract, and gallbladder) that are functionally related to fat metabolism.
10.1002/oby.23722
Association between gut microbiota and seven gastrointestinal diseases: A Mendelian randomized study.
The journal of gene medicine
BACKGROUND:Observational research has shed light on the ability of gut microbes to influence the onset and progression of gastrointestinal diseases. The causal relationships between specific gut microbiomes and various gastrointestinal conditions, however, remain unknown. METHODS:We investigated the relationship between gut microbiota and seven specific gastrointestinal disorders using a robust two-sample Mendelian randomization (MR) approach. The inverse variance-weighted (IVW) method was used as the primary analysis tool in our study. Furthermore, we conducted multiple sensitivity analyses to strengthen the robustness of our findings and ensure the reliability of the IVW method. RESULTS:Our research has discovered significant links between the composition of gut microbiota and a variety of gastrointestinal ailments. We found compelling links between 13 gut microbiota and fatty liver, four gut microbiota and cirrhosis, eight gut microbiota and hepatocellular carcinoma, four gut microbiota and cholelithiasis, 12 gut microbiota and acute pancreatitis, eight gut microbiota and chronic pancreatitis, and 11 gut microbiota and pancreatic cancer. These findings shed light on the intricate relationship between gut microbes and the emergence of these specific gastrointestinal conditions. CONCLUSIONS:The findings of this extensive study not only validate the potential role of specific gut microbiota in gastrointestinal diseases, but also fill a critical gap in previous research. The discovery of these specific gut microbiota is a significant step forward because they may serve as novel and promising biomarkers for both the prevention and treatment of gastrointestinal conditions.
10.1002/jgm.3623
Assessing causality between osteoarthritis and gastrointestinal disorders: a Mendelian randomization study.
Scientific reports
The association between osteoarthritis (OA) and gastrointestinal disorders was found in observational studies. However, the causality is still elusive. A bidirectional Mendelian randomization (MR) analysis using genome wide association studies data was conducted to assess the causal association between OA and gastrointestinal diseases [including peptic ulcer disease (PUD), gastroesophageal reflux disease (GORD), and inflammatory bowel disease (IBD)]. A two-step MR (TSMR) was conducted between OA, gastrointestinal diseases and drugs to explore the mediating effects of non-steroidal anti-inflammatory drugs (NSAIDs) and opioids use. We used multivariable MR (MVMR) analysis to further validate the impact of prescription history on diseases. Results had statistical significance at a Bonferroni corrected P-value below 0.008. We observed that genetically predicted OA had a significant positive association with GORD [odds ratio (OR) = 1.26, P = 5e-05], but not with PUD or IBD. Regarding the other direction, gastrointestinal disorders as exposure had a null association with OA. Using TSMR, OA patients tended to increase the use of NSAIDs (OR = 1.45, P = 0.001) and opioids (OR = 1.77, P = 2e-05), but only the use of opioids increased the risk of GORD (OR = 1.43, P = 5e-09). Further MVMR analysis showed that the adverse effect of OA on GORD was significantly reduced after adjusting for opioids use (OR = 1.20, P = 0.038). This study provides evidence for the causal association between OA and increased risk of GORD, which is partly attributed to opioids use in OA patients but not NSAIDs.
10.1038/s41598-023-46767-9
Causal relationship between gut microbiota and gastrointestinal diseases: a mendelian randomization study.
Journal of translational medicine
BACKGROUND:Recent research increasingly highlights a strong correlation between gut microbiota and the risk of gastrointestinal diseases. However, whether this relationship is causal or merely coincidental remains uncertain. To address this, a Mendelian randomization (MR) analysis was undertaken to explore the connections between gut microbiota and prevalent gastrointestinal diseases. METHODS:Genome-wide association study (GWAS) summary statistics for gut microbiota, encompassing a diverse range of 211 taxa (131 genera, 35 families, 20 orders, 16 classes, and 9 phyla), were sourced from the comprehensive MiBioGen study. Genetic associations with 22 gastrointestinal diseases were gathered from the UK Biobank, FinnGen study, and various extensive GWAS studies. MR analysis was meticulously conducted to assess the causal relationship between genetically predicted gut microbiota and these gastrointestinal diseases. To validate the reliability of our findings, sensitivity analyses and tests for heterogeneity were systematically performed. RESULTS:The MR analysis yielded significant evidence for 251 causal relationships between genetically predicted gut microbiota and the risk of gastrointestinal diseases. This included 98 associations with upper gastrointestinal diseases, 81 with lower gastrointestinal diseases, 54 with hepatobiliary diseases, and 18 with pancreatic diseases. Notably, these associations were particularly evident in taxa belonging to the genera Ruminococcus and Eubacterium. Further sensitivity analyses reinforced the robustness of these results. CONCLUSIONS:The findings of this study indicate a potential genetic predisposition linking gut microbiota to gastrointestinal diseases. These insights pave the way for designing future clinical trials focusing on microbiome-related interventions, including the use of microbiome-dependent metabolites, to potentially treat or manage gastrointestinal diseases and their associated risk factors.
10.1186/s12967-024-04894-5
Sedentary and 21 gastrointestinal disorders: A Mendelian randomization study.
Medicine
Sedentary behavior (SB) has been linked in the past by observational studies to gastrointestinal illnesses, although the exact cause of the link is still unknown. To deal with this problem, we carried out a Mendelian randomization (MR) study to thoroughly examine the connection between SB and common gastrointestinal illnesses. We selected instrumental variables representing the SB from the UK Biobank study, including watching television viewing, playing computer, and driving. In addition, we obtained genetic associations of 21 common gastrointestinal disorders from the FinnGen research. After adjusting for common risk factors associated with gastrointestinal diseases, we analyzed the independent association between genetic. Furthermore, we used the inverse-variance weighted (IVW) method in conjunction with complementing techniques like MR-Egger (Mendelian randomization based on Egger Regression) and weighted median to assure the accuracy and dependability of the results. Our findings suggest that genetic susceptibility to prolonged television viewing is significantly associated with an increased risk of 9 out of 21 gastrointestinal disorders. Specifically, these disorders include gastroesophageal reflux disease, chronic gastritis, cholelithiasis, acute pancreatitis, chronic pancreatitis, gastroduodenal ulcer, fatty liver, irritable bowel syndrome, and acute appendicitis. These associations remained significant even after correcting for potential confounding factors. The replication analysis confirms the same conclusion. The results of this study demonstrate a causal relationship between cachexia and genetically predicted SB. To further understand the underlying pathogenic mechanisms at play, more study is required.
10.1097/MD.0000000000039813
Sedentary lifestyle, physical activity, and gastrointestinal diseases: evidence from mendelian randomization analysis.
EBioMedicine
BACKGROUND:The causal associations of physical activity and sedentary behavior with the risk of gastrointestinal disease are unclear. We performed a Mendelian randomization analysis to examine these associations. METHODS:Genetic instruments associated with leisure screen time (LST, an indicator of a sedentary lifestyle) and moderate-to-vigorous intensity physical activity (MVPA) at the genome-wide significance (P < 5 × 10) level were selected from a genome-wide association study. Summary statistics for gastrointestinal diseases were obtained from the UK Biobank study, the FinnGen study, and large consortia. Multivariable MR analyses were conducted for genetically determined LST with adjustment for MVPA and vice versa. We also performed multivariable MR with adjustment for genetically proxied smoking, body mass index (BMI), waist-to-hip ratio, type 2 diabetes, and fasting insulin for both exposures. FINDINGS:Genetically proxied longer LST was associated with an increased risk of gastrointestinal reflux, gastric ulcer, duodenal ulcer, chronic gastritis, irritable bowel syndrome, diverticular disease, Crohn's disease, ulcerative colitis, non-alcoholic fatty liver disease, alcoholic liver disease, cholangitis, cholecystitis, cholelithiasis, acute pancreatitis, chronic pancreatitis, and acute appendicitis. Most associations remained after adjustment for genetic liability to MVPA. Genetic liability to MVPA was associated with decreased risk of gastroesophageal reflux, gastric ulcer, chronic gastritis, irritable bowel syndrome, cholecystitis, cholelithiasis, acute and chronic pancreatitis. The associations attenuated albeit directionally remained after adjusting for genetically predicted LST. Multivariable MR analysis found that BMI and type 2 diabetes mediated the associations of LST and MVPA with several gastrointestinal diseases. INTERPRETATION:The study suggests that a sedentary lifestyle may play a causal role in the development of many gastrointestinal diseases. FUNDING:Natural Science Fund for Distinguished Young Scholars of Zhejiang Province (LR22H260001), Natural Science Foundation of Hunan Province (2021JJ30999), Swedish Heart-Lung Foundation (Hjärt-Lungfonden, 20210351), Swedish Research Council (Vetenskapsrådet, 2019-00977), Swedish Cancer Society (Cancerfonden), the Wellcome Trust (225790/7/22/Z), United Kingdom Research and Innovation Medical Research Council (MC_UU_00002/7) and National Institute for Health Research Cambridge Biomedical Research Centre (NHIR203312).
10.1016/j.ebiom.2024.105110
Gastrointestinal Consequences of Type 2 Diabetes Mellitus and Impaired Glycemic Homeostasis: A Mendelian Randomization Study.
Diabetes care
OBJECTIVE:We conducted a Mendelian randomization (MR) study to examine the associations of type 2 diabetes and glycemic traits with gastrointestinal diseases (GDs). RESEARCH DESIGN AND METHODS:Uncorrelated genetic variants associated with type 2 diabetes (n = 231), fasting insulin (n = 38), fasting glucose (n = 71), and hemoglobin A1c (n = 75) at the genome-wide significance were selected as instrument variables. Genetic associations with 23 common GDs were obtained from the FinnGen and UK Biobank studies and other large consortia. RESULTS:Genetic liability to type 2 diabetes was associated with the risk of 12 GDs. Per 1-unit increase in the log-transformed odds ratio (OR) of type 2 diabetes, the OR was 1.06 (95% CI, 1.03-1.09) for gastroesophageal reflux disease, 1.12 (95% CI, 1.07-1.17) for gastric ulcer, 1.11 (95% CI, 1.03-1.20) for acute gastritis, 1.07 (95% CI, 1.01-1.13) for chronic gastritis, 1.08 (95% CI, 1.03-1.12) for irritable bowel syndrome, 1.04 (95% CI, 1.01-1.07) for diverticular disease, 1.08 (95% CI, 1.02-1.14) for acute pancreatitis, 1.09 (95% CI, 1.05-1.12) for cholelithiasis, 1.09 (95% CI, 1.05-1.13) for cholelithiasis with cholecystitis, 1.29 (95% CI, 1.17-1.43) for nonalcoholic fatty liver disease, 1.12 (95% CI, 1.03-1.21) for liver cirrhosis, and 0.93 (95% CI, 0.89-0.97) for ulcerative colitis. Genetically predicted higher levels of fasting insulin and glucose were associated with six and one GDs, respectively. CONCLUSIONS:Associations were found between genetic liability to type 2 diabetes and an increased risk of a broad range of GDs, highlighting the importance of GD prevention in patients with type 2 diabetes.
10.2337/dc22-1385
Depression and 24 gastrointestinal diseases: a Mendelian randomization study.
Translational psychiatry
The causality of the association between depression and gastrointestinal diseases is undetermined. We conducted Mendelian randomization (MR) analyses to systematically explore the associations of depression with 24 gastrointestinal diseases. Independent genetic variants associated with depression at the genome-wide significance level were selected as instrumental variables. Genetic associations with 24 gastrointestinal diseases were obtained from the UK Biobank study, the FinnGen study, and large consortia. Multivariable MR analysis was conducted to explore the mediation effects of body mass index, cigarette smoking, and type 2 diabetes. After multiple-testing corrections, genetic liability to depression was associated with an increased risk of irritable bowel syndrome, non-alcohol fatty liver disease, alcoholic liver disease, gastroesophageal reflux, chronic pancreatitis, duodenal ulcer, chronic gastritis, gastric ulcer, diverticular disease, cholelithiasis, acute pancreatitis, and ulcerative colitis. For the causal effect of genetic liability to depression on non-alcoholic fatty liver disease, a substantial proportion was mediated by body mass index. Genetic predisposition to smoking initiation mediated half of effect of depression on acute pancreatitis. This MR study suggests that depression may play a causal role in many gastrointestinal diseases.
10.1038/s41398-023-02459-6
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
Experiences of the effects of physical activity in persons with irritable bowel syndrome (IBS): a qualitative content analysis.
Johannesson Elisabet,Jakobsson Ung Eva,Sadik Riadh,Ringström Gisela
Scandinavian journal of gastroenterology
OBJECTIVE:Increased physical activity has been tested among patients with irritable bowel syndrome (IBS) in a randomized trial which demonstrated improvement in gastrointestinal (GI) symptoms. The patients' experiences of the effects of physical activity on IBS symptoms are unknown. This knowledge is necessary to enable suitable support from health care professionals. The aim of this study was therefore to explore patients' experiences of the effects of physical activity. MATERIALS AND METHODS:Deep interviews were conducted with 15 patients (10 women and 5 men) aged 31-78 years. Their IBS had lasted for 10-57 years. The transcribed interviews were analyzed through a qualitative content analysis. RESULTS:The analysis of the material revealed three themes; GI symptoms, extra-intestinal symptoms, and quality of life (QOL). In relation to GI symptoms, the patients discussed how physical activity affected these symptoms and how they used physical activity to normalize and control their GI symptoms. Extra-intestinal symptoms were also affected by physical activity, and the patients described how they experienced a general bodily wellbeing as well as improved mood and energy in relation to physical activity. In terms of QOL, the patients discussed their perspectives on physical activity as giving them achievements, being pleasurable, and being strengthening of the self. CONCLUSIONS:Our results emphasize the importance of taking into account the patient's experiences of the effects of physical activity when coaching patients with IBS to be physically active. Using a person-centred approach incorporating, the patient's own experiences and resources is the key to successfully promoting physical activity in the clinic.
10.1080/00365521.2018.1519596
Intervention to increase physical activity in irritable bowel syndrome shows long-term positive effects.
Johannesson Elisabet,Ringström Gisela,Abrahamsson Hasse,Sadik Riadh
World journal of gastroenterology
AIM:To assess the long-term effects of physical activity on irritable bowel syndrome (IBS) symptoms and on quality of life, fatigue, depression and anxiety. METHODS:Seventy-six patients from a previous randomized controlled interventional study on increased physical activity in IBS were asked to participate in this long-term follow-up study. The included patients attended one visit in which they filled out questionnaires and they underwent a submaximal cycle ergometer test. The primary end point was the change in the IBS Severity Scoring System (IBS-SSS) at baseline, i.e., before the intervention and at follow-up. The secondary endpoints were changes in quality of life, fatigue, depression and anxiety. RESULTS:A total of 39 [32 women, median age 45 (28-61) years] patients were included in this follow-up. Median follow-up time was 5.2 (range: 3.8-6.2) years. The IBS symptoms were improved compared with baseline [IBS-SSS: 276 (169-360) vs 218 (82-328), P = 0.001]. This was also true for the majority of the dimensions of psychological symptoms such as disease specific quality of life, fatigue, depression and anxiety. The reported time of physical activity during the week before the visit had increased from 3.2 (0.0-10.0) h at baseline to 5.2 (0.0-15.0) h at follow-up, P = 0.019. The most common activities reported were walking, aerobics and cycling. There was no significant difference in the oxygen uptake 31.8 (19.7-45.8) mL per min per kg at baseline vs 34.6 (19.0-54.6) mL/min per kg at follow-up. CONCLUSION:An intervention to increase physical activity has positive long-term effects on IBS symptoms and psychological symptoms.
10.3748/wjg.v21.i2.600
Gastrointestinal complaints in runners are not due to small intestinal bacterial overgrowth.
Schommer Kai,Reljic Dejan,Bärtsch Peter,Sauer Peter
Journal of negative results in biomedicine
BACKGROUND:Gastrointestinal complaints are common among long distance runners. We hypothesised that small intestinal bacterial overgrowth (SIBO) is present in long distance runners frequently afflicted with gastrointestinal complaints. FINDINGS:Seven long distance runners (5 female, mean age 29.1 years) with gastrointestinal complaints during and immediately after exercise without known gastrointestinal diseases performed Glucose hydrogen breath tests for detection of SIBO one week after a lactose hydrogen breath test checking for lactose intolerance. The most frequent symptoms were diarrhea (5/7, 71%) and flatulence (6/7, 86%). The study was conducted at a laboratory.In none of the subjects a pathological hydrogen production was observed after the intake of glucose. Only in one athlete a pathological hydrogen production was measured after the intake of lactose suggesting lactose intolerance. CONCLUSIONS:Gastrointestinal disorders in the examined long distance runners were not associated with small intestinal bacterial overgrowth.
10.1186/1477-5751-10-8
Physical inactivity during leisure time and irregular meals are associated with functional gastrointestinal complaints in middle-aged and elder subjects.
Ohlsson Bodil,Manjer Jonas
Scandinavian journal of gastroenterology
OBJECTIVES:Few studies have examined how lifestyle factors affect functional gastrointestinal disorders. The aim of this study was to see if leisure time physical inactivity, dietary habits or body mass index (BMI) were associated with increased risk of functional abdominal pain, functional bloating, functional constipation or functional diarrhea. METHODS AND MATERIALS:This study was based on a questionnaire as part of the Swedish EpiHealth study. The cohort included 16,840 subjects between 45 and 75 years of age. Subjects with organic gastrointestinal diseases were excluded. Gastrointestinal symptoms were defined as functional abdominal pain, functional bloating, functional constipation and functional diarrhea. A meal (breakfast, lunch and dinner) was considered irregular if not taken every day. The impact of leisure time physical activity, dietary habits and BMI on functional symptoms were examined by logistic regression, adjusted for age, gender, socio-economy, smoking and alcohol habits. RESULTS:Higher the degree of physical activity, lower the risk for all kind of gastrointestinal complaints (p ≤ 0.001). Intakes of lunch more seldom or never versus every day were associated with diarrhea (OR: 1.592; 95% CI: 1.046-2.422). Irregular breakfast habits tended to associate with bloating (OR: 1.366; 95% CI 0.995-1.874). BMI was not significantly associated with gastrointestinal complaints, but BMI ≥25 kg/m(2) tended to reduce risk of constipation compared with BMI <25 kg/m(2). CONCLUSION:Physical inactivity during leisure time shows independent associations with all functional gastrointestinal symptoms, whereas irregular dietary habits mainly associates with functional diarrhea. Higher degree of physical activity is associated with corresponding risk reductions of symptoms.
10.1080/00365521.2016.1209786
The Experiences of Female IBS Patients Concerning Physical Activity as Treatment Modality: A Qualitative Study.
Qualitative health research
The purpose of this study is to investigate the patient's perspective on physical activity as treatment modality for irritable bowel syndrome (IBS). An interpretive phenomenological analysis (IPA) approach was used to examine the experiences of IBS patients with physical activity, through in-depth interviews with 11 female IBS patients. Experiences with physical activity varied substantially among patients. Patients attributed negative experiences with physical activity to embarrassment, anxiety, inability, and symptom deterioration. Positive experiences with physical activity were attributed to symptom relief and improvements in overall health. Accordingly, patients discussed how they considered the application of physical activity in respect of IBS. Disease activity and the timing, type, and intensity of physical activities all could alter a patient's response to physical activity. Physical activity seems to relieve complaints in most scenarios; however, a personal approach is required to tailor physical activity to the needs of each patient.
10.1177/10497323221110109
Systematic review: exercise-induced gastrointestinal syndrome-implications for health and intestinal disease.
Costa R J S,Snipe R M J,Kitic C M,Gibson P R
Alimentary pharmacology & therapeutics
BACKGROUND:"Exercise-induced gastrointestinal syndrome" refers to disturbances of gastrointestinal integrity and function that are common features of strenuous exercise. AIM:To systematically review the literature to establish the impact of acute exercise on markers of gastrointestinal integrity and function in healthy populations and those with chronic gastrointestinal conditions. METHODS:Search literature using five databases (PubMed, EBSCO, Web of Science, SPORTSdiscus, and Ovid Medline) to review publications that focused on the impact of acute exercise on markers of gastrointestinal injury, permeability, endotoxaemia, motility and malabsorption in healthy populations and populations with gastrointestinal diseases/disorders. RESULTS:As exercise intensity and duration increases, there is considerable evidence for increases in indices of intestinal injury, permeability and endotoxaemia, together with impairment of gastric emptying, slowing of small intestinal transit and malabsorption. The addition of heat stress and running mode appears to exacerbate these markers of gastrointestinal disturbance. Exercise stress of ≥2 hours at 60% VO appears to be the threshold whereby significant gastrointestinal perturbations manifest, irrespective of fitness status. Gastrointestinal symptoms, referable to upper- and lower-gastrointestinal tract, are common and a limiting factor in prolonged strenuous exercise. While there is evidence for health benefits of moderate exercise in patients with inflammatory bowel disease or functional gastrointestinal disorders, the safety of more strenuous exercise has not been established. CONCLUSIONS:Strenuous exercise has a major reversible impact on gastrointestinal integrity and function of healthy populations. The safety and health implications of prolonged strenuous exercise in patients with chronic gastrointestinal diseases/disorders, while hypothetically worrying, has not been elucidated and requires further investigation.
10.1111/apt.14157
Circadian rhythms in the pathogenesis of gastrointestinal diseases.
Codoñer-Franch Pilar,Gombert Marie
World journal of gastroenterology
The etiology of digestive pathologies such as irritable bowel syndrome (IBS), inflammatory bowel diseases (IBD) and cancer is not yet fully understood. In recent years, several studies have evidenced circadian variations in mechanisms involved in digestive health. In situations of disturbed circadian rhythms (chronodisruption) where the central clock and the peripheral clocks receive incoherent signals, the synchronicity is lost producing implications for health. This lack of coordination could alter the tissue function and cause long term damage to the organs. Life habits such as sleep, physical exercise, social interaction, and feeding times are determinants for stability and integrity of circadian rhythms. In recent years, experimental and clinical studies have consistently evidenced that the alteration of circadian rhythms is associated with the development of digestive pathologies mainly linked to dismotility or changes in microbiota composition. Likewise, it seems reasonable to deep into the importance of chronodisruption as a factor that may participate in the development of pathologies such as IBS, IBD and digestive cancers. Moreover, life habits respecting circadian rhythms should be promoted for the prevention of these diseases. Further studies will allow us a better understanding of the mechanisms acting at molecular level, and the development of new therapeutic targets.
10.3748/wjg.v24.i38.4297
Gastrointestinal Conditions in the Female Athlete.
Diduch Barry Kent
Clinics in sports medicine
Exercise can have significant effects on gastrointestinal diseases. Regular, moderate exercise can impart beneficial effects for the intestinal microbiome, irritable bowel syndrome symptoms, and inflammatory bowel disease. High-intensity training or prolonged endurance training, on the other hand, can have negative effects on these same entities. Female athletes report a higher prevalence of irritable bowel syndrome and celiac disease, and furthermore, have gastrointestinal symptoms modulated by the menstrual cycle. Management of gastrointestinal problems in the athletic population is widespread and includes training adjustments, dietary measures, and medicine management of symptoms.
10.1016/j.csm.2017.06.001
Influence of metabolic syndrome on upper gastrointestinal disease.
Sogabe Masahiro,Okahisa Toshiya,Kimura Tetsuo,Okamoto Koichi,Miyamoto Hiroshi,Muguruma Naoki,Takayama Tetsuji
Clinical journal of gastroenterology
A recent increase in the rate of obesity as a result of insufficient physical exercise and excess food consumption has been seen in both developed and developing countries throughout the world. Additionally, the recent increased number of obese individuals with lifestyle-related diseases associated with abnormalities in glucose metabolism, dyslipidemia, and hypertension, defined as metabolic syndrome (MS), has been problematic. Although MS has been highlighted as a risk factor for ischemic heart disease and arteriosclerotic diseases, it was also recently shown to be associated with digestive system disorders, including upper gastrointestinal diseases. Unlike high body weight and high body mass index, abdominal obesity with visceral fat accumulation is implicated in the onset of various digestive system diseases because excessive visceral fat accumulation may cause an increase in intra-abdominal pressure, inducing the release of various bioactive substances, known as adipocytokines, including tumor necrosis factor-α, interleukin-6, resistin, leptin, and adiponectin. This review article focuses on upper gastrointestinal disorders and their association with MS, including obesity, visceral fat accumulation, and the major upper gastrointestinal diseases.
10.1007/s12328-016-0668-1
Gut-Joint Axis: The Role of Physical Exercise on Gut Microbiota Modulation in Older People with Osteoarthritis.
de Sire Alessandro,de Sire Roberto,Petito Valentina,Masi Letizia,Cisari Carlo,Gasbarrini Antonio,Scaldaferri Franco,Invernizzi Marco
Nutrients
Osteoarthritis (OA) is considered one of the most common joint disorders worldwide and its prevalence is constantly increasing due to the global longevity and changes in eating habits and lifestyle. In this context, the role of gut microbiota (GM) in the pathogenesis of OA is still unclear. Perturbation of GM biodiversity and function, defined as 'gut dysbiosis', might be involved in the development of inflammaging, one of the main risk factors of OA development. It is well known that physical exercise could play a key role in the prevention and treatment of several chronic diseases including OA, and it is recommended by several guidelines as a first line intervention. Several studies have shown that physical exercise could modulate GM composition, boosting intestinal mucosal immunity, increasing the Bacteroidetes-Firmicutes ratio, modifying the bile acid profile, and improving the production of short chain fatty acids. Moreover, it has been shown that low intensity exercise might reduce the risk of gastrointestinal diseases, confirming the hypothesis of a strict correlation between skeletal muscle and GM. However, up to date, there is still a lack of clinical trials focusing on this research field. Therefore, in this narrative, we aimed to summarize the state-of-the-art of the literature regarding the correlation between these conditions, supporting the hypothesis of a 'gut-joint axis' and highlighting the role of physical exercise combined with adequate diet and probiotic supplements in rebalancing microbial dysbiosis.
10.3390/nu12020574
Genetic evidence supports a causal relationship between air pollution and brain imaging-derived phenotypes.
Ecotoxicology and environmental safety
BACKGROUND:Observational studies have reported associations between air pollutants and brain imaging-derived phenotypes (IDPs); however, whether this relationship is causal remains uncertain. METHODS:We conducted bidirectional two-sample Mendelian randomization (MR) analyses to explore the causal relationships between 5 types of air pollutants (N=423,796 to 456,380 individuals) and 587 reliable IDPs (N=33,224 individuals). Two-step MR was also conducted to assess whether the identified effects are mediated through the modulation of circulating cytokines (N=8293). RESULTS:We found genetic evidence supporting the association of nitrogen oxides (NO) with mean intra-cellular volume fraction (ICVF) in the left uncinate fasciculus (IVW β=-0.42, 95 % CI -0.62 to -0.23, P=1.51×10) and mean fractional anisotropy (FA) in the left uncinate fasciculus (IVW β=-0.42, 95 % CI -0.62 to -0.21, P=4.89×10). In further two-step MR analyses, we did not find evidence that genetic predictions of any circulating cytokines mediated the association between NO and IDPs. CONCLUSION:This study provides evidence for the association between air pollutants and brain IDPs, emphasizing the importance of controlling air pollution to improve brain health.
10.1016/j.ecoenv.2024.116664