
Genomic correlation, shared loci, and causal relationship between insomnia and psoriasis: a large-scale genome-wide cross-trait analysis.
Archives of dermatological research
Psoriasis and insomnia have co-morbidities, however, their common genetic basis is still unclear. We analyzed psoriasis and insomnia with summary statistics from genome-wide association studies. We first quantified overall genetic correlations, then ascertained multiple effector loci and expression-trait associations, and lastly, we analyzed the causal effects between psoriasis and insomnia. A prevalent genetic link between psoriasis and insomnia was found, four pleiotropic loci affecting psoriasis and insomnia were identified, and 154 genes were shared, indicating a genetic link between psoriasis and insomnia. Yet, there is no causal relationship between psoriasis and insomnia by two-sample Mendelian randomization. We discovered a genetic connection between insomnia and psoriasis driven by biological pleiotropy and unrelated to causation. Cross-trait analysis indicates a common genetic basis for psoriasis and insomnia. The results of this study highlight the importance of sleep management in the pathogenesis of psoriasis.
10.1007/s00403-024-03178-8
Relationship between periodontitis and psoriasis: A two-sample Mendelian randomization study.
Journal of clinical periodontology
AIM:Observational research suggests that periodontitis affects psoriasis. However, observational studies are prone to reverse causation and confounding, which hampers drawing causal conclusions and the effect direction. We applied the Mendelian randomization (MR) method to comprehensively assess the potential bi-directional association between periodontitis and psoriasis. MATERIALS AND METHODS:We used genetic instruments from the largest available genome-wide association study of European descent for periodontitis (17,353 cases, 28,210 controls) to investigate the relationship with psoriasis (13,229 cases, 21,543 controls), and vice versa. Causal Analysis Using Summary Effect (CAUSE) estimates and inverse variance-weighted (IVW) MR analyses were used for the primary analysis. Robust MR approaches were used for sensitivity analyses. RESULTS:Both univariable methods, CAUSE and IVW MR analyses, did not reveal any impact of periodontitis on psoriasis (CAUSE odds ratio [OR] = 1.00, p = 1.00; IVW OR = 1.02, p = .6247), or vice versa (CAUSE OR = 1.01, p = .5135; IVW OR = 1.00, p = .7070). The null association was corroborated by pleiotropy-robust methods with ORs close to 1 and p-values >.59. Overall, MR analyses did not suggest any effect of periodontitis on psoriasis. Similarly, there was no evidence to support an effect of psoriasis on periodontitis. CONCLUSIONS:Within the limitations of this MR study, the outcomes supported neither periodontitis affecting psoriasis nor psoriasis affecting periodontitis.
10.1111/jcpe.13620
Genomics-Microbiome Based Assessment of Bidirectional Causality Between Gut Microbiota and Psoriasis.
Clinical, cosmetic and investigational dermatology
Background:Traditional observational studies have found a possible risk association of the gut microbiota for psoriasis. Meanwhile, psoriasis may also affect the changes in the gut microbiota. However, the available evidence does not demonstrate a reciprocal relationship between the gut microbiota and psoriasis. This limits our understanding on the role of the gut microbiota in the mechanisms of psoriasis. Methods:To address this question we used Mendelian randomization, a novel epidemiological approach, and acquired the largest current gut microbiota GWAS data from the MiBioGen consortium as well as psoriasis GWAS data from the FinnGen consortium, and performed two-sample bidirectional MR analyses using a multiple MR analysis approach. Finally, the robustness of the results was assessed by sensitivity analysis. Results:Our results indicate that five bacterial genera are causally related to psoriasis and psoriasis is causally related to four bacterial genera. Conclusion:These results suggest a bidirectional causal influence of psoriasis on the gut microbiota. Our results somewhat challenge the causal inferences of previous observational studies. We found that the specific bacterial genera with a risk effect on psoriasis were different from those found to characterize psoriasis in previous observational studies, and that these psoriasis-characterizing genera were inversely associated with psoriasis.
10.2147/CCID.S450227
Genetic causality and metabolite pathway identifying the relationship of blood metabolites and psoriasis.
Skin research and technology : official journal of International Society for Bioengineering and the Skin (ISBS) [and] International Society for Digital Imaging of Skin (ISDIS) [and] International Society for Skin Imaging (ISSI)
BACKGROUND:Psoriasis is a chronic inflammatory disease that causes significant disability. However, little is known about the underlying metabolic mechanisms of psoriasis. Our study aims to investigate the causality of 975 blood metabolites with the risk of psoriasis. MATERIALS AND METHODS:We mainly applied genetic analysis to explore the possible associations between 975 blood metabolites and psoriasis. The inverse variance weighted (IVW) method was used as the primary analysis to assess the possible association of blood metabolites with psoriasis. Moreover, generalized summary-data-based Mendelian randomization (GSMR) was used as a supplementary analysis. In addition, linkage disequilibrium score regression (LDSC) was used to investigate their genetic correction further. Metabolic pathway analysis of the most suggested metabolites was also performed using MetaboAnalyst 5.0. RESULTS:In our primary analysis, 17 metabolites, including unsaturated fatty acids, phospholipids, and triglycerides traits, were selected as potential factors in psoriasis, with odd ratios (OR) ranging from 0.986 to 1.01. The GSMR method confirmed the above results (β = 0.001, p < 0.05). LDSC analysis mainly suggested the genetic correlation of psoriasis with genetic correlations (rg) from 0.088 to 0.155. Based on the selected metabolites, metabolic pathway analysis suggested seven metabolic pathways including ketone body that may be prominent pathways for metabolites in psoriasis. CONCLUSION:Our study supports the causal role of unsaturated fatty acid properties and lipid traits with psoriasis. These properties may be regulated by the ketone body metabolic pathway.
10.1111/srt.13840
Genetic overlap and Mendelian randomization analysis highlighted the causal relationship between psoriatic disease and migraine.
Archives of dermatological research
Despite observational studies suggesting a link between psoriatic disease (including psoriasis and psoriatic arthritis) and migraine, it is unclear whether there is a shared genetic etiology or a causal relationship between the two conditions. We aimed to reveal the genetic overlap and causality using the Mendelian randomization (MR) framework. The genetic analysis utilized summary data from the most extensive European genome-wide association study (GWAS) of migraine. Well-powered psoriatic disease GWAS data were obtained from two independent cohort studies, which served as discovery and validation datasets. Global and regional genetic correlations between psoriatic disease and migraine were assessed, and pleiotropic regions identified by pairwise GWAS analysis were further annotated. We further applied a two-sample MR multivariate MR to investigate the potential causal relationship between them. The global genetic correlation test indicated weak correlations between psoriatic disease and migraine, while regional correlation analyses delineated one significant shared locus between psoriasis and migraine. Pathway enrichment analysis revealed that shared genes were involved biological processes to the major histocompatibility and antigen processing and presentation. In terms of causality estimates, genetically predicted psoriasis (P = 0.003) and psoriatic arthritis (P = 0.028) were associated with an increased risk of migraine. Multivariate MR analysis indicated that psoriasis was an independent risk factor for migraine (P < 0.05). No significant associations were found in the reverse direction. Our study supported the causal role of psoriasis on migraine, and the central role for immunomodulatory etiology. These findings have significant implications for the management of migraine and clinical practice in patients with psoriasis.
10.1007/s00403-024-03295-4
Assessing the relationship between psoriasis and thyroid dysfunction through two sample MR analysis.
Archives of dermatological research
BACKGROUND:The association between psoriasis and hyperthyroidism/hypothyroidism remains inconclusive, with conflicting findings in prior studies. OBJECTIVES:This study employs Mendelian randomization methods to assess the potential relationship. METHODS:Given the inability to accurately observe the link between psoriasis and thyroid dysfunction, we prioritized utilizing known genetic variants to investigate the potential impacts of the disease.We analyzed data from genome-wide association studies (GWASs), FinnGen, and UK Biobank to extract information on psoriasis, hyperthyroidism, and hypothyroidism. Three MR approaches (MR Egger, weighted median, and inverse variance weighted) were used to scrutinize the causal link. RESULTS:Our analysis revealed no correlation between psoriasis and hyperthyroidism/hypothyroidism. However, vulgar psoriasis and guttate psoriasis were associated with hypothyroidism/myxedema (IVW odds ratio (OR) = 1.00, 95% confidence interval (CI) = 1.00-1.00, P = 2.53E-03), and Graves' disease (IVW OR = 0.86, 95% CI = 0.72-1.01, P = 4.75E-02).In a subsequent analysis, we observed that hypothyroidism with mucinous edema showed no correlation with Graves' disease in the opposite(P = 9.33E-01). CONCLUSION:This MR analysis suggests no association between psoriasis and thyroid dysfunction, but highlights associations of vulgar/guttate psoriasis with hypothyroidism/myxedema and Graves' disease. In clinical practice, diagnosing guttate psoriasis requires vigilance for associated risks from hypothyroidism and Graves' disease. For patients with both vulgar psoriasis and hypothyroidism, careful monitoring for mucinous edema is crucial, as it may signal a hypothyroid crisis.
10.1007/s00403-024-03069-y
Causal Effects of Circulating Cytokines on the Risk of Psoriasis Vulgaris: A Mendelian Randomization Study.
Frontiers in genetics
Psoriasis vulgaris is an inflammatory skin disease. Observational studies have shown associations between circulating cytokine levels and psoriasis vulgaris. But the causal relationship between circulating cytokine and psoriasis vulgaris remains elusive. To assess the causal effects of cytokine levels on the risk of psoriasis vulgaris and vice versa, we performed a two-sample Mendelian randomization (MR) study by using the inverse-variance weighted (IVW), weighted median, and Mendelian randomization pleiotropy residual sum and outlier (MR-PRESSO) in genome-wide association summary statistics of 41 circulating cytokines in up to 8,293 individuals and psoriasis vulgaris in 399,883 individuals. We identified that increasing RANTES level induced an elevated risk of psoriasis vulgaris in IVW ( = 0.33, S.E. = 0.12, = 0.006). This causal effect showed consistency across the weighted median ( = 0.35, S.E. = 0.15, = 0.022) and MR-PRESSO method ( = 0.33, S.E. = 0.11, = 0.028). Our results suggest a potential causal effect of elevated RANTES concentration on the increased risk of psoriasis vulgaris.
10.3389/fgene.2022.941961
Cysteine cathepsins and autoimmune diseases: A bidirectional Mendelian randomization.
Medicine
Cysteine cathepsins are proteolytic enzymes crucial in various physiological and pathological processes, primarily operating within lysosomes. Their functions include protein degradation, immune system regulation, and involvement in various diseases. While some cysteine cathepsins play important roles in the immune system, their connection to autoimmune diseases remains unclear. This study proposes using Mendelian randomization to explore the causal relationship between cysteine cathepsins and autoimmune diseases. Single nucleotide polymorphisms (SNPs) for cysteine cathepsins were obtained from a publicly available genome-wide association study (GWAS) dataset, while outcome SNP data were sourced from 10 separate GWAS datasets. Mendelian randomization (MR) analysis employed the Wald ratio (WR) and inverse variance weighted (IVW) approach as primary methods, supplemented by the weighted median and MR-Egger methods. Heterogeneity was assessed using Cochran Q test, and sensitivity analysis was conducted using the MR-PRESSO method. The association strength between exposure and outcome was evaluated using odds ratios (OR) with 95% confidence intervals (CI). The study identified a potential positive correlation between elevated cathepsin B and psoriasis (Wald ratio OR = 1.449, 95% CI: 1.053-1.993, P = .0227). Elevated cathepsin F was potentially linked to ulcerative colitis (WR OR = 1.073, 95% CI: 1.021-1.127, P = .0056), ankylosing spondylitis (WR OR = 1.258, 95% CI: 1.082-1.463, P = .0029), and primary biliary cholangitis(PBC) (WR OR = 1.958, 95% CI: 1.326-2.889, P = .0007). Conversely, cathepsin H appeared protective against celiac disease (WR OR = 0.881, 95% CI: 0.838-0.926, P = 6.5e-7), though elevated levels may increase the risk of type 1 diabetes (IVW OR = 1.121, 95% CI: 1.053-1.194, P = .0003) and PBC (WR OR = 1.792, 95% CI: 1.062-3.024, P = .0288). Cathepsin Z was also associated with an increased risk of type 1 diabetes (IVW OR = 1.090, 95% CI: 1.006-1.181, P = .0349). The MR analysis suggests potential risks of cathepsin B with psoriasis, cathepsin F with ulcerative colitis, ankylosing spondylitis, and PBC, and cathepsin Z with type 1 diabetes. Conversely, cathepsin H may protect against celiac disease but could increase the risk of type 1 diabetes and PBC.
10.1097/MD.0000000000040268
Association Between Inflammatory Bowel Disease and Both Psoriasis and Psoriatic Arthritis: A Bidirectional 2-Sample Mendelian Randomization Study.
JAMA dermatology
Importance:Psoriasis, psoriatic arthritis, and inflammatory bowel disease, ie, Crohn disease and ulcerative colitis, are chronic systemic immune-mediated disorders affecting an increasing proportion of adults and children worldwide. Observational studies have suggested an association between inflammatory bowel disease and psoriasis and vice versa. So far, however, it remains unclear whether and in which direction causal relationships exist. Objective:To investigate the association between inflammatory bowel disease, particularly Crohn disease and ulcerative colitis, and psoriasis or psoriatic arthritis. Design, Setting, and Participants:A bidirectional 2-sample mendelian randomization study was conducted using summary statistics from genome-wide association studies including up to 463 372 European individuals. Total and direct effects were derived performing an iterative radial and robust inverse-variance weighted method within the univariable and multivariable mendelian randomization setting, respectively. Causal estimates were verified using a validation inflammatory bowel disease sample, a series of pleiotropy-robust mendelian randomization methods, and sensitivity analyses based on a PhenoScanner search in conjunction with network analysis. Data analysis was performed from April to May 2022. Main Outcomes and Measures:Inflammatory bowel disease, Crohn disease, ulcerative colitis, psoriasis, and psoriatic arthritis were used as both exposures and outcomes. Results:The European samples included 12 882 cases of inflammatory bowel disease and 5621 cases of psoriasis. The proportion of women ranged between 48% and 56%. Genetically predicted inflammatory bowel disease was associated with higher risk of psoriasis (pooled odds ratio [OR], 1.10; 95% CI, 1.05-1.15; P < .001) and psoriatic arthritis (pooled OR, 1.10; 95% CI, 1.04-1.18; P = .003). In contrast with ulcerative colitis, the Crohn disease subentity was associated with psoriasis (OR, 1.16; 95% CI, 1.12-1.20; P < .001) and psoriatic arthritis (OR, 1.13; 95% CI, 1.06-1.20; P < .001). Regarding the reverse directions, no notable associations could be found. Conclusions and Relevance:Findings of this mendelian randomization study support a causal effect between inflammatory bowel disease and psoriasis as well as psoriatic arthritis, but not vice versa. It seems that especially Crohn disease and not ulcerative colitis is responsible for the causal effect of inflammatory bowel disease on both psoriasis outcomes. These findings have implications for the management of inflammatory bowel disease and psoriasis in clinical practice.
10.1001/jamadermatol.2022.3682
Smoking is an independent but not a causal risk factor for moderate to severe psoriasis: A Mendelian randomization study of 105,912 individuals.
Frontiers in immunology
Background:Smoking is strongly associated with higher risk of psoriasis in several observational studies; however, whether this association is causal or can be explained by confounding or reverse causation is not fully understood. Randomized controlled trials are the gold standard when examining causality; however, when this method is not feasible, the Mendelian randomization design is an alternative. Herein genetic variants can be used as robust proxies for modifiable exposures and thereby avoiding confounding and reverse causation.In this study, we hypothesized that smoking is an independent and causal risk factor for psoriasis and tested this using a Mendelian randomization design. Methods:We used data from the Copenhagen General Population Study including 105,912 individuals with full information on lifestyle factors, biochemistry, and genotype data. In total, 1,240 cases of moderate to severe psoriasis were included to investigate the association between smoking and psoriasis. To assess causality of the association, we used the genetic variant rs1051730, where the T-allele is strongly associated with high lifelong cumulative smoking, as a proxy for smoking. Results:In observational analyses, the multivariable adjusted hazard ratio of developing moderate to severe psoriasis was 1.64 (95% confidence interval: 1.35-2.00) in ever smokers with ≤ 20 pack-years and 2.23 (1.82-2.73) in ever smokers with > 20 pack-years compared to never smokers. In genetic analyses, the odds ratio of developing moderate to severe psoriasis was 1.05 (0.95-1.16) per rs10511730 T-allele in ever smokers. Conclusion:Smoking was an independent risk factor for moderate to severe psoriasis in observational analyses. However, using a genetic variant as a robust proxy for smoking, we did not find this association to be causal.
10.3389/fimmu.2023.1119144
Exploring the Link Between Genetic Predictors of Cardiovascular Disease and Psoriasis.
JAMA cardiology
Importance:The epidemiological link between immune-mediated diseases (IMIDs) and cardiovascular disease has often been attributed to systemic inflammation. However, the direction of causality and the biological mechanisms linking cardiovascular disease with IMIDs are incompletely understood. Given the robust epidemiological association and the growing body of supportive mechanistic evidence, psoriasis is an exemplary IMID model for exploring this relationship. Objective:To assess the bidirectional relationships between genetic predictors of psoriasis and the 2 major forms of cardiovascular disease, coronary artery disease (CAD) and stroke, and to evaluate the association between genetic predictors of cardiovascular disease with 9 other IMIDs. Design, Setting, and Participants:This was a genetic association study using mendelian randomization (MR), a powerful genetic tool to help distinguish causation from associations observed in epidemiological studies, to provide supportive evidence for causality between traits. The study conducted 2-sample MR analyses using summary-level data from large-scale genome-wide association meta-analysis studies (GWAS) for each trait. The analysis focused on individuals of European descent from GWAS meta-analyses, involving CAD, stroke, psoriasis, and 9 other IMIDs. Data were analyzed from January 2023 to May 2024. Exposures:Genetic predictors of CAD, stroke, psoriasis, and 9 other IMIDs. Main Outcomes and Measures:The primary outcomes were the associations of genetic predictors of CAD and stroke with the risk of psoriasis and 9 other IMIDs, determined using inverse-variance weighted (IVW) MR estimates. Results:This study included 181 249 cases and 1 165 690 controls with CAD, 110 182 cases and 1 503 898 controls with stroke, 36 466 cases and 458 078 controls with psoriasis, for a total of approximately 3 400 000 individuals, and 9 other IMIDs. In contrast to previous assumptions, genetic predictors of psoriasis were found to have no association with CAD or stroke. In the reverse direction, genetic predictors of both CAD (MR estimate IVW odds ratio [OR], 1.07; 95% CI, 1.04-1.10; P = .003) and stroke (IVW OR, 1.22; 95% CI, 1.05-1.41; P = .01) were found to have risk-increasing associations with psoriasis. Adjusting for stroke rendered the associations of genetically predicted CAD with psoriasis risk nonsignificant (and vice versa), suggesting that a shared effect underlying genetic risk for CAD and stroke associates with increased psoriasis risk. No risk-increasing associations were observed for genetic predictors of cardiovascular disease with other common IMIDs, including rheumatoid arthritis and inflammatory bowel disease. Conclusions and Relevance:Findings of this mendelian randomization study indicate that genetic predictors of cardiovascular disease were associated with increased psoriasis risk with no reciprocal effect or association with other IMIDs. Elucidating mechanisms underpinning this association could lead to novel therapeutic approaches in both diseases.
10.1001/jamacardio.2024.2859
Evidence for a causal association between psoriasis and psychiatric disorders using a bidirectional Mendelian randomization analysis in up to 902,341 individuals.
Journal of affective disorders
BACKGROUND:The causal association between psoriasis and psychiatric disorders remains ambiguous. OBJECTIVES:This study aimed to investigate the causal relationship between psoriasis and common psychiatric disorders using bidirectional Mendelian randomization (MR) analysis. METHODS:Major depressive disorder (MDD) (N = 217,584), bipolar disorder (N = 51,710), schizophrenia (N = 77,096), and anxiety disorder (N = 218,792) were obtained as outcomes, and psoriasis (N = 337,159) were as exposure. Inverse variance weighting (IVW) was used as the main method, with other sensitivity methods as auxiliary methods. Sensitivity analysis and heterogeneity tests were performed to ensure the robustness of the results. We also performed a subgroup analysis of cases with psoriatic arthritis (PsA) (N = 213,879) by using the same testing methods. RESULTS:MR showed that the genetic risk of psoriasis was positively associated with bipolar disorder (odds ratio (OR) = 13.54, 95 % confidence interval (95%CI): 2.43-75.37, P = 0.002) and MDD (OR = 1.08, 95%CI: 1.01-1.15, P = 0.027), which indicated possible causal relationships between psoriasis and these two diseases. Schizophrenia (OR = 3.52, 95%CI: 0.22-55.71, P = 0.372) and anxiety disorders (OR = 0.65, 95%CI: 0.16-2.63, P = 0.546) indicated no significant causal association. No reverse causal effects of psychiatric disorders on psoriasis were found. Subgroup analysis also suggested causal association of PsA with the bipolar affective disorder (OR = 1.05, 95%CI: 1.01-1.08, P = 0.005). LIMITATIONS:Potential pleiotropic effects, restriction to European populations, and differences in diagnostic criteria. CONCLUSIONS:This study has supported the causal association of psoriasis with MDD and bipolar disorder, and the subtype PsA with bipolar disorder, which informed the intervention for mental illnesses in patients with psoriasis.
10.1016/j.jad.2023.05.059
Is erectile dysfunction genetically associated with psoriasis?
Translational andrology and urology
Background:The association between psoriasis and erectile dysfunction (ED) is currently inconsistent in epidemiological and observational studies and the causal relationship between them has not been established. The aim of our study is to explore the potential genetic association between ED and psoriasis. Methods:We explored the putative causality between psoriasis and ED by bidirectional Mendelian randomization (MR). The single nucleotide polymorphisms (SNPs) associated with psoriasis were retrieved from a large-scale public genome-wide association study (GWAS). The summary statistics of ED were obtained from individuals of European ancestry with 6,175 cases 217,630 controls. Inverse-variant weighted (IVW), weighted median (WM), MR-Egger, MR-Steiger, and MR pleiotropy residual sum and outlier (MR-PRESSO) test were employed in MR analyses to investigate the bidirectional causal relationship between psoriasis and ED. Several sensitivity analyses were employed to confirm the findings of the MR analysis. Results:Our MR analysis indicated that genetically predicted psoriasis showed no association with a higher risk of ED [odds ratio (OR) 2.878, 95% confidence interval (CI): 0.175-47.289, P=0.46]. As for the other direction, no causal association was disclosed between ED and psoriasis (OR 0.999, 95% CI: 0.997-1.002, P=0.62). These findings remained consistent in sensitivity analyses. Conclusions:The study revealed a negative genetic association between psoriasis and ED. Certain acquired factors may contribute to a strong clinical connection between the two, highlighting the need for comprehensive management of these risk factors.
10.21037/tau-24-10
Alcohol consumption and smoking in relation to psoriasis: a Mendelian randomization study.
The British journal of dermatology
BACKGROUND:Alcohol consumption and smoking have been reported to be associated with psoriasis risk. However, a conclusion with high-quality evidence of causality could not be easily drawn from regular observational studies. OBJECTIVES:This study aims to assess the causal associations of alcohol consumption and smoking with psoriasis. METHODS:Genome-wide association study (GWAS) summary-level data for alcohol consumption (N = 941 280), smoking initiation (N = 1 232 091), cigarettes per day (N = 337 334) and smoking cessation (N = 547 219) was obtained from the GSCAN consortium (Sequencing Consortium of Alcohol and Nicotine use). The GWAS results for lifetime smoking (N = 462 690) were obtained from the UK Biobank samples. Summary statistics for psoriasis were obtained from a recent GWAS meta-analysis of eight cohorts comprising 19 032 cases and 286 769 controls and the FinnGen consortium, comprising 4510 cases and 212 242 controls. Linkage disequilibrium score regression was applied to compute the genetic correlation. Bidirectional Mendelian randomization (MR) analyses were conducted to determine casual direction using independent genetic variants that reached genome-wide significance (P < 5 × 10 ). RESULTS:There were genetic correlations between smoking and psoriasis. MR revealed a causal effect of smoking initiation [odds ratio (OR) 1·46, 95% confidence interval (CI) 1·32-1·60, P = 6·24E-14], cigarettes per day (OR 1·38, 95% CI 1·13-1·67, P = 0·001) and lifetime smoking (OR 1·96, 95% CI 1·41-2·73, P = 7·32E-05) on psoriasis. Additionally, a suggestive causal effect of smoking cessation on psoriasis was observed (OR 1·39, 95% CI 1·07-1·79, P = 0·012). We found no causal relationship between alcohol consumption and psoriasis (P = 0·379). The reverse associations were not statistically significant. CONCLUSIONS:Our findings provide causal evidence for the effects of smoking on psoriasis risk. What is already known about this topic? Alcohol consumption and smoking have been reported to be associated with psoriasis risk. Whether alcohol consumption and smoking have a causal effect on psoriasis risk remains unclear. What does this study add? This Mendelian randomization study shows a causal association between smoking, but not alcohol consumption, and the risk of developing psoriasis. Restricting smoking could be helpful in reducing the burden of psoriasis.
10.1111/bjd.21718
Psoriasis and progression of Parkinson's disease: a Mendelian randomization study.
Journal of the European Academy of Dermatology and Venereology : JEADV
BACKGROUND:Epidemiological studies have suggested psoriasis was associated with an increased risk of Parkinson's disease (PD). However, whether psoriasis has an effect on PD progression is not explored yet. OBJECTIVES:To evaluate the causal role of psoriasis in PD progression. METHODS:We conducted a two-sample Mendelian randomization analysis using summary statistics from genome-wide association study of psoriasis (N = 33 394), age at onset (N = 28 568) and progression (N = 4093) of PD. RESULTS:One standard deviation increase in genetically determined psoriasis risk was significantly associated with faster progression to dementia (OR = 1.07, 95% CI: 0.1.03-1.1, P = 4.71E-04). Meanwhile, higher psoriasis risk was nominally associated with faster progression of PD measured by time to Hoehn and Yahr stage 3 (OR = 1.05, 95% CI: 1.02-1.08, P = 1.53E-03) and depression (OR = 1.06, 95% CI: 1.02-1.11, P = 1.77E-03) of PD. The results were robust under all sensitivity analyses. CONCLUSIONS:These results suggested psoriasis accelerated overall progression of PD, and increased risk of dementia and depression of PD. A deeper understanding of neuroinflammation and immune response is likely to elucidate the potential pathogenesis of PD progression and identify novel therapeutic targets.
10.1111/jdv.18459
Association between allergic diseases and both psoriasis and psoriatic arthritis: a bidirectional 2-sample Mendelian randomization study.
Archives of dermatological research
Background An increasing body of observational studies has indicated a potential link between allergic diseases, namely atopic dermatitis (AD), allergic rhinitis (AR), allergic asthma (AA), and psoriasis (PSO) as well as psoriatic arthritis (PSA). However, the presence and causal direction of this association remain uncertain. Methods We conducted two-sample Mendelian randomization (TSMR) analyses utilizing summary statistics derived from genome-wide association studies (GWAS) consortia. The summary statistics were obtained from a substantial participant cohort, consisting of 116,000 individuals (21,000 AD cases and 95,000 controls), 462,933 individuals (26,107 AR cases and 436,826 controls), and 140,308 individuals (4859 AA cases and 135,449 controls). The summary statistics for PSO (9267 cases and 360,471 controls) and PSA (3186 cases and 240,862 controls) were sourced from the FinnGen database. The primary analytical approach employed inverse variance weighting (IVW) as the main method within TSMR. We validated our findings through a series of sensitivity analyses. Furthermore, we performed reverse TSMR analyses to evaluate the potential presence of reverse causality. Results Our investigation revealed a potential protective effect of AD against both PSO (OR = 0.922, 95% CI = 0.863-0.984, p = 0.015)and PSA(OR = 0.915, 95% CI = 0.843-0.993, p = 0.033). Moreover, employing inverse MR analysis, we obtained compelling evidence supporting the protective role of PSO in preventing AD (OR = 0.891, 95% CI = 0.829-0.958, p = 0.002), as well as AR (OR = 0.998, 95% CI = 0.996-0.999, p = 0.008), these associations remained statistically significant even after Bonferroni correction was applied to account for multiple comparisons. Furthermore, our findings did not reveal any substantial causal relationship between AA and either PSO or PSA. Conclusion Our study provides compelling evidence that PSO significantly confers protection against both AD and AR, while AD is likely to act as a protective factor for both PSO and PSA. Despite previous studies suggesting an association between allergic diseases and the incidence of PSO and PSA, our findings do not support this claim. To obtain more accurate and reliable conclusions regarding the causal mechanisms involved, larger sample sizes in randomized controlled trials or MR studies are warranted.
10.1007/s00403-024-02978-2
Mendelian randomization study of the genetic interaction between psoriasis and celiac disease.
Scientific reports
Epidemiological studies have observed some relationship between psoriasis and celiac disease (CD), while the causal link between these 2 autoimmune diseases was unclear. In the current study, we aimed to explore the causal link between psoriasis and celiac disease with bidirectional 2-sample Mendelian Randomization (MR) study. Eligible instrument variables (IVs) with genome-wide significance (p < 5E-08) were extracted from the summary-level datasets from the published genome-wide association studies (GWAS), which were conducted in the European population. The inverse variance weighted (IVW) method was performed as the main analysis, sensitivity analyses and post-MR analyses were also performed. Our MR analyses found that genetically doubling the odds of CD would increase the risk for psoriasis (p = 1.58e-03, OR [95% CI] 1.232 [1.061-1.432]). And the results were supported by sensitivity analyses. While we found that genetically determined psoriasis was not associated with the risk for CD (IVW: p = 0.985, OR [95% CI] 1.000 [0.965-1.037]). Our study provided novel genetic evidence that patients with CD were at an increased risk of developing psoriasis, while psoriasis was not associated with the risk for CD. Clinicians should be aware of the associations and pay attention to skin manifestations in patients with CD.
10.1038/s41598-022-25217-y
Investigating the gut microbiota's influence on psoriasis and psoriatic arthritis risk: a Mendelian randomization analysis.
Precision clinical medicine
Background:Numerous investigations have revealed the interplay between gut microbiota (GM) and psoriasis (Ps) and psoriatic arthritis (PsA). However, the causal relationship between them remains unknown. Methods:We curated a collection of genetic variants ( < 1 × 10) associated with GM ( = 18 340) derived from the MiBioGen study. To explore the intricate relationship between GM and Ps as well as PsA, we harnessed the comprehensive resources of the FinnGen database, encompassing a vast cohort of individuals, including 4510 Ps cases and 212 242 controls and 1637 PsA cases and 212 242 controls. Mendelian randomization (MR) was used, including an inverse variance weighting method, followed by a sensitivity analysis to verify the robustness of the results. Results:For Ps, some bacterial taxa, including , and , were identified as risk factors; but demonstrated a protective effect against Ps. In the case of PsA, , and were identified as risk factors; and exhibited a protective effect against the development of PsA. Conclusion:Our study establishes a causal link between the GM and Ps and PsA. These findings provide insights into the underlying mechanisms and suggest potential therapeutic targets.
10.1093/pcmedi/pbad023
The relationship between psoriasis and vitiligo: From a comprehensive study.
Skin research and technology : official journal of International Society for Bioengineering and the Skin (ISBS) [and] International Society for Digital Imaging of Skin (ISDIS) [and] International Society for Skin Imaging (ISSI)
BACKGROUND:Both psoriasis and vitiligo are autoimmune skin diseases. Previous observational studies have indicated a relationship between the two conditions, and simultaneous onset of both diseases poses increased health risks to patients. However, limited research has explored the causal relationship between psoriasis and vitiligo. OBJECTIVES:To investigate whether a causal association exists between psoriasis and vitiligo. METHODS:A case of Chinese patients diagnosed with psoriasis and vitiligo has been reported. Transcriptome sequencing was performed on normal, psoriasis, vitiligo, and co-morbid skin tissues of the patients, and single-cell transcriptome sequencing was conducted on the co-morbid skin tissues. A comprehensive Mendelian randomization analysis of Genome-wide association studies (GWAS) was performed on a cohort of 261 018 European individuals with psoriasis from the IEU Open GWAS Project and vitiligo from the National Institutes of Health (NIH) Database of Genotypes and Phenotypes. RESULTS:Case report and transcriptome results showed that skin tissue with vitiligo combined with psoriasis exhibited both vitiligo and psoriasis. Single-cell transcriptome sequencing results showed that in comparison to normal skin and psoriatic skin, the proportions of CD8+ T cells, natural killer cells, naive T cells, T helper cells 17, regulatory T cells, conventional type 1 dendritic cells, Conventional type 2 dendritic cells, and plasmacytoid dendritic cells were all increased in skin tissue with vitiligo combined with psoriasis. Mendelian randomization analysis included 4510 patients with psoriasis and 4680 patients with vitiligo. The results showed no causal relationship between vitiligo and psoriasis in the forward direction (p = 0.192; odds ratio [OR], 1.059; 95% confidence interval [CI], 0.971-1.155) or in the reverse direction (p = 0.459; OR, 0.927; 95% CI, 0.757-1.134). CONCLUSIONS:This study suggests that the association between psoriasis and vitiligo may be closely related to immunity, however, Mendelian randomization studies do not support a causal relationship. These findings hold significant implications for clinicians aiming to enhance their understanding and treatment approaches for psoriasis and vitiligo.
10.1111/srt.13868
An observational and genetic investigation into the association between psoriasis and risk of malignancy.
Nature communications
The relationship between psoriasis and site-specific cancers remains unclear. Here, we aim to investigate whether psoriasis is causally associated with site-specific cancers. We use observational and genetic data from the UK Biobank, obtaining GWAS summary data, eQTL analysis data, TCGA data, and GTEx data from public datasets. We perform PheWAS, polygenic risk score analysis, and one-sample and two-sample Mendelian randomization analyses to investigate the potential causal associations between psoriasis and cancers. In the unselected PheWAS analysis, psoriasis is associated with higher risks of 16 types of cancer. Using one-sample Mendelian randomization analyses, it is found that genetically predicted psoriasis is associated with higher risks of anal canal cancer, breast cancer, follicular non-Hodgkin's lymphoma and nonmelanoma skin cancer in women; and lung cancer and kidney cancer in men. Our two-sample Mendelian randomization analysis indicates that psoriasis is causally associated with breast cancer and lung cancer. Gene annotation shows that psoriasis-related genes, such as ERAP1, are significantly different in lung and breast cancer tissues. Taken together, clinical attention to lung cancer and breast cancer may be warranted among patients with psoriasis.
10.1038/s41467-024-51824-6
Association between psoriasis and lung cancer: two-sample Mendelian randomization analyses.
BMC pulmonary medicine
BACKGROUND:Observational studies reported an association between psoriasis and risk of lung cancer. However, whether psoriasis is causally associated with lung cancer is unclear. METHODS:Genetic summary data of psoriasis were retrieved from two independent genome-wide association studies (GWAS). Genetic information of lung cancer was retrieved from GWAS of International Lung Cancer Consortium. A set of quality control steps were conducted to select instrumental tools. We performed two independent two-sample Mendelian randomization (MR) analyses and a meta-analysis based on the two independent MR estimates to assess the causal relationship between psoriasis and lung cancer (LUCA) as well as its subtypes, squamous cell carcinoma (LUSC) and adenocarcinoma (LUAD). RESULTS:Between-SNP heterogeneity was present for most MR analyses, whereas horizontal pleiotropy was not detected for all MR analyses. Multiplicative random-effect inverse variance weighted (IVW-MRE) method was therefore selected as the primary MR approach. Both IVW-MRE estimates from the two independent MR analyses suggested that there was no significant causal relationship between psoriasis and LUCA as well as its histological subtypes. Sensitivity analyses using other four MR methods gave similar results. Meta-analysis of the two IVW-MRE derived MR estimates yielded an odds ratio (OR) of 1.00 (95% CI 0.95-1.06) for LUCA, 1.01 (95% CI 0.93-1.08) for LUSC, and 0.97 (95% CI 0.90-1.06) for LUAD. CONCLUSION:Our results do not support a genetic association between psoriasis and lung cancer and its subtypes. More population-based and experimental studies are warranted to further dissect the complex correlation between psoriasis and lung cancer.
10.1186/s12890-022-02297-0
Mendelian Randomization Studies in Psoriasis and Psoriatic Arthritis: A Systematic Review.
The Journal of investigative dermatology
Psoriasis (PSO) and psoriatic arthritis (PSA) are inflammatory diseases with complex genetic and environmental contributions. Although studies have identified environmental and clinical associations with PSO/PSA, causality is difficult to establish. Mendelian randomization (MR) employs the random assortment of genetic alleles at birth to evaluate the causal impact of exposures. We systematically reviewed 27 MR studies in PSO/PSA examining health behaviors, comorbidities, and biomarkers. Exposures, including smoking, obesity, cardiovascular disease, and Crohn's disease, were causal for PSO and PSA, whereas PSO was causally associated with several comorbidities. These findings provide insights that can guide preventive counseling and precision medicine.
10.1016/j.jid.2022.11.014
Casual association between childhood body mass index and risk of psoriasis: A Mendelian randomization study.
Journal of cosmetic dermatology
BACKGROUND:Observational studies have suggested that childhood body mass index (BMI) is associated with the risk of psoriasis. However, their causal relationship remains unclear. In this investigation, we aimed to determine whether an association exists between childhood BMI and psoriasis. METHODS:Using summary statistics for childhood BMI of European descent from publicly available GWAS meta-analyses (n = 39 620), we conducted Mendelian randomization (MR) research using the inverse variance weighting (IVW), weighted median, and MR-Egger regression techniques. The outcome was a genome-wide association studies (GWAS) for the self-reported non-cancer disease classification psoriasis in the UK Biobank population (total n = 337 159; case = 3871; control = 333 288). RESULTS:We selected instrumental variables from 16 single-molecule polymorphisms that attained genome-wide significance in GWAS on childhood BMI. Using the IVW method, our findings supported a causal relationship between childhood BMI and psoriasis (beta = 0.003, standard error [SE] = 0.001, p = 0.006). Using MR-Egger regression analysis, we evaluated the potential for directional pleiotropy to bias our results (intercept = 0.00039, p-value = 0.247) and found no causal relationship between childhood BMI and psoriasis (beta = -0.002, SE = 0.004, p = 0.625). The weighted median method, however, provided proof of a causal relationship (beta = 0.003, SE = 0.001, p = 0.029). Cochran's Q test and the funnel plot revealed little proof of heterogeneity or asymmetry, indicating the lack of directional pleiotropy. CONCLUSION:According to the findings of the MR analysis, an increased childhood BMI may be linked to a higher likelihood of psoriasis.
10.1111/jocd.15875
Lipid Metabolism Traits Mediate the Effect of Psoriasis on Myocardial Infarction Risk: A Two-Step Mendelian Randomization Study.
Metabolites
Mendelian randomization (MR) analysis was performed to explore the effect of psoriasis on lipid metabolism traits and myocardial infarction (MI) risk and to analyze the proportion of the mediatory effect of lipid metabolism traits. Publicly accessible summary-level data for psoriasis, lipid metabolism traits, and MI were provided by the genome-wide association studies (GWASs) of the FinnGen Biobank, UK Biobank, and CARDIoGRAMplusC4D, respectively. A two-sample MR was carried out to evaluate the association of psoriasis with lipid metabolism traits and MI. Furthermore, the current research focused on determining if the impact of psoriasis on MI is mediated by lipid metabolism traits. The outcomes of the random effect inverse-variance-weighted (IVW) technique indicated a substantial link between genetically predicted psoriasis and a higher risk of low-density lipoprotein (LDL) cholesterol (OR: 1.006, 95% CI: 1.005-1.007, = 0.024), apolipoprotein B (OR: 1.018, 95% CI: 1.010-1.026, = 0.015), lipoprotein A (OR: 1.006, 95% CI: 1.002-1.010, = 0.039), and MI (OR: 1.066, 95% CI: 1.014-1.121, = 0.012). The percentages of the mediatory effect of LDL cholesterol, apolipoprotein B, and lipoprotein A under psoriasis conditions on MI risk was 7.4%, 10.2%, and 4.1%, respectively. Psoriasis was causally linked to an elevated risk of lipid metabolism levels and MI. This study further demonstrated that LDL cholesterol, apolipoprotein B, and lipoprotein A mediated the effect of psoriasis on MI risk. And timely lipid-lowering treatment should be given to MI patients.
10.3390/metabo13090976
Psoriasis and risk of chronic kidney diseases: A population-based cross-sectional study and Mendelian randomization analysis.
Nephrology (Carlton, Vic.)
BACKGROUND:Conflicting results have been reported regarding the association between psoriasis and risk of chronic kidney diseases (CKD). Furthermore, the causal nature of the possible association remains unexplored. METHODS:We conducted a population-based cross-sectional study using data from National Health and Nutrition Examination Survey (NHANES). Logistic regression analyses were conducted to estimate potential association between psoriasis and CKD risk. Further, we evaluated causality by performing a Mendelian randomization analysis using large-scale genome-wide association studies of psoriasis and CKD. Inverse variance-weighted (IVW) analysis was used as the primary method. RESULTS:In the observational study, 16 750 participants were included. Overall, 39 of 429 patients with psoriasis had CKD (9.1%) compared with 1481 of 16 321 without psoriasis (9.1%). In the fully adjusted model, psoriasis was not associated with CKD (OR: 0.77, 95%CI: 0.53-1.10). In the MR analysis, 36 single-nucleotide polymorphisms (SNPs) were selected as instrumental variables. The IVW analysis reported that genetically predicted psoriasis was associated with a higher risk of CKD (OR: 1.025, 95%CI: 1.001-1.049). After removing 2 SNPs associated with heterogeneity, the association remained (OR: 1.028, 95%CI: 1.006-1.050). CONCLUSION:Genetically predicted psoriasis was associated with a higher risk of CKD. This association may be important for clinicians to monitor kidney function and prescribe potentially nephrotoxic drugs during psoriasis management.
10.1111/nep.14220
The effects of unsaturated fatty acids on psoriasis: A two-sample Mendelian randomization study.
Food science & nutrition
Unsaturated fatty acids have been reported to be associated with the risk of psoriasis. However, the causal relationship between them remains unclear This study aimed to explore the causal relationship between unsaturated FAs and psoriasis. Firstly, we obtained genome-wide association study (GWAS) data for psoriasis from the FINNGEN database (number of cases = 4510, number of controls = 212,242) and different FA levels (number of samples = 114,999) from the IEU OpenGWAS Project. Secondly, the genetic correlation coefficient was calculated using linkage disequilibrium fractional regression. Thirdly, a two-sample Mendelian randomization (MR) analysis was performed using independent instrumental variables ( < 5 × 10) to determine the direction of randomization. Finally, expression quantitative trait loci (eQTL)-related analyses of common single nucleotide polymorphisms (SNPs) were carried out to explore the potential molecular mechanisms of unsaturated FAs affecting psoriasis. We found that an increase in the ratio of monounsaturated fatty acids (MUFAs) to total fatty acids could increase the risk of psoriasis (inverse-variance weighted [IVW], adjusted odds ratio [OR] = 1.175; adjusted 95% confidence interval [CI] = 1.045-1.321; adjusted = .007). However, an increase in the ratio of polyunsaturated fatty acids (PUFAa) to total fatty acids could decrease the risk of psoriasis (IVW, adjusted OR = 0.754; adjusted 95% CI = 0.631-0.901; adjusted = .002). Moreover, an increase in the ratio of PUFAs to MUFAs could decrease the risk of psoriasis (IVW, adjusted OR = 0.823; adjusted 95% CI = 0.715-0.948; adjusted = .007). The heterogeneity of data was eliminated, and pleiotropy was not detected. There was no statistical difference in the MR analysis of other fatty acids indices with psoriasis. Further, no statistically significant evidence was found to verify a causal relationship between psoriasis and fatty acid levels in reverse MR. Functional enrichment analysis showed that these eQTL related to common SNPs were mainly involved in organic ion transport, choline metabolism, and the expression of key metabolic factors mediated by PKA, ChREBP, and PP2A. Our study indicated that the ratio of MUFAs to total fatty acids had a positive causal effect on psoriasis, while the ratio of PUFAs to total fatty acids and the ratio of PUFAs to MUFAs had a negative causal effect on psoriasis. Moreover, PKA-, PP2A-, and ChREBP-mediated activation of metabolic factors may play an important role in this process.
10.1002/fsn3.3543
Investigating modifiable pathways in psoriasis: A Mendelian randomization study.
Journal of the American Academy of Dermatology
BACKGROUND:Potentially modifiable risk factors have previously been investigated only in conventional observational studies. OBJECTIVE:To assess whether genetically predicted exposures to modifiable factors are associated with the risk of psoriasis. METHODS:Two-sample Mendelian randomization (MR) analysis. RESULTS:An increased risk of psoriasis was noted for genetically predicted lifetime smoking index (odds ratio [OR] = 2.11; 95% confidence interval [CI], 1.28-3.51), childhood (OR = 1.40; 95% CI, 1.14-1.71) and adult body mass index (OR = 1.63; 95% CI, 1.32-2), waist (OR = 1.86; 95% CI, 1.31-2.64), and hip circumference (OR = 1.55; 95% CI, 1.15-2.07). Protective association was also reported between genetically predicted longer sleep duration (OR = 0.56; 95% CI 0.37-0.84) and increased years of education (OR = 0.78; 95% CI, 0.62-0.98). This effect of education persisted in multivariable MR after adjusting for genetic predictors of smoking and adult body mass index (OR = 0.72; 95% CI, 0.56-0.92). LIMITATIONS:It was not possible to stratify for psoriasis severity. CONCLUSION:Smoking cessation and prevention of obesity are important strategies for decreasing the incidence of psoriasis. Similarly, targeting education inequality is expected to lead further to reductions in cases of psoriasis.
10.1016/j.jaad.2022.11.010
Exploring casual effects and shared molecular mechanism between psoriasis and liver cancer through Mendelian randomization and comprehensive bioinformatic analyses.
Computational biology and chemistry
Psoriasis (Ps), a chronic inflammatory disease affecting approximately 2 % of the global population, has been associated with an increased risk of liver cancer in observational studies. However, their causal relationships as well as underlying shared molecular mechanisms between Ps and liver cancer remain unclear. Using bidirectional Mendelian randomization analysis, we revealed that a genetic predisposition to liver cancer increased the risk of Ps in European and East Asian populations but not the other way around. Moreover, we analyzed three transcriptomic datasets of patients with Ps and liver cancer from open-source databases. Differentially expressed genes (DEGs) and disease-specific gene co-expression module analyses revealed that cell-cycle dysregulation was the shared mechanism of Ps and liver cancer. Moreover, we identified a rank-conservative gene signature shared between these two diseases, which demonstrated significance in diagnostic and prognostic predictions. These findings provided valuable insights into the interconnections between Ps and liver cancer, which may be helpful to guide therapeutic management.
10.1016/j.compbiolchem.2024.108089
Relationship between genetically proxied vitamin D and psoriasis risk: a Mendelian randomization study.
Clinical and experimental dermatology
BACKGROUND:Observational research suggests that vitamin D levels affect psoriasis. However, observational studies are prone to potential confounding or reverse causation, which complicates interpreting the data and drawing causal conclusions. AIM:To apply Mendelian randomization (MR) methods to comprehensively assess a potential association between vitamin D and psoriasis. METHODS:Genetic variants strongly associated with 25-hydroxyvitamin D (25OHD) in genome-wide association study (GWAS) data from 417 580 and 79 366 individuals from two independent studies served as instrumental variables (used as the discovery and replication datasets, respectively). As the outcome variable, we used GWAS data of psoriasis (13 229 people in the case group, 21 543 in the control group). We used (i) biologically validated genetic instruments, and (ii) polygenic genetic instruments to assess the relationship between genetically proxied vitamin D and psoriasis. We carried out inverse-variance weighted (IVW) MR analyses for the primary analysis. In sensitivity analyses, we used robust MR approaches. RESULTS:MR analyses of both the discovery and replication datasets did not show an effect of 25OHD on psoriasis. Neither the IVW MR analysis of the biologically validated instruments [discovery dataset: odds ratio (OR) 0.99; 95% confidence interval (CI) 0.88-1.12, P = 0.873; replication dataset: OR 0.98, 95% CI 0.66-1.46, P = 0.930] nor that of the polygenic genetic instruments (discovery dataset: OR 1.00, 95% CI 0.81-1.22, P = 0.973; replication dataset: OR 0.94, 95% CI 0.64-1.38, P = 0.737) revealed an impact of 25OHD on psoriasis. CONCLUSION:The present MR study did not support the hypothesis that vitamin D levels, measured by 25OHD, affect psoriasis. This study was conducted on Europeans, so the conclusions may not be applicable to all ethnicities.
10.1093/ced/llad095
Association of Lipid-Lowering Drugs With Risk of Psoriasis: A Mendelian Randomization Study.
JAMA dermatology
Importance:Lipid pathways have been implicated in the pathogenesis of psoriasis, and some lipid-lowering drugs, such as statins, are hypothesized to have disease-modifying properties. However, large population-level studies are scarce, and causal interpretation of results from traditional observational designs is limited by confounding. Objective:To investigate the causal association between genetically proxied lipid-lowering drugs and psoriasis risk. Design, Setting, and Participants:This 2-sample mendelian randomization study was performed from August to October 2022 and included population-level genome-wide association studies of psoriasis in the UK Biobank and FinnGen studies and low-density lipoprotein (LDL) by the Global Lipids Genetics Consortium. The inverse variance-weighted method was used with pleiotropy robust methods and colocalization as sensitivity analyses. Exposures:Genetically proxied inhibition of 3-hydroxy-3-methylglutaryl CoA reductase (HMGCR, targeted by statins), Niemann-Pick C1-like 1 (NPC1L1, targeted by ezetimibe), and proprotein convertase subtilisin/kexin type 9 (PCSK9, targeted by, eg, alirocumab), using LDL as the biomarker. Main Outcomes and Measures:Risk of psoriasis. Results:Data from 12 116 patients with psoriasis and approximately 1.3 million individuals with LDL measurement were analyzed. Genetically proxied PCSK9 inhibition was associated with reduced risk of psoriasis (odds ratio, 0.69 per standard deviation reduction in LDL; 95% CI, 0.55-0.88; P = .003), which was replicated in FinnGen (odds ratio, 0.71; 95% CI, 0.57-0.88; P = .002). Sensitivity analyses did not provide statistical evidence of bias from pleiotropy or genetic confounding. No robust association was found for HMGCR or NPC1L1 inhibition. Conclusions and Relevance:This mendelian randomization study suggests that PCSK9 is implicated in psoriasis pathogenesis, and its inhibition is associated with reduced psoriasis risk. These findings potentially pave the way for future studies that may allow personalized selection of lipid-lowering drugs for those at risk of psoriasis.
10.1001/jamadermatol.2022.6051
Adenosine 5'monophosphate-activated protein kinase activation reduces the risks of psoriasis and its comorbidities: a Mendelian randomization study in the UK Biobank.
Rheumatology (Oxford, England)
OBJECTIVE:Whether metformin and its adenosine 5'monophosphate-activated protein kinase (AMPK) activation protect from psoriasis risk is unconcluded. We investigated the effect of AMPK, a pharmacological target of metformin, on the risk of psoriasis and its comorbidities and mortality among participants in the UK Biobank (UKB). METHODS:To avoid immortal time biases in pharmacoepidemiologic studies, Mendelian randomization was used to infer the AMPK pathway-dependent effects. The cut-off age for distinguishing early-onset/late-onset psoriasis (EOP/LOP) was set at 60 years, based on the incident psoriasis peak in UKB. A genetic instrument comprising 44 single-nucleotide polymorphisms associated with glycated haemoglobin (HbA1c), serving as a proxy for AMPK genetic risk score (negatively associated with AMPK activation), was employed as previously reported in the literature. Log-binomial models were used to estimate the effect size of AMPK regarding relative risk (RR) and 95% CI. RESULTS:A total of 407 159 participants were analysed, including 9126 EOP and 3324 LOP. The AMPK genetic risk score was associated with a 12.4% increase in the risk of LOP in men (RR = 1.124, 95% CI: 1.022-1.236). This association was not significant for EOP or women. AMPK genetic risk score exhibited an elevated risk of ischemic heart disease (RR = 1.217, 95% CI 1.062-1.395) in male psoriasis patients. CONCLUSIONS:AMPK activation may protect against LOPs and associated ischemic heart disease in men. A sex-specific, comorbidity-targeted intervention for psoriasis is needed.
10.1093/rheumatology/kead462
No causal effect of genetically determined circulating homocysteine levels on psoriasis in the European population: evidence from a Mendelian randomization study.
Frontiers in immunology
Background:Although numerous studies demonstrated a link between plasma homocysteine (Hcy) levels and psoriasis, there still exists a certain level of controversy. Therefore, we conducted a Mendelian randomization study to investigate whether homocysteine plays a causative role in the development or exacerbation of psoriasis. Methods:A two-sample Mendelian randomization (MR) analysis was conducted. Summary-level data for psoriasis were acquired from the latest R9 release results from the FinnGen consortium (9,267 cases and 364,071 controls). Single nucleotide polymorphisms (SNPs) robustly linked with plasma Hcy levels at the genome-wide significance threshold ( < 5 × 10) (18 SNPs) were recognized from the genome-wide meta-analysis on total Hcy concentrations ( = 44,147 participants) in individuals of European ancestry. MR analyses were performed utilizing the random-effect inverse variance-weighted (IVW), weighted median, and MR-Egger regression methods to estimate the associations between the ultimately filtrated SNPs and psoriasis. Sensitivity analyses were conducted to evaluate heterogeneity and pleiotropy. Results:MR analyses revealed no causal effects of plasma Hcy levels on psoriasis [IVW: odds ratio (OR) = 0.995 (0.863-1.146), = 0.941; weighed median method: OR = 0.985 (0.834-1.164), = 0.862; MR-Egger regression method: OR = 0.959 (0.704-1.305), = 0.795]. The sensitivity analyses displayed no evidence of heterogeneity and directional pleiotropy, and the causal estimates of Hcy levels were not influenced by any individual SNP. Conclusion:Our study findings did not demonstrate a causal effect of genetically determined circulating Hcy levels on psoriasis.
10.3389/fimmu.2023.1288632
Integrated analysis of Mendelian Randomization and Bayesian colocalization reveals bidirectional causal association between inflammatory bowel disease and psoriasis.
Annals of medicine
BACKGROUND:Observational studies have suggested an association between inflammatory bowel disease [IBD] and psoriasis. However, the detailed genetic basis, causality, and direction of this association remain unclear. METHODS:Bidirectional two-sample Mendelian Randomization [MR] analysis was conducted using summary statistics from published genome-wide association studies. Bayesian Colocalization and multivariable MR [MVMR] analyses were performed to identify candidate variants and risk genes involved in the shared genetic basis between IBD, psoriasis, and their subtypes. RESULTS:Genetically predicted IBD and Crohn's disease [CD] were associated with an increased risk of psoriasis, psoriasis vulgaris [PsV], and psoriatic arthritis [PsA] (IBD on psoriasis: pooled odds ratio [OR] 1.09, 95% confidence interval [CI] 1.04-1.14, = .0001; CD on psoriasis: pooled OR 1.10, 95% CI 1.06-1.15, < .0001) and vice versa (psoriasis on IBD: pooled OR 1.11, 95%CI 1.02-1.21), whereas CD only exhibited a unidirectional association with psoriasis. Colocalization analysis revealed eight candidate genetic variants and risk genes (including LINC00824, CDKAL1, IL10, IL23R, DNAJC27, LPP, RUNX3, and RGS14) associated with a shared genetic basis. Among these, IL23R, DNAJC27, LPP, and RGS14 were further validated by MVMR analysis. CONCLUSION:Our findings indicated bidirectional causal associations between IBD and psoriasis (including PsV and PsA), which were attributed primarily to CD rather than Ulcerative colitis [UC]. Furthermore, we identified several candidate variants and risk genes involved in the shared genetic basis of IBD and psoriasis. Acquiring a better understanding of the shared genetic architecture underlying IBD and psoriasis would help improve clinical strategies.
10.1080/07853890.2023.2281658
Primary biliary cirrhosis and psoriasis: a two-sample Mendelian randomization study.
Frontiers in immunology
Background:Primary biliary cirrhosis (PBC) and psoriasis are frequently observed to co-occur in clinical settings. However, the causal associations and underlying mechanisms between PBC and psoriasis remain poorly defined. Methods:In this study, we conducted bidirectional MR analysis to explore the causal relationship between PBC and psoriasis using four MR methods: inverse-variance weighted, MR-Egger regression, weighted median, and weighted mode. Sensitivity analyses were carried out, employing different models and testing methods for comparison to assess the influence of heterogeneity and pleiotropy on our findings and to confirm the robustness of these results. Results:A causal relationship between the risk of PBC and psoriasis was identified, as confirmed by IVW analysis (OR: 1.081, 95%CI: 1.028~1.137, <0.05). The other three MR methods also produced similar results. However, psoriasis did not have a causal effect on PBC risk (OR: 1.022, 95%CI: 0.935~1.118, >0.05). The intercept of MR-Egger regression was 0.0013 (>0.05), indicating that genetic pleiotropy did not influence the results. Additionally, the leave-one-out analysis demonstrated the robustness of our MR findings. Conclusion:This study reveals a causal relationship between PBC and psoriasis, with PBC increasing the risk of psoriasis, but not the reverse. This potential causal relationship offers a new perspective on the etiology of PBC.
10.3389/fimmu.2023.1264554
Causal associations between psoriasis, eczema, urticaria, and mental illness: A bidirectional Mendelian randomization study of the European population.
Medicine
Observational studies have reported a relationship between multiple common dermatoses and mental illness. To assess the potential bidirectional causality between 3 skin disorders (psoriasis, eczema, and urticaria) and 4 psychiatric disorders (bipolar disorder, schizophrenia, major depressive disorder, and anxiety) in the European population, we used Mendelian randomization (MR) analysis, which provides definitive evidence for causal inference. Eligible single nucleotide polymorphisms were screened for dermatological and psychiatric disorders using a genome-wide association study database. We conducted bidirectional, 2-sample MR analysis using instrumental variables related to psoriasis, eczema, and urticaria as exposure factors, and bipolar disorder, schizophrenia, major depression, and anxiety as outcomes. Reverse MR analysis with bipolar disorder, schizophrenia, major depression, and anxiety as exposure and psoriasis, eczema, and urticaria as outcomes were also performed, and the causality was analyzed using inverse-variance weighting (IVW), MR-Egger, and weighted median methods. To thoroughly assess causality, sensitivity analyses were conducted using the IVW, MR-PRESSO, and MR-Egger methods. The results showed that bipolar disorder increased the incidence of psoriasis (odds ratio = 1.271, 95% confidence interval = 1.003-1.612, P = .047), heterogeneity test with Cochran Q test in the IVW showed P value > .05, (P = .302), the MR-Pleiotropy and MR-PRESSO (outlier methods) in the multiplicity test showed P value > .05, (P = .694; P = .441), and MR-Pleiotropy evidence showed no apparent intercept (intercept = -0.060; SE = 0.139; P = .694). Major depression increased the risk of eczema (odds ratio = 1.002, 95% confidence interval = 1.000-1.004, P = .024), heterogeneity test showed P value > .05, (P = .328), multiplicity detection showed P value > .05, (P = .572; P = .340), and MR-Pleiotropy evidence showed no apparent intercept (intercept = -0.099; SE = 0.162; P = .572). Sensitivity analyses of the above results were reliable, and no heterogeneity or multiplicity was found. This study demonstrated a statistically significant causality between bipolar disorder and psoriasis, major depression, and eczema in a European population, which could provide important information for physicians in the clinical management of common skin conditions.
10.1097/MD.0000000000038586
The causal relationship between pure hypercholesterolemia and psoriasis: A bidirectional, two-sample Mendelian randomization study.
Skin research and technology : official journal of International Society for Bioengineering and the Skin (ISBS) [and] International Society for Digital Imaging of Skin (ISDIS) [and] International Society for Skin Imaging (ISSI)
BACKGROUND:Several studies have reported the association between pure hypercholesterolemia (PH) and psoriasis, but the causal effect remains unclear. METHODS:We explored the causal effect between PH and psoriasis using two-sample bidirectional Mendelian randomization (MR) analysis using data from genome-wide association studies. Single nucleotide polymorphisms related with exposures at the genome-wide significance level (p < 5×10 ) and less than the linkage disequilibrium level (r < 0.001) were chosen as instrumental variables. Subsequently, we used inverse variance weighting (IVW), MR-Egger and weighted median (WM) methods for causal inference. p < 0.05 was considered statistically significant. Heterogeneity was tested using Cochran's Q-test, and horizontal pleiotropy was examined using the MR-Egger intercept. Leave-one-out analyses were performed to assess the robustness and reliability of the results. RESULTS:MR results showed a positive causal effect of PH on psoriasis [IVW: odds ratios (OR): 1.139, p = 0.032; MR-Egger: OR: 1.434, p = 0.035; WM: OR: 1.170, p = 0.045] and psoriatic arthritis (PsA) (IVW: OR: 1.210, p = 0.049; MR-Egger regression: OR: 1.796, p = 0.033; WM: OR: 1.317, p = 0.028). However, there is no causal relationship between PH and psoriasis vulgaris as well as other unspecified psoriasis. Inverse MR results suggested a negative causal relationship between PsA and PH (IVW: OR: 0.950, p = 0.037). No heterogeneity and horizontal pleiotropy exist, and these results were confirmed to be robust. CONCLUSION:PH has a positive casual effect on psoriasis and PsA, and PsA may reduce the risk of having PH.
10.1111/srt.13533
The association between ACE inhibitors and psoriasis based on the drug-targeted Mendelian randomization and real-world pharmacovigilance analyses.
Expert review of clinical pharmacology
BACKGROUND:Although a growing number of observational studies suggest that angiotensin-converting enzyme inhibitors (ACEIs) intake may be a risk factor for psoriasis, evidence is still insufficient to draw definitive conclusions. RESEARCH DESIGN AND METHODS:Drug-targeted Mendelian randomization (DTMR) was used to analyze the causality between genetic proxied ACEIs and psoriasis. Furthermore, we performed a disproportionality analysis based on the FDA adverse event reporting system (FAERS) database to identify more suspicious subclasses of ACEIs. RESULTS:Using two kinds of genetic proxy instruments, the present DTMR research identified genetic proxied ACEIs as risk factors for psoriasis. Furthermore, our disproportionality analysis revealed that ramipril, trandolapril, perindopril, lisinopril, and enalapril were associated with the risk of psoriasis, which validates and refines the findings of the DTMR. CONCLUSIONS:Our integrative study verified that ACEIs, especially ramipril, trandolapril, perindopril, lisinopril, and enalapril, tended to increase the risk of psoriasis statistically.
10.1080/17512433.2023.2292605
A bidirectional two-sample Mendelian randomization study to evaluate the relationship between psoriasis and interstitial lung diseases.
BMC pulmonary medicine
BACKGROUND:Prior observational studies have suggested a potential direct link between psoriasis (PSO) and interstitial lung disease (ILD). Consequently, we applied Mendelian randomization (MR) to further evaluate the bidirectional causal relationships between PSO and its different phenotypes [psoriatic arthritis (PSA)/psoriasis vulgaris (PSV)] and ILD. METHODS:Data regarding PSO/PSA/PSV and ILD were sourced from publicly accessible genome-wide association studies (GWAS) databases, focusing on European populations. We used five algorithms- MR Egger, weighted median, inverse-variance weighted (IVW), simple mode, and weighted mode- to evaluate the causal relationships between PSO/PSA/PSV and ILD, with a primary emphasis on the IVW method. RESULTS:The analysis indicated a potential association between PSA and an elevated risk of ILD [IVW odds ratio (OR): 1.035 (95% CI 1.008, 1.064; P = 0.012)], with no evidence of a direct relationship between total PSO and PSV with ILD. Conversely, no substantial evidence emerged from the reverse MR analysis to suggest that ILD significantly affects total PSO or the specific PSA/PSV phenotypes. CONCLUSION:Our findings provide genetic evidence supporting the notion that PSA may be a contributory risk factor for ILD. Further investigations are warranted to explore the underlying mechanisms of this potential causal relationship between PSA and ILD.
10.1186/s12890-024-03146-y
The causal relationship between serum metabolites and the risk of psoriasis: a Mendelian randomization and meta-analysis study.
Frontiers in immunology
Objective:To explore the influence of serum metabolites on the risk of psoriasis. Methods:In the initial stage, we applied Mendelian randomization to evaluate the association between 1,400 serum metabolites and the risk of psoriasis. Causal effects were primarily assessed through the Inverse-Variance Weighted method and Wald Ratio's odds ratios, and 95% confidence intervals. False Discovery Rate was used for multiple comparison corrections. Sensitivity analyses were conducted using Cochran's Q Test, MR-PRESSO. MR-Steiger Test was employed to check for reverse causality. In the validation stage, we sought other sources of psoriasis GWAS data to verify the initial results and used meta-analysis to combine the effect sizes to obtain robust causal relationships. In addition, we also conducted metabolic pathway enrichment analysis on known metabolites that have a causal relationship with the risk of psoriasis in both stages. Results:In the initial stage, we identified 112 metabolites causally associated with psoriasis, including 32 metabolite ratios and 80 metabolites (69 known and 11 unknown). In the validation stage, 24 metabolites (16 known, 1 unknown, and 7 metabolite ratios) were confirmed to have a causal relationship with psoriasis onset. Meta-analysis results showed that the overall effect of combined metabolites was consistent with the main analysis in direction and robust in the causal relationship with psoriasis onset. Of the 16 known metabolites, most were attributed to lipid metabolism, with 5 as risk factors and 8 as protective factors for psoriasis. Peptidic metabolite Gamma-glutamylvaline levels had a negative causal relationship with psoriasis, while exogenous metabolite Catechol sulfate levels and amino acid 3-methylglutaconate levels had a positive causal relationship with the disease onset. The metabolites associated with psoriasis risk in the two stages are mainly enriched in the following metabolic pathways: Glutathione metabolism, Alpha Linolenic Acid and Linoleic Acid Metabolism, Biosynthesis of unsaturated fatty acids, Arachidonic acid metabolism, Glycerophospholipid metabolism. Conclusion:Circulating metabolites may have a potential causal relationship with psoriasis risk, and targeting specific metabolites may benefit psoriasis diagnosis, disease assessment, and treatment.
10.3389/fimmu.2024.1343301
The causal relationship between psoriasis and artificial joint re-operation after arthroplasty: A two-sample Mendelian randomization study.
Skin research and technology : official journal of International Society for Bioengineering and the Skin (ISBS) [and] International Society for Digital Imaging of Skin (ISDIS) [and] International Society for Skin Imaging (ISSI)
BACKGROUND:Psoriasis is observationally associated with a higher risk of complications of arthroplasty; however, the causal effects of psoriasis on complications of arthroplasty are yet to be established. This study was to explore the causal effect of psoriasis on artificial joint re-operation after arthroplasty through two-sample Mendelian randomization (MR). METHODS:In the MR analysis, psoriasis was selected as the exposure in this study while single-nucleotide polymorphisms (SNPs) from a genome-wide association study (GWAS) were selected as the instrumental variables (IVs). Summary statistics data on artificial joint re-operation was extracted from publicly available GWAS data, including 218 792 European descent individuals. MR analysis was performed using the standard inverse variance weighted method (IVW). Furthermore, MR Egger, weighted median, simple mode, weighted mode, and the MR-PRESSO (Mendelian Randomization Pleiotropy Residual Sum and Outlier) test were also done to verify the results. Finally, the sensitivity analysis was executed. RESULTS:The IVW showed that psoriasis increases the risk of artificial joint re-operation (OR = 1.12; 95% CI = (1.01, 1.25); p = 0.036). This outcome was also verified by other methods including weighted median (OR = 1.16; 95% CI = (1.03, 1.31); p = 0.015), MR Egger (OR = 1.22; 95% CI = (1.03, 1.44); p = 0.038), and weighted mode (OR = 1.16; 95% CI = (1.03, 1.30); p = 0.025). No heterogeneity and directional pleiotropy were observed upon sensitivity analysis. CONCLUSION:The present study showed that psoriasis has a potential causal effect on artificial joint re-operation after arthroplasty. Further studies are warranted to elucidate the underlying mechanisms of causal associations between psoriasis on re-operation.
10.1111/srt.13560
Multiple long-term conditions in people with psoriasis: a latent class and bidirectional Mendelian randomization analysis.
The British journal of dermatology
BACKGROUND:Coexisting long-term conditions (LTCs) in psoriasis and their potential causal associations with the disease are not well -established. OBJECTIVES:To determine distinct clusters of LTCs in people with psoriasis and the potential bidirectional causal association between these LTCs and psoriasis. METHODS:Using latent class analysis, cross-sectional data from people with psoriasis from the UK Biobank were analysed to identify distinct psoriasis-related comorbidity profiles. Linkage disequilibrium score regression (LDSR) was applied to compute the genetic correlation between psoriasis and LTCs. Two-sample bidirectional Mendelian randomization (MR) analysis assessed the potential causal direction using independent genetic variants that reached genome-wide significance (P < 5 × 10-8). RESULTS:Five comorbidity clusters were identified in a population of 10 873 people with psoriasis. LDSR revealed that psoriasis was positively genetically correlated with heart failure [genetic correlation (rg) = 0.23, P = 8.8 × 10-8], depression (rg = 0.12, P = 2.7 × 10-5), coronary artery disease (CAD; rg = 0.15, P = 2 × 10-4) and type 2 diabetes (rg = 0.19, P = 3 × 10-3). Genetic liability to CAD was associated with an increased risk of psoriasis [inverse variance weighted (IVW) odds ratio (ORIVW) 1.159, 95% confidence interval (CI) 1.055-1.274; P = 2 × 10-3]. The MR pleiotropy residual sum and outlier (MR-PRESSO; ORMR-PRESSO 1.13, 95% CI 1.042-1.228; P = 6 × 10-3) and the MR-robust adjusted profile score (RAPS) (ORMR-RAPS 1.149, 95% CI 1.062-1.242; P = 5 × 10-4) approaches corroborate the IVW findings. The weighted median (WM) generated similar and consistent effect estimates but was not statistically significant (ORWM 1.076, 95% CI 0.949-1.221; P = 0.25). Evidence for a suggestive increased risk was detected for CAD (ORIVW 1.031, 95% CI 1.003-1.059; P = 0.03) and heart failure (ORIVW 1.019, 95% CI 1.005-1.033; P = 9 × 10-3) in those with a genetic liability to psoriasis; however, MR sensitivity analyses did not reach statistical significance. CONCLUSIONS:Five distinct clusters of psoriasis comorbidities were observed with these findings to offer opportunities for an integrated approach to comorbidity prevention and treatment. Coexisting LTCs share with psoriasis common genetic and nongenetic risk factors, and aggressive lifestyle modification in these people is anticipated to have an impact beyond psoriasis risk. Genetically predicted CAD is possibly associated with an increased risk of psoriasis, altering our prior knowledge.
10.1093/bjd/ljad410
Evidence for a causal relationship between psoriasis and cutaneous melanoma: a bidirectional two-sample Mendelian randomized study.
Frontiers in immunology
Background and objective:Existing cross-sectional and retrospective studies were unable to establish a causal relationship between psoriasis and cutaneous melanoma (CM). We sought to evaluate the causal role between psoriasis and CM. Methods:We performed a bidirectional two-sample Mendelian randomization analysis using summary statistics from genome-wide association studies of psoriasis and CM among individuals of predominantly European ancestry. Mendelian randomization-Egger regression, inverse variance weighting, Mendelian Randomization Pleiotropy RESidual Sum and Outlier, weighted mode, and weighted median were used to examine the causal effect between psoriasis and CM. Results:Genetically predicted psoriasis was a significant risk factor for CM (odds ratio, 1.69; 95% confidence interval, 1.15-2.48; P = 0.025). In contrast, no association was observed between genetically predicted CM and psoriasis. Conclusion:Our findings corroborated the existence of genetically predicted psoriasis increases risk of CM. Enhanced early screening of cutaneous melanoma in patients with psoriasis may improve clinical burden. However, we did not find evidence for a causal link from CM to psoriasis, so further studies are required to elucidate the effect of CM activity on psoriasis.
10.3389/fimmu.2023.1201167
Cholesterol and low-density lipoprotein as a cause of psoriasis: Results from bidirectional Mendelian randomization.
Journal of the European Academy of Dermatology and Venereology : JEADV
BACKGROUND:Psoriasis is an inflammatory disease that affects many people. However, the causal effect of lipid metabolism on psoriasis has not yet been verified. This study aimed to identify the genetic relationship between serum lipid levels and psoriasis. METHODS:Bidirectional two-sample Mendelian randomization (MR) was used to analyse the causal relationship between cholesterol and psoriasis. The outcome of the forward causality test was psoriasis. In the analysis of reverse causality, psoriasis was exposed, and 79 single-nucleotide polymorphisms were detected in the genome-wide association study (GWASs) database from the IEU GWASs Project. MR-Egger regression, inverse variance-weighted, weighted median, weighted mode and simple mode were used for the MR analyses. RESULTS:The level of triglyceride, lipase member N, chylomicrons, extremely large very low-density lipoprotein (VLDL) particles, high-density lipoprotein (HDL) cholesterol levels, cholesterol esters in large HDL, cholesterol esters in medium HDL and cholesterol esters in medium VLDL have not affected the development of psoriasis. However, total cholesterol, total free cholesterol, low-density lipoprotein (LDL) cholesterol levels, cholesterol esters in large VLDL and cholesterol esters in medium LDL were unidirectional causal effects on psoriasis. CONCLUSION:Bidirectional two-sample MR analysis indicated that high levels of total cholesterol, total free cholesterol, LDL cholesterol, cholesterol esters in large VLDL and cholesterol esters in medium LDL are genetic risk factors for psoriasis.
10.1111/jdv.19670
The causal relationship between psoriasis and cancers: a two-sample Mendelian randomization analysis.
Frontiers in oncology
Background:Although observational studies suggest a correlation between psoriasis (PS) and cancers, it is still unknown whether this association can replace causal relationships due to the limitations of observational studies. Therefore, we conducted a two-sample Mendelian randomization (MR) analysis to evaluate the causal relationship between PS and cancers. Methods:PS genetic summary data were obtained from two genome-wide association studies (GWAS). We employed MR Base for individuals retrieving tumors from distinct locations. Inverse-variance weighted analysis was the principal method used for MR, supplemented by weighted median, MR Egger, simple mode, and weighted mode. To investigate the possible link between psoriasis and cancers, we performed two independent two-sample MR studies and a meta-analysis based on two independent MR analyses. Results:Two independent MR analyses both found no significant causal relationship between PS and overall cancers (OR=1.0000, 95% confidence interval [CI]:0.9999-1.0001, =0.984; OR=1.0000, 95% CI:0.9999-1.0001, =0.761), and no significant causal relationship with 17 site-specific cancers. In the meta-analysis conducted by two two-sample MR analyses, there was no significant causal relationship between PS and overall cancers (OR=1.0000, 95% CI: 0.9999-1.0001, =1.00, 0.0%), and there was no significant causal relationship with 17 site-specific cancers. Conclusions:Our findings do not support a genetic link between PS and cancers. More population-based and experimental investigations will be required better to understand the complicated relationship between PS and cancers.
10.3389/fonc.2024.1366958
Association between Psoriasis and Renal Functions: An Integration Study of Observational Study and Mendelian Randomization.
Biomedicines
Psoriasis is an autoimmune-mediated disease with several comorbidities in addition to typical skin lesions. Increasing evidence shows the relationships between psoriasis and renal functions, but the relationship and causality remain unclear. We aimed to investigate the associations and causality between psoriasis and four renal functions, including the estimated glomerular filtration rate (eGFR), blood urea nitrogen (BUN), urine albumin to creatinine ratio (UACR), and chronic kidney disease (CKD). For the population-based study, we analyzed the National Health and Nutrition Examination Survey (NHANES) data from five cycles (2003-2006 and 2009-2014) on psoriasis and renal functions. Subgroup analyses were conducted among different categories of participants. Meanwhile, a bidirectional two-sample Mendelian randomization (TSMR) study in European populations was also performed using summary-level genetic datasets. Causal effects were derived by conducting an inverse-variance weighted (MR-IVW) method. A series of pleiotropy-robust MR methods was employed to validate the robustness. Multivariable MR (MVMR) was conducted to complement the result when five competing risk factors were considered. A total of 20,244 participants were enrolled in the cross-sectional study, where 2.6% of them had psoriasis. In the fully adjusted model, participants with psoriasis had significantly lower eGFR ( = 0.025) compared with the healthy group. Individuals who are nonoverweight are more likely to be affected by psoriasis, leading to an elevation of BUN ( = 0.018). In the same line, TSMR showed a negative association between psoriasis and eGFR ( = 0.016), and sensitive analysis also consolidated the finding. No causality was identified between psoriasis and other renal functions, as well as the inverse causality ( > 0.05). The MVMR method further provided quite consistent results when adjusting five confounders ( = 0.042). We detected a significant negative effect of psoriasis on eGFR, with marginal association between BUN, UACR, and CKD. The adverse of psoriasis on the renal should merit further attention in clinical cares.
10.3390/biomedicines12010249
Assessing causal relationships between gut microbiota and psoriasis: evidence from two sample Mendelian randomization analysis.
Scientific reports
Mounting data hints that the gut microbiota's role may be pivotal in understanding the emergence of psoriasis. However, discerning a direct causal link is yet elusive. In this exploration, we adopted a Mendelian randomization (MR) strategy to probe the prospective causal interplay between the gut's microbial landscape and the predisposition to psoriasis. Genetic markers acting as instrumental variables for gut microbiota were extrapolated from a genome-wide association study (GWAS) encompassing 18,340 individuals. A separate GWAS yielded summary data for psoriasis, which covered 337,159 patients and 433,201 control subjects. The primary analysis hinged on inverse variance weighting (IVW). Additional methods like the weighted median approach and MR-Egger regression were employed to validate the integrity of our findings. Intriguing correlations emerged between psoriasis risk and eight specific bacterial traits. To illustrate: Mollicutes presented an odds ratio (OR) of 1.003 with a 95% confidence interval (CI) spanning 1.001-1.005 (p = 0.016), while the family. Victivallaceae revealed an OR of 0.998 with CI values between 0.997 and 0.999 (p = 0.023). Eubacterium (coprostanoligenes group) revealed an OR of 0.997 with CI values between 0.994 and 0.999 (p = 0.027). Eubacterium (fissicatena group) revealed an OR of 0.997 with CI values between 0.996 and 0.999 (p = 0.005). Holdemania revealed an OR of 1.001 with CI values 1-1.003 (p = 0.034). Lachnospiraceae (NK4A136 group) revealed an OR of 0.997 with CI values between 0.995 and 0.999 (p = 0.046). Lactococcus revealed an OR of 0.998 with CI values between 0.996 and 0.999 (p = 0.008). Tenericutes revealed an OR of 1.003 with CI values between 1.001 and 1.006 (p = 0.016). Sensitivity analysis for these bacterial features yielded congruent outcomes, reinforcing statistically significant ties between the eight bacterial entities and psoriasis. This comprehensive probe underscores emerging evidence pointing towards a plausible causal nexus between diverse gut microbiota and the onset of psoriasis. It beckons further research to unravel the intricacies of how the gut's microbial constituents might sway psoriasis's pathogenesis.
10.1038/s41598-024-59603-5
Causal association between psoriasis vulgaris and bullous pemphigoid: a two-sample bidirectional Mendelian randomization study.
Frontiers in immunology
Background:The association between psoriasis vulgaris and bullous pemphigoid (BP) remains largely unknown. Objectives:To investigate whether there is a causal effect between psoriasis vulgaris and BP. Methods:Two-sample bidirectional Mendelian randomization (MR) analyses were conducted using publicly released genome-wide association studies (GWAS) summary statistics. The GWAS summary statistics for BP were downloaded online from FinnGen Biobank Documentation of the R12 release, which includes 219 BP cases and 218,066 controls. The GWAS data for psoriasis vulgaris were extracted from Sakaue et al., which comprises 5072 cases and 478,102 controls. Single-nucleotide polymorphisms (SNPs) associated with exposure were selected as instrumental variables by performing additional quality control steps. The inverse-variance-weighted (IVW) method was used for the primary MR analyses, and the MR-Egger regression, weighted mode method, weighted median method, and simple mode were employed for sensitivity analyses. The MR-Egger intercept test and "leave-one-out" sensitivity analysis were performed to evaluate the horizontal pleiotropy and the potentially influential SNPs, respectively. Results:Genetically determined log odds of psoriasis vulgaris were associated with an increased risk of BP (IVW: odds ratio (OR) = 1.263, 95% confidence interval (CI): 1.013-1.575, =0.038). Sensitivity analyses by the weighted mode (OR=1.255, 95%CI: 0.973-1.618, =0.106), MR Egger (OR=1.315, 95%CI: 0.951-1.817, =0.126), simple mode (OR=1.414, 95%CI: 0.823-2.429, =0.234) and weighted median method (OR=1.177, 95%CI: 0.889-1.559, =0.254) derived directionally consistent relationship between the genetically predicted log odds of psoriasis vulgaris and risks of developing BP. On the contrary, we found that genetically predicted BP had no significant effect on psoriasis vulgaris (IVW: OR=0.996, = 0.707), indicating the unidirectionality of the relationship. MR-Egger intercept tests showed no evidence of horizontal pleiotropy. No influential SNP driving the results was detected by the leave-one-out sensitivity analysis. Conclusions:Our results suggested that psoriasis vulgaris causally increases the risk of BP, highlighting the need for potential strategies for the prevention and early diagnosis of comorbid BP in patients with psoriasis vulgaris. Further researches into this association and underlying mechanisms are warranted.
10.3389/fimmu.2024.1365118
Examining the causal association between psoriasis and bladder cancer: A two-sample Mendelian randomization analysis.
Skin research and technology : official journal of International Society for Bioengineering and the Skin (ISBS) [and] International Society for Digital Imaging of Skin (ISDIS) [and] International Society for Skin Imaging (ISSI)
BACKGROUND:Previous epidemiological observational studies have potentially associated psoriasis with bladder cancer, but the results are inconsistent, and the causality remains unknown. The present study aimed to examine whether there are causal associations between psoriasis and bladder cancer using bidirectional two-sample Mendelian randomization (MR) analysis. MATERIALS AND METHODS:A two-sample MR analysis was conducted using publicly available genome-wide association study (GWAS) data for individuals diagnosed with psoriasis and bladder cancer. The inverse variance weighted (IVW) method was the primary method. The complementary methods used included the weighted median, MR-Egger, weighted mode, and simple mode methods. Heterogeneity and pleiotropy of the MR results were detected. Moreover, leave-one-out sensitivity analysis was also employed to evaluate the robustness and validity of the findings. RESULTS:No significant causal association was detected between psoriasis incidence and the risk of bladder cancer using the IVW method (OR = 0.999, 95% CI 0.977-1.022; P = 0.956). Similarly, the IVW model revealed no evidence of a causal relationship between bladder cancer and the risk of psoriasis (OR = 0.979, 95%CI = 0.873-1.098; P = 0.716). The results of the complementary methods were consistent with those of the IVW method. There was no notable horizontal pleiotropy or heterogeneity (P > 0.05) in our MR analysis. The results of sensitivity analysis confirmed that the MR estimates were not driven by single-nucleotide polymorphisms (SNPs). CONCLUSION:This study does not support a causal relationship between psoriasis and bladder cancer.
10.1111/srt.13663
The causal relationship between psoriasis and chronic obstructive pulmonary disease: A bidirectional mendelian randomization study.
Skin research and technology : official journal of International Society for Bioengineering and the Skin (ISBS) [and] International Society for Digital Imaging of Skin (ISDIS) [and] International Society for Skin Imaging (ISSI)
PURPOSE:Although many studies have investigated the association between psoriasis and chronic obstructive pulmonary disease (COPD), the causal relationship between psoriasis and COPD is still unknown. METHODS:We employed bidirectional Mendelian randomization to investigate the causal relationship between psoriasis and COPD. Genetic instruments for exposure were selected from two distinct genome-wide association study databases. Single nucleotide polymorphisms associated with exposures at the genome-wide significance level (p < 5 × 10^ ) and exhibiting low linkage disequilibrium (r < 0.001) were chosen as instrumental variables. Causality was assessed using multiple MR methods, including Inverse-Variance Weighted (IVW), MR-Egger, Weighted Median, Simple Mode, and Weighted Mode. A significance level of p < 0.05 was considered statistically significant. Heterogeneity was examined using Cochran's Q test, and MR-Egger regression was employed to detect pleiotropy. The robustness and reliability of the results were further evaluated through leave-one-out analysis. RESULTS:We found a positive causal association between psoriasis and COPD [IVW: odds ratio (OR): 1.0006; p = 0.0056]. Heterogeneity and pleiotropy have not been discovered, so the results of the study are reliable. In the reverse analysis, no causal association between CPOD and psoriasis was found. CONCLUSION:Our findings revealed that psoriasis was associated with an elevated risk of COPD. However, no causal association between COPD and psoriasis was identified in our study.
10.1111/srt.13629
Causal Associations Between Gut Microbiota and Psoriasis: A Mendelian Randomization Study.
Dermatology and therapy
INTRODUCTION:Previous studies have proposed a possible gut-skin axis, and linked gut microbiota to psoriasis risks. However, there is heterogeneity in existing evidence. Observational research is prone to bias, and it is hard to determine causality. Therefore, this study aims to evaluate possible causal associations between gut microbiota (GM) and psoriasis. METHODS:With published large-scale GWAS (genome-wide association study) summary datasets, two-sample Mendelian randomization (MR) was performed to sort out possible causal roles of GM in psoriasis and arthropathic psoriasis (PsA). The inverse variance weighted (IVW) method was taken as the primary evaluation of causal association. As complements to the IVW method, we also applied MR-Egger, weighted median. Sensitivity analyses were conducted using Cochrane's Q test, MR-Egger intercept test, MR-PRESSO (Mendelian Randomization Pleiotropy RESidual Sum and Outlier) global test, and leave-one-out analysis. RESULTS:By primary IVW analysis, we identified nominal protective roles of Bacteroidetes (odds ratio, OR 0.81, P = 0.033) and Prevotella9 (OR 0.87, P = 0.045) in psoriasis risks. Bacteroidia (OR 0.65, P = 0.03), Bacteroidales (OR 0.65, P = 0.03), and Ruminococcaceae UCG002 (OR 0.81, P = 0.038) are nominally associated with lower risks for PsA. On the other hand, Pasteurellales (OR 1.22, P = 0.033), Pasteurellaceae (OR 1.22, P = 0.033), Blautia (OR 1.46, P = 0.014), Methanobrevibacter (OR 1.27, P = 0.026), and Eubacterium fissicatena group (OR 1.21, P = 0.028) are nominal risk factors for PsA. Additionally, E. fissicatena group is a possible risk factor for psoriasis (OR 1.22, P = 0.00018). After false discovery rate (FDR) correction, E. fissicatena group remains a risk factor for psoriasis (P = 0.03798). CONCLUSION:We comprehensively evaluated possible causal associations of GM with psoriasis and arthropathic psoriasis, and identified several nominal associations. E. fissicatena group remains a risk factor for psoriasis after FDR correction. Our results offer promising therapeutic targets for psoriasis clinical management.
10.1007/s13555-023-01007-w
The bidirectional causal association between psoriasis and psychological illnesses: a 2-sample Mendelian randomization study.
Archives of dermatological research
There have been reports of association between psoriasis and psychological illnesses. Nevertheless, it is not easy to draw conclusions with high quality causality from conventional observational studies. The objective of this study was to evaluate the causality of psoriasis and psychological illnesses. All summary-level data from genome-wide association studies for psoriasis and psychological illnesses were collected from Neale Lab and MRC Integrative Epidemiology Unit. Bidirectional Mendelian randomization analysis was performed to determine the random orientation with an independent genetic variation. The main estimated effects are derived using Inverse-Variance Weighted, weighted median, and MR Egger methods. Multiple data sets were validated against each other, and a series of sensitivity studies were conducted to ensure the reliability of the results. Mendelian randomization analysis revealed a causal effect of psoriasis [odds ratio (OR) 1·34, 95% confidence interval (CI) 1·21-1·46, P < 0.001; and OR 1.28, CI 1.17-1.39, P < 0.001] on psychological illnesses, and vice versa (OR 1.23, CI 1.14-1.31, P < 0.001; and OR 1.21, CI 1.11-1.31, P < 0.001). The results were supported by a series of sensitivity analyses. The findings of this Mendelian randomization study support a causal effect between psoriasis and psychological illnesses, and vice versa.
10.1007/s00403-023-02736-w
Association between schizophrenia and psoriasis: A two-sample bidirectional Mendelian randomization study.
Journal of cosmetic dermatology
BACKGROUND:Observational studies have showed an association between schizophrenia and risk of psoriasis and vice versa. However, whether schizophrenia is causally associated with psoriasis is unclear. METHODS:A two-sample bidirectional Mendelian randomization (MR) analysis was performed with publicly available genome-wide association study data including schizophrenia (n = 77 096) and psoriasis (n = 462 933). The inverse-variance weighted method was performed as the main analysis, with a complementary with the other two analyses: MR-Egger and weighted median method. A series of sensitivity analyses were also conducted to evaluate the robustness of the results. RESULTS:MR analyses indicated that genetically predicted schizophrenia was significantly associated with an increased risk of psoriasis [OR: 1.001, 95% confidence interval (CI): 1.000-1.002, p = 0.012]. However, no causal effect of genetically predicted psoriasis on schizophrenia (OR: 0.221, 95% CI: 0.029-1.682, p = 0.145) was detected. No pleiotropy or heterogeneity was detected in sensitivity analysis (all p > 0.05). CONCLUSIONS:Our study provides genetic evidence for the causal association between schizophrenia and psoriasis.
10.1111/jocd.16140
Causality of unsaturated fatty acids and psoriasis a Mendelian randomization study.
Frontiers in nutrition
Background:Many observational studies have identified a link between unsaturated fatty acids and psoriasis. However, they contain reverse causality and confounding factors, and there is no definite causal study between unsaturated fatty acids and psoriasis. Objectives:Analysis of causality between unsaturated fatty acids and psoriasis by Mendelian randomization. Methods:We used IEU Open GWAS Project, omega-3 PUFA and omega-6 PUFA data from 114,999 subjects, MUFA data from 13,535 subjects, and psoriasis data from 4,510 cases and 212,242 controls were included. We employed the inverse-variance weighted (IVW) method as the primary analytical approach and four additional MR methods. Moreover, we performed heterogeneity and horizontal pleiotropy assessments using Cochrane's Q and MR-Egger intercept tests, respectively. Finally, we performed sensitivity analyses to enhance our findings' precision and veracity. Results:IVW results showed no causal effect of omega-3 PUFA on psoriasis ( = 0.334; OR, 0.909; 95% CI, 0.748-1.104), omega-6 PUFA cause psoriasis ( = 0.046; OR, 1.174; 95% CI, 1.003-1.374), MUFA cause psoriasis ( = 0.032; OR, 1.218; 95% CI, 1.018-1.457), no causal effect of omega-3 PUFA in psoriasis ( = 0.695; OR, 0.989; 95% CI, 0.937-1.044), no causal effect of omega-6 PUFA in psoriasis ( = 0.643; OR, 1.013; 95% CI, 0.960-1.068), psoriasis is not causal to MUFA ( = 0.986; OR, 1.000; 95% CI, 0.949-1.055). Heterogeneity, horizontal pleiotropy, and sensitivity analyses showed reliable results. Conclusion:We found that circulating omega-6 PUFA and MUFA cause psoriasis, while omega-3 PUFA do not. Treatments that lower circulating omega-6 PUFA and MUFA are effective in psoriasis. After a better understanding of fatty acid intake and circulation, the population can be advised to regulate their diet.
10.3389/fnut.2024.1280962
Causal relationship between psoriasis vulgaris and dementia: Insights from Mendelian randomization analysis.
Experimental dermatology
Many clinical studies have demonstrated a correlation between psoriasis vulgaris and dementia, yet this correlation remains controversial. Our study employed the Mendelian randomization (MR) method to investigate the causal relationship between psoriasis vulgaris and dementia. Data were obtained from the summary statistics of the genome-wide association studies from IEU-OpenGWAS project database. In univariate Mendelian randomization (UVMR) analysis, psoriasis vulgaris was used as exposure. Alzheimer disease (AD), vascular dementia (VaD), dementia with Lewy bodies (DLB), Parkinson's disease with dementia (PDD) and frontotemporal dementia (FTD) served as the outcomes. In multivariate Mendelian randomization (MVMR) analysis, VaD served as the outcome. The first MVMR analysis used psoriasis vulgaris, mean platelet volume (MPV), platelet distribution width (PDW) and platelet count (PLT) as exposures. The second MVMR analysis used psoriasis vulgaris, vitamin D level and 25 hydroxyvitamin D level as exposures. The main analysis employed the inverse variance weighted method, and the outcomes were evaluated by odds ratio (OR) and 95% confidence interval (95% CI). In UVMR analysis, the results depicted that psoriasis vulgaris was associated with VaD (OR: 0.903, 95% CI: 0.818-0.996, p = 0.041). The results revealed insignificant associations between psoriasis vulgaris and other dementia types. After adjusting the effects of MPV, PDW and PLT in MVMR analysis, the association between psoriasis vulgaris and VaD was no longer significant (p = 0.164). Similarly, after adjusting the effects of vitamin D level and 25 hydroxyvitamin D level in MVMR analysis, the association between psoriasis vulgaris and VaD was also no longer significant (p = 0.533). Our study suggests that psoriasis vulgaris may potentially decrease VaD incidence. However, the causal association between psoriasis vulgaris and VaD may be impeded by platelet-related indices, vitamin D level and 25 hydroxyvitamin D level.
10.1111/exd.14984
Causal association between B cell count and psoriasis using two-sample Mendelian randomization.
Journal of cellular and molecular medicine
To investigate the causality between B cell count and psoriasis by Mendelian randomization (MR). Collected B cell count and psoriasis data from IEU Open GWAS Project. Employed inverse variance weighting (IVW), MR-Egger, WM, weighted mode for analysis, ensuring result robustness. Assessed horizontal pleiotropy with MR-Egger, detected outliers using MR-PRESSO and examined instrumental variables heterogeneity with Cochran's Q-test. The IVW method suggested an association between a genetically predicted memory B cell count and the risk of psoriasis vulgaris. IVW results also showed no causality between other exposure factors and the corresponding outcomes. Also, the global test of MR-PRESSO analysis showed a significant association between a genetically predicted transitional absolute B cell count and the lower risk of psoriasis vulgaris. MR-Egger regression showed that horizontal pleiotropy did not influence the analysis results. We found that memory B cell absolute counts are associated with a lower risk of psoriasis. These data further elucidate the role of memory B cells in psoriasis and provide new options for psoriasis treatment.
10.1111/jcmm.70089
Reverse causation between multiple sclerosis and psoriasis: a genetic correlation and Mendelian randomization study.
Scientific reports
Observational studies have found a potential bidirectional positive association between multiple sclerosis and psoriasis, but these studies are susceptible to confounding factors. We examined the directionality of causation using Mendelian randomization and estimated the genetic correlation using the linkage disequilibrium score. We performed Mendelian randomization analysis using large-scale genome-wide association studies datasets from the International Multiple Sclerosis Genetics Consortium (IMSGC, 115,803 individuals of European ancestry) and FinnGen (252,323 individuals of European ancestry). We selected several Mendelian randomization methods including causal analysis using summary effect (CAUSE), inverse variance-weighted (IVW), and pleiotropy-robust methods. According to CAUSE and IVW the genetic liability to MS reduces the risk of psoriasis (CAUSE odds ratio [OR] 0.93, p = 0.045; IVW OR 0.93, p = 2.51 × 10), and vice versa (CAUSE OR 0.72, p = 0.001; IVW OR 0.71, p = 4.80 × 10). Pleiotropy-robust methods show the same results, with all p-values < 0.05. The linkage disequilibrium score showed no genetic correlation between psoriasis and MS (rg = - 0.071, p = 0.2852). In summary, there is genetic evidence that MS reduces the risk of psoriasis, and vice versa.
10.1038/s41598-024-58182-9
Causal relationships between dietary antioxidant vitamin intake and atopic dermatitis: A two-sample Mendelian randomization study.
Skin research and technology : official journal of International Society for Bioengineering and the Skin (ISBS) [and] International Society for Digital Imaging of Skin (ISDIS) [and] International Society for Skin Imaging (ISSI)
OBJECTIVE:Oxidative stress is strongly associated with atopic dermatitis (AD), and increased antioxidant intake could potentially reduce the risk of or alleviate its symptoms. However, the argument is disputed. Therefore, we conducted a Mendelian randomization (MR) analysis to explore the causal relationship between dietary antioxidant vitamin intake and AD. METHODS:We applied MR analysis to examine the causative association between dietary antioxidant vitamin intake (vitamin C, vitamin E, carotene, and retinol) and AD. The genome-wide association study (GWAS) summary data for antioxidant vitamins intake and AD were obtained from the IEU OpenGWAS database and the UK biobank. Our study consisted of two major parts, MR analysis to detect the causal relationship between exposure and outcome, and sensitivity analysis as supplemental evidence to verify the robustness of the results. RESULT:The results revealed a suggestive causal relationship between vitamin E intake and AD (p = 0.038, OR 95% CI = 0.745-0.992). However, there was no causal relationship between the other three vitamins (vitamin C, carotene, and retinol) and AD (p = 0.507, OR 95% CI = 0.826-1.099) (p = 0.890, OR 95% CI = 0.864-1.184) (p = 0.492, OR 95% CI = 0.893-1.264). None of the single nucleotide polymorphisms (SNPs) were detected as heterogeneous and pleiotropy in the sensitivity analysis (p > 0.05). CONCLUSION:The analysis suggested that dietary intake of vitamin E may potentially lower the risk of AD. Conversely, intake of vitamin C, retinol, and carotene is not causally related to AD. Although vitamin E intake could be protective against AD, intake of dietary antioxidant vitamins to prevent or treat AD is not necessary.
10.1111/srt.13883
The Potential Role of Female Sex Hormones in Patients With Inflammatory Bowel Disease: A 2-Sample Mendelian Randomization Study.
Clinical and translational gastroenterology
INTRODUCTION:An association between female sex hormones and inflammatory bowel disease (IBD) has been reported in epidemiological studies. However, a solid causal relationship has not been established. Therefore, we performed a 2-sample Mendelian randomization (MR) study to explore the causal association between genetically predicted female sex hormone exposure, especially estrogen, and IBD. METHODS:Genetic variants for female sex hormone exposure (ovulatory function, reproductive function, oral contraceptive pills, and hormone replacement therapy) were obtained from genome-wide association studies. Summary statistics for IBD were derived from the International Inflammatory Bowel Disease Genetics Consortium. We applied inverse variance weighted (IVW), MR-Egger, and weighted median (WM) methods in this MR study. Heterogeneity, horizontal pleiotropy, and sensitivity analyses were conducted to confirm the accuracy and robustness of our results. RESULTS:Our study found that genetically predicted age at menarche was associated with an increased risk of Crohn's disease (odds ratio [OR] IVW 1.235, 95% confidence interval [CI] 1.028-1.484, P = 0.024), genetically predicted age of the last used hormone replacement therapy was associated with an increased risk of ulcerative colitis (OR WM 1.636, 95% CI 1.011-2.648, P = 0.045), and genetically predicted number of live births was related to a decreased risk of Crohn's disease (OR IVW 0.583, 95% CI 0.373-0.912, P = 0.018). DISCUSSION:This study provided evidence for a link between female sex hormone exposure, especially estrogen, and IBD. Further investigations are needed to explore the causal effect of estrogen on IBD activity and the underlying mechanism of estrogen in IBD.
10.14309/ctg.0000000000000748
Association of psoriasis with depression, anxiety, and suicidality: A bidirectional two-sample Mendelian randomization study.
The Journal of dermatology
Psoriasis is a chronic, refractory inflammatory skin disease, with a high prevalence of psychiatric comorbidities, including depression, anxiety, and even suicidality, which may in turn initiate or exacerbate skin inflammation. However, the causal relationships between these comorbidities remain unclear. To investigate the cause-effect relationships between psoriasis and mental disorders including depression, anxiety, and suicidality, we conducted a bidirectional two-sample Mendelian randomization (MR) study utilizing summary statistics from the most comprehensive genome-wide association studies of psoriasis (n = 306 123), broad depression (n = 500 199), major depressive disorder (n = 173 005), anxiety (n = 17 310), and suicide attempts (n = 50 264). Using the random-effects inverse-variance weighted method as primary method, the forward MR analyses indicated that psoriasis was significantly associated with higher odds of broad depression (odds ratio [OR] 1.030, 95% confidence interval [CI] 1.010-1.051, P = 0.003) and suggestively associated with an increased risk of major depressive disorder (OR 1.054, 95% CI 1.002-1.109, P = 0.040), but not with the risk of anxiety (P = 0.160) or suicide attempts (P = 0.648). In reverse MR analyses, significant causal impact of broad depression (OR 1.363, 95% CI 1.103-1.684, P = 0.004) and major depressive disorder (OR 1.890, 95% CI 1.285-2.781, P = 0.001), but not anxiety (P = 0.787) and suicide attempts (P = 0.961) on psoriasis risk was observed. In addition, the results of primary analysis are consistent across sensitivity analyses, albeit the MR-Egger regression model produced wide CIs and negative results in several analyses. In conclusion, this MR study indicates a bidirectional causal relationship between psoriasis and depression that was previously unrecognized, which highlights the significance of screening for depression in psoriasis patients and initiating appropriate interventions. Further studies are required to elucidate the pathophysiology of the bidirectional causal relationship between these two conditions.
10.1111/1346-8138.16941
The role of digital device use on the risk of migraine: a univariable and multivariable Mendelian randomization study.
Frontiers in neurology
Background:The pervasive integration of digital devices into daily life has raised concerns about their potential health impacts. This study aimed to explore the causal relationships between digital device use and the risk of migraine using Mendelian randomization (MR). Methods:Genetic data on digital device use and migraines were sourced from large-scale genome-wide association studies conducted by the UK Biobank, the FinnGen study, and the International Headache Genetics Consortium. Univariable MR (UVMR), meta-analysis, and multivariable MR (MVMR) approaches were conducted to explore and verify the causal effects of digital device use (including mobile phone use, computer use, playing computer games, and watching television) on migraine risk. Sensitivity analyses were conducted using Cochran's Q, MR-Egger intercept test, MR pleiotropy residual sum and outlier, MR Radial, MR Steiger, and leave-one-out methods. Results:UVMR analyses revealed that genetically predicted mobile phone use was significantly associated with an increased risk of overall migraine (odds ratio [OR] = 2.39, = 9.78e-5) and migraine without aura (MO) (OR = 2.25, = 0.024). Additionally, there were significant positive associations between genetically predicted television watching and the risk of overall migraine (OR = 1.63, = 2.12e-5) and MO (OR = 2.10, = 4.98e-5). These results were further supported by the meta-analysis and MVMR analysis. Sensitivity analysis indicated no heterogeneity or pleiotropy. Conclusion:This comprehensive MR study provides preliminary evidence for the causal impact of mobile phone use and television watching on the risk of migraines. Further studies are needed to explore these associations across different populations.
10.3389/fneur.2024.1462414
Association Between Telomere Length and Skin Cancer and Aging: A Mendelian Randomization Analysis.
Frontiers in genetics
Telomere shortening is a hallmark of cellular senescence. However, telomere length (TL)-related cellular senescence has varying effects in different cancers, resulting in a paradoxical relationship between senescence and cancer. Therefore, we used observational epidemiological studies to investigate the association between TL and skin cancer and aging, and to explore whether such a paradoxical relationship exists in skin tissue. This study employed two-sample Mendelian randomization (MR) to analyze the causal relationship between TL and skin cancer [melanoma and non-melanoma skin cancers (NMSCs)] and aging. We studied single nucleotide polymorphisms (SNPs) obtained from pooled data belonging to genome-wide association studies (GWAS) in the literature and biobanks. Quality control was performed using pleiotropy, heterogeneity, and sensitivity analyses. We used five algorithms to analyze the causal relationship between TL and skin aging, melanoma, and NMSCs, and obtained consistent results. TL shortening reduced NMSC and melanoma susceptibility risk with specific odds ratios (ORs) of 1.0344 [95% confidence interval (CI): 1.0168-1.0524, = 0.01] and 1.0127 (95% CI: 1.0046-1.0209, = 6.36E-07), respectively. Conversely, TL shortening was validated to increase the odds of skin aging (OR = 0.96, 95% CI: 0.9332-0.9956, = 0.03). Moreover, the MR-Egger, maximum likelihood, and inverse variance weighted (IVW) methods found significant heterogeneity among instrumental variable (IV) estimates (identified as MR-Egger skin aging Q = 76.72, = 1.36E-04; melanoma Q = 97.10, = 1.62E-07; NMSCsQ = 82.02, = 1.90E-05). The leave-one-out analysis also showed that the SNP sensitivity was robust to each result. This study found that TL shortening may promote skin aging development and reduce the risk of cutaneous melanoma and NMSCs. The results provide a reference for future research on the causal relationship between skin aging and cancer in clinical practice.
10.3389/fgene.2022.931785
Causal Association Between Sedentary Behaviors and Health Outcomes: A Systematic Review and Meta-Analysis of Mendelian Randomization Studies.
Sports medicine (Auckland, N.Z.)
BACKGROUND:Different types of sedentary behavior are associated with several health outcomes, but the causality of these associations remains unclear. OBJECTIVES:To conduct a systematic review and meta-analysis of Mendelian randomization (MR) studies investigating the associations between sedentary behaviors and health outcomes. METHODS:A systematic search on PubMed, Embase, Web of Science, Scopus, and PsycINFO up to August 2023 was conducted to identify eligible MR studies. We selected studies that assessed associations of genetically determined sedentary behaviors and health outcomes. A meta-analysis was conducted to examine the causal associations when two or more MR studies were available. We graded the evidence level of each MR association based on the results of the main method and sensitivity analyses in MR studies. RESULTS:A total of 31 studies with 168 MR associations between six types of sedentary behavior and 47 health outcomes were included. Results from meta-analyses suggested a total of 47 significant causal associations between sedentary behaviors and health outcomes. Notably, more leisure TV watching is robustly correlated with increased risks of myocardial infarction, coronary artery disease, all-cause ischemic stroke, and type 2 diabetes. Conversely, robust inverse associations were observed between leisure computer use and risks of rheumatoid arthritis, Alzheimer's disease, and gastroesophageal reflux disease. CONCLUSION:These findings suggest that different types of sedentary behavior have distinct causal effects on health outcomes. Therefore, interventions should focus not only on reducing sedentary time but also on promoting healthier types of sedentary behavior. PROSPERO REGISTRATION:CRD42023453828.
10.1007/s40279-024-02090-5
The relationship between blood lipid and risk of psoriasis: univariable and multivariable Mendelian randomization analysis.
Frontiers in immunology
Background:Psoriasis is a chronic inflammatory skin disease. Dyslipidemia may be a risk factor of psoriasis. But the causal relationship between psoriasis and blood lipid still remains uncertain. Methods:The two data of blood lipid were obtained from UK Biobank (UKBB) and Global Lipid Genetics Consortium Results (GLGC). The primary and secondary database were from large publicly available genome-wide association study (GWAS) with more than 400,000 and 170,000 subjects of European ancestry, respectively. The psoriasis from Finnish biobanks of FinnGen research project for psoriasis, consisting of 6,995 cases and 299,128 controls. The single-variable Mendelian randomization (SVMR) and multivariable Mendelian randomization (MVMR) were used to assess the total and direct effects of blood lipid on psoriasis risk. Results:SVMR estimates in primary data of blood lipid showed low-density lipoprotein cholesterol (LDL-C) (odds ratio (OR): 1.11, 95%, confidence interval (CI): 0.99-1.25, = 0.082 in stage 1; OR: 1.15, 95% CI: 1.05-1.26, = 0.002 in stage 2; OR: 1.15, 95% CI: 1.04-1.26, = 0.006 in stage 3) and triglycerides (TG) (OR: 1.22, 95% CI: 1.10-1.35, = 1.17E-04 in stage 1; OR: 1.15, 95% CI: 1.06-1.24, = 0.001 in stage 2; OR: 1.14, 95% CI: 1.05-1.24, = 0.002 in stage 3) had a highly robust causal relationship on the risk of psoriasis. However, there were no robust causal associations between HDL-C and psoriasis. The SVMR results in secondary data of blood lipid were consistent with the primary data. Reverse MR analysis showed a causal association between psoriasis and LDL-C (beta: -0.009, 95% CI: -0.016- -0.002, = 0.009) and HDL-C (beta: -0.011, 95% CI: -0.021- -0.002, = 0.016). The reverse causation analyses results between psoriasis and TG did not reach significance. In MVMR of primary data of blood lipid, the LDL-C (OR: 1.05, 95% CI: 0.99-1.25, = 0.396 in stage 1; OR: 1.07, 95% CI: 1.01-1.14, = 0.017 in stage 2; OR: 1.08, 95% CI: 1.02-1.15, = 0.012 in stage 3) and TG (OR: 1.11, 95% CI: 1.01-1.22, = 0.036 in stage 1; OR: 1.09, 95% CI: 1.03-1.15, = 0.002 in stage 2; OR: 1.07, 95% CI: 1.01-1.13 = 0.015 in stage 3) positively correlated with psoriasis, and there had no correlation between HDL-C and psoriasis. The results of the secondary analysis were consistent with the results of primary analysis. Conclusions:Mendelian randomization (MR) findings provide genetic evidence for causal link between psoriasis and blood lipid. It may be meaningful to monitor and control blood lipid level for a management of psoriasis patients in clinic.
10.3389/fimmu.2023.1174998
Evaluating the effect of tanning response to sun exposure on the risk of skin diseases through Mendelian randomization.
Frontiers in genetics
Until now, the relevance of the tanning response to sun exposure and skin diseases has incomplete and inconsistent epidemiological observations. In this case, it is valuable to find out the causality of tanning response to sun exposure and skin diseases, and take a step further toward developing effective therapies as well as prevention methods. We investigated the causal effect of tanning response to sun exposure on 10 major skin diseases that have been studied in recent large-scale genome-wide association studies (GWASs). Significant independent genetic variants from large-scale GWAS on ease of skin tanning (N = 453,065) are selected as the effective instrumental variables (IVs). For each skin disease, we extracted the summary statistics of those IVs (or their proxies) from the corresponding skin disease-GWAS as the valid IVs. Mendelian randomization (MR) was further performed to evaluate the causal association of ease of skin tanning with each of the skin diseases using different statistical methods, including inverse-variance weighted (IVW), the weighted median, and MR-Egger. Sensitivity analysis was also conducted to evaluate the effect of horizontal pleiotropy and heterogeneity. We observe significant associations between six skin diseases with tanning response to sun exposure with adjusted -value derived by IVW less than 0.05 and with nominal value less than 0.05 at the same time derived by either MR-Egger or weighted median. The six skin diseases include actinic keratosis (IVW FDR = 1.71E-40, MR Egger -value = 3.46E-22), seborrhoeic keratosis (IVW FDR = 2.97E-4, MR Egger -value = 1.06E-3), blepharochalasis (IVW FDR = 1.30E-3, MR Egger -value = 2.91E-4), seborrhoeic dermatitis (IVW FDR = 1.29E-2, MR Egger -value = 1.23E-2), malignant melanoma of skin (IVW FDR = 2.95E-2, MR Egger -value = 1.91E-2), and freckles (IVW FDR = 2.95E-2, weighted median -value = 1.02E-3). Interestingly, we find increased trends of developing all of the six skin diseases with increased tanning response to sun exposure (beta values are positive using IVW, MR-egger, and weighted median methods). We also replicate the association on three skin diseases using an independent outcome GWAS cohort, including malignant melanoma of the skin (replication IVW -value = 2.13E-39), actinic keratosis (replication IVW -value = 4.64E-32), and seborrhoeic keratosis (replication IVW -value = 1.79E-3). Our observation shows that the tanning response to sun exposure is positively correlated with the development of skin diseases in people of European descent by Mendelian randomization studies. But randomized controlled trials are still needed to add proof to our observations.
10.3389/fgene.2022.967696
A Mendelian randomization study on the causal effects of circulating cytokines on the risk of vitiligo.
Frontiers in medicine
Background:Accumulating evidence reveals an association between circulating cytokine levels and vitiligo. However, the causal association between circulating cytokine levels and vitiligo remains unrevealed. Methods:We performed a two-sample Mendelian randomization (MR) analysis using a genome-wide association study of the 41 cytokines dataset, which was conducted with 3 Finnish cohorts ( = 8,293). Vitiligo data were acquired from strictly defined vitiligo data collected by FinnGenbiobank analysis, which included 207,613 European ancestors (131 vitiligo patients, 207,482 controls). The inverse-variance weighted (IVW) method, weighted median (WME), simple model, weighted model, and MR-Egger were used to determine the changes in vitiligo pathogenic cytokine taxa, followed by sensitivity analysis, including horizontal pleiotropy analysis. The MR Steiger test evaluated the strength of a causal association, and the leave-one-out method was used to assess the reliability of the results. The possibility of reverse causality was also investigated using a reverse MR study. Results:We observed that rising IL-4 levels generated an enhanced probability of vitiligo in IVW (OR 2.72, 95%CI 1.19-6.22, = 0.018). According to the results of the MR analysis, there were causal links between IL-4 and vitiligo. Results were steady after sensitivity and heterogeneity analyses. Conclusion:Our research reveals that a genetically determined increased level of circulating IL-4 may be linked to a higher risk of developing vitiligo. The development of innovative treatment approaches (such as tofacitinib or dupilumab) that focus on blocking IL-4 as a novel way of preventing and treating vitiligo is significantly impacted by our findings.
10.3389/fmed.2024.1375339
Mendelian randomization indicates that atopic dermatitis contributes to the occurrence of diabetes.
BMC medical genomics
BACKGROUND:An association has been indicated between atopic dermatitis (AD), a prevalent chronic inflammatory skin disease, and diabetes mellitus. However, the exact causal relationship between AD and both type 1 diabetes (T1D) and type 2 diabetes (T2D) remains controversial. This study aimed to explore the causal association between AD and diabetes by Mendelian Randomization (MR) approaches. METHODS:Public genetic summary data for AD was obtained from EAGLE study. Single nucleotide polymorphisms of diabetes were retrieved from four genome-wide association studies that had been performed in European populations. Inverse variance weighted (IVW) in MR analysis was used as the primary means of causality estimation. Several complementary analyses and sensitivity analyses were performed to calculate MR estimates and to enhance the causal inference, respectively. The R package 'TwoSampleMR' was used for analysis. RESULTS:Genetically predicted AD led to a higher risk of T1D (OR, 1.19; 95% CI, 1.05, 1.34; P = 0.006) and T2D (OR, 1.07; 95% CI, 1.02, 1.11; P = 0.003) based on random-effect IVW method. The complementary analyses provided similar positive results. Cochran's Q test and I statistics indicated moderate heterogeneity between AD and both T1D and T2D. No significant horizontal pleiotropy was detected by MR-Egger Intercept p except summary data from FinnGen consortium. CONCLUSION:Genetically predicted AD is a risk factor for both T1D and T2D. These findings imply potential shared pathological mechanisms between AD and diabetes, thus suggesting the significance of early clinical diagnosis and prevention of AD in reducing the incidence of diabetes.
10.1186/s12920-023-01575-y
Causal associations of air pollution with rheumatoid arthritis: A transethnic Mendelian randomization study.
PloS one
BACKGROUND:Rheumatoid arthritis is a common rheumatic disease, and its onset is closely related to genetic and environmental factors, however, the relationship between air pollution and RA is still hotly debated. Further investigation of the relationship between air pollution and rheumatoid arthritis is conducive to a comprehensive understanding of the risk factors of the disease, providing certain value for the clinical prevention and treatment of RA. METHODS:We used a Two-Sample Mendelian Randomization approach, integrating the large-scale public genomewide association study, to assess the genetically predicted causal effect of air pollution (including: PM2.5, PM2.5-10, PM10, nitrogen dioxide, nitrogen oxides) on RA in European and European East Asian populations, respectively. Indicators related to air pollution (2,505 individuals to 423,796 individuals), including European and East Asian populations were obtained from the Integrative Epidemiology Unit open GWAS project. Published East Asian RA data were also obtained from the IEU open GWAS project (212,453 individuals), while large-scale publicly available European RA data were obtained from finngen R10 (13,621 cases and 262,844 controls). Inverse variance weighting was used as the primary analytical method, complemented by MR-egger, Weighed median, and Weighted mode results. Cochran Q tested for heterogeneity, and MR-Egger regression analyses were performed to test for multiplicity. leave-one-out analysis allowed for the robustness and reliability were assessed. RESULTS:No statistically significant effects of PM2.5, PM2.5-10, PM10, nitrogen dioxide, nitrogen oxides and RA were observed in either European or East Asian populations. Results from European data: PM2.5 (IVW OR: 0.71; 95% CI: 0.27-1.91; p = 0.498; number of SNPs: 5), PM2.5-10 (IVW OR: 1.20; 95% CI: 0.61-2.40; p = 0.596; number of SNPs: 15), PM10 (IVW OR: 1.69; 95% CI: 0.84-3.39; p = 0.142; number of SNPs: 9), nitrogen dioxide (IVW OR: 3.88; 95% CI: 0.19-77.77; p = 0.375; number of SNPs: 2), nitrogen oxides (IVW OR: 0.51; 95% CI: 0.16-1.67; p = 0.268; number of SNPs: 4). East Asian data results: PM2.5 (IVW OR: 1.16; 95% CI: 0.98-1.38; p = 0.086; number of SNPs: 4), PM2.5-10 (IVW OR: 1.14; 95% CI: 0.95-1.38; p = 0.166; number of SNPs: 2), PM10 (IVW OR: 0.95; 95% CI: 0.81-1.11; p = 0.503; number of SNPs: 3), nitrogen dioxide (IVW OR: 0.87; 95% CI: 0.76-1.00; p = 0.051; number of SNPs: 6), nitrogen oxides (IVW OR: 0.96; 95% CI: 0.82-1.14; p = 0.671; number of SNPs: 3). No signs of pleiotropy or heterogeneity were observed in the MR-Egger intercept, MR-PRESSO and Cochrane's Q (p>0.05). In addition, no outliers were found in the MR-PRESSO analysis. The results were further validated by leave-one-out tests, confirming the robustness of the findings. CONCLUSIONS:We performed transethnic MR analysis suggesting that there may not be a genetically predicted causal relationship between air pollution and RA.
10.1371/journal.pone.0307514
Identification of dietary factors that impact the gut microbiota associated with vitiligo: A Mendelian randomization study and meta-analysis.
Experimental dermatology
Previous observational studies have suggested that gut microbiota might be associated with vitiligo. However, owing to the limitations in observational studies of reverse causality and confounders, it remains unclear that whether and how the causal relationships exist. The results suggested that pylum.Bacteroidetes, family.BacteroidalesS24.7, genus.LachnospiraceaeND3007, genus.Marvinbryantia are protective factors for vitiligo. Conversely, family.Lachnospiraceae, order.Burkholderiales, genus.Adlercreutzia, genus.Catenibacterium and genus.Lachnospira are risk factors for vitiligo. In addition, the causative connection between dietary factors and the gut microbiota associated with vitiligo was also investigated. The results revealed that 'alcohol intake versus 10 years pervious' results in a reduction in the abundance of genus.Lachnospiraceae ND3007 and family.BacteroidalesS24.7, bread intake leads to a reduction of genus.Marvinbryantia, 'average weekly red wine intake' is linked to a decrease in the abundance of order.Burkholderiales, tea intake is associated with an augmentation in the abundance of genus.Catenibacterium, salad/raw vegetable intake elevates the abundance of order.Burkholderiales. In summary, this Mendelian randomization study substantiates potential causal effects of gut microbiota on vitiligo. Modulating the gut microbiota through regulating dietary composition may be a novel strategy for preventing vitiligo.
10.1111/exd.15176
Psoriasis may increase the risk of idiopathic pulmonary fibrosis: a two-sample Mendelian randomization study.
Respiratory research
BACKGROUND:Although some studies have indicated that Psoriasis could contribute to the risk of idiopathic pulmonary fibrosis (IPF), no study has reported a clear causal association between them. Our aim was to explore the potential relationship between Psoriasis and IPF using Mendelian randomization (MR) design. METHODS:To explore a causal association between Psoriasis and IPF, we used genetic instruments from the largest available genome-wide association study (GWAS) of European ancestry, including psoriasis (5314 cases, 457,619 controls) and IPF (1028 cases, 196,986 controls). Our main analyses were conducted by inverse-variance weighted (IVW) method with random-effects model, with the other complementary four analyses: weighted median method, weighted mode, multivariable MR and MR-Egger approach. RESULTS:The results of IVW methods demonstrated that genetically predicted psoriasis was significantly associated with higher odds of IPF, with an odds ratio (OR) of 1.09 (95%CI, 1.01-1.18; P = 0.02). Weighted median method, weighted mode and multivariable MR also demonstrated directionally similar results (P < 0.05), while the MR-Egger regression did not reveal the impact of psoriasis on IPF (OR = 1.09, 95%CI, 0.98-1.21; P = 0.11). In addition, both funnel plots and MR-Egger intercepts indicated no directional pleiotropic effects between psoriasis and IPF. CONCLUSIONS:Our study provided potential evidence between genetically predicted psoriasis and IPF, which suggests that understanding the mutual risk factors between psoriasis and IPF can facilitate the clinical management of both diseases.
10.1186/s12931-024-02721-5
Effects of menstrual disorders and dysmenorrhea on cardiovascular disease: a Mendelian randomization study.
Frontiers in endocrinology
Background:Observational studies have demonstrated associations between menstrual disorders, dysmenorrhea, and cardiovascular disease (CVD). However, it remains unclear whether these associations are causal. This study is to investigate whether menstrual disorders and dysmenorrhea causally affect the risk of CVD. Methods:The summary data for menstrual disorders (excessive menstruation and irregular menses) and dysmenorrhea were obtained from FinnGen study, summary data for CVD were obtained from UK Biobank and meta-analysis. The inverse-variance-weighted method was mainly used in the Mendelian randomization for causality analysis. Sensitivity analyses were performed by several methods under different model assumptions. Results:Genetic liability to excessive menstruation was associated with higher risk of atrial fibrillation (odds ratio (OR), 1.078 [95% confidence interval (CI), 1.015-1.145]; =0.014), but a lower risk of hypertension (OR, 0.994 [95% CI: 0.989-0.999]; =0.016). Irregular menses was associated with higher risk of atrial fibrillation (OR, 1.095 [95% CI: 1.015-1.182]; =0.02), hypertension (OR, 1.007 [95% CI: 1.000-1.013]; =0.047), myocardial infarction (OR, 1.172 [95% CI: 1.060-1.295]; =0.02), ischemic heart disease, (OR, 1.005 [95% CI: 1.000-1.010]; =0.037) and coronary heart disease (OR, 1.004 [95% CI: 1.001-1.008]; =0.026). Dysmenorrhea was associated with higher risk of atrial fibrillation (OR, 1.052 [95% CI: 1.014-1.092]; =0.008) and Ischemic stroke (cardioembolic) (OR, 1.122 [95% CI: 1.002-1.257]; =0.046). After Benjamini-Hochberg correction, irregular menses was associated with higher risk of myocardial infarction. Conclusion:We confirmed a causal relationship of excessive menstruation, irregular menses and dysmenorrhea on cardiovascular outcomes independent of sex hormone levels, with an emphasis on the link between irregular menses and myocardial infarction. These clinical features can be utilized as markers to identify women at higher risk of developing CVD in the future, recommending early clinical intervention of menstrual diseases.
10.3389/fendo.2024.1302312
The effect of antioxidant dietary supplements and diet-derived circulating antioxidants on vitiligo outcome: evidence from genetic association and comprehensive Mendelian randomization.
Frontiers in nutrition
Background:Previous studies have indicated that antioxidant diets may have a positive impact on vitiligo by interfering with oxidative stress mechanisms. However, there has been a lack of research utilizing the Mendelian randomization (MR) method to analyze the relationship between antioxidant diet intake and vitiligo. Methods:In this study, we employed both univariate Mendelian randomization (UVMR) and multivariate Mendelian randomization (MVMR) approaches. The specific antioxidant dietary supplements (such as coffee intake, green tea intake, herbal tea intake, standard tea intake, and average weekly red wine intake) as well as diet-derived circulating antioxidants, including Vit. C (ascorbate), Vit. E (α-tocopherol), Vit. E (γ-tocopherol), Carotene, Vit. A (retinol), Zinc, and Selenium ( = 2,603-428,860) were significantly associated with independent single-nucleotide polymorphisms (SNPs). We obtained pooled statistics on vitiligo from a meta-analysis of three genome-wide association studies (GWASs) of European ancestry, including 4,680 cases and 39,586 controls. Inverse variance weighted (IVW) was employed as the primary analytical method, and sensitivity analysis was conducted to assess the robustness of the main findings. Results:Genetically, coffee intake [odds ratio (OR) = 0.17, 95% confidence interval (CI) 0.07-0.37, = 1.57 × 10], average weekly red wine intake (OR = 0.28, 95% CI 0.08-1.00, = 0.049), and standard tea intake (OR = 0.99, 95% CI 0.98-0.99, = 5.66 × 10) were identified as protective factors against vitiligo. However, no causal effect between the intake of other antioxidant diets and vitiligo was found. Moreover, no instances of pleiotropy or heterogeneity were observed in this study. Conclusion:Our study indicates that coffee, standard tea, and red wine consumption can potentially reduce the risk of vitiligo. However, there is insufficient evidence to support that other antioxidant diets have a significant effect on vitiligo.
10.3389/fnut.2023.1280162
The effect of inflammatory cytokines on the risk of hypertrophic scar: a mendelian randomization study.
Archives of dermatological research
Hypertrophic scar (HS) results from burns or trauma, causing aesthetic and functional issues. However, observational studies have linked inflammatory cytokines to HS, but the causal pathways involved are unclear. We aimed to determine how circulating inflammatory cytokines contribute to HS formation. Two-sample Mendelian randomization (MR) was used to identify genetic variants associated with hypertrophic scar in a comprehensive, publicly available genome-wide association study (GWAS) involving 766 patients and 207,482 controls of European descent. Additionally, data on 91 plasma proteins were drawn from a GWAS summary involving 14,824 healthy participants. Causal relationships between exposures and outcomes were investigated primarily using the inverse variance weighted (IVW) method. Furthermore, a suite of sensitivity analyses, including MR‒Egger and weighted median approaches, were concurrently employed to fortify the robustness of the conclusive findings. Finally, reverse MR analysis was conducted to evaluate the plausibility of reverse causation between hypertrophic scar and the cytokines identified in our study. In inflammatory cytokines, there was evidence of inverse associations of osteoprotegerin(OPG) levels(OR = 0.59, 95% CI = 0.41 ∼ 0.85, p = 0.01), and leukemia inhibitory factor(LIF) levels(OR = 0.51, 95% CI = 0.32 ∼ 0.82, p = 0.01) are a nominally negative association with hypertrophic scar risk, while CUB domain-domain-containing protein 1(CDCP1) level(OR = 0.59, 95% CI = 0.41 ∼ 0.85, p = 0.01) glial cell line-derived neurotrophic factor(GDNF) levels(OR = 1.42, 95% CI = 1.03 ∼ 1.96, p = 0.01) and programmed cell death 1 ligand 1(PD-L1) levels(OR = 1.47, 95% CI = 1.92 ∼ 2.11, p = 0.04) showed a positive association with hypertrophic scar risk. These associations were similar in the sensitivity analyses. According to our MR findings, OPG and LIF have a protective effect on hypertrophic scar, while CDCP1, GDNF, and PD-L1 have a risk-increasing effect on Hypertrophic scar. Our study adds to the current knowledge on the role of specific inflammatory biomarker pathways in hypertrophic scar. Further validation is needed to assess the potential of these cytokines as pharmacological or lifestyle targets for hypertrophic scar prevention and treatment.
10.1007/s00403-024-03303-7
The influence of genetic predisposition to oxidative stress on painful diabetic peripheral neuropathy: A mendelian randomization study.
Cellular and molecular biology (Noisy-le-Grand, France)
Genetic predisposition to oxidative stress (OS) may influence the risk of Painful Diabetic Peripheral Neuropathy (PDPN). This study employed a Mendelian Randomization (MR) approach to investigate the causal relationship between genetic predisposition to OS and PDPN. Genetic instruments associated with OS biomarkers were selected as exposures. Summary-level data on PDPN was obtained from the largest available genome-wide association study (GWAS). MR analyses were conducted using the inverse-variance weighted (IVW) method, with sensitivity analyses employing the MR-Egger, weighted median, and MR-PRESSO approaches. Genetic predisposition to increased glutathione S-transferase (GST) activity was associated with a reduced risk of PDPN (OR=0.66, 95%CI: 0.49-0.89, P=0.006). Higher ascorbate levels conferred a protective effect against PDPN (OR=0.83, 95%CI: 0.71-0.97, P=0.018). No significant association was observed between genetic predisposition to OS biomarkers and PDPN severity. Genetic predisposition to increased GST activity and higher ascorbate levels protect against the development of PDPN, suggesting a causal relationship.
10.14715/cmb/2024.70.3.25
Smoking and the risk of atopic dermatitis: A two-sample mendelian randomization study.
Medicine
Atopic dermatitis (AD) is considered to be one of the most common chronic diseases. It has been shown that smoking is associated with atopic dermatitis, but previous studies were mainly observational, which may be biased. The present study conducted a 2-sample mendelian randomization (MR) study to investigate the causal relationship. The present study obtained data on "ever smoked" and "atopic dermatitis" from published large-scale genome-wide association studies. The data were obtained from the UK Biobank and BioBank Japan. Three methods were used to perform a 2-sample MR analysis and also performed sensitivity analysis. The odds ratio and 95% confidence interval (CI) between smoking and AD calculated by MR-Egger regression, weighted median, and random-effects inverse variance weighting method were 1.096 (95% CI.756-1.587) and 1.159 (95% CI 1.040-1.292), respectively, 1.137 (95% CI .975-1.325). The inverse variance weighting method showed statistical significance between the 2 and a causal relationship between smoking and AD. In conclusion, the results of our MR analysis suggest that smoking is likely to affect the incidence of AD.
10.1097/MD.0000000000036050
The impact of smoking and alcohol consumption on rosacea: a multivariable Mendelian randomization study.
Frontiers in public health
Backgrounds:Observational studies have shown that cigarette smoking is inversely associated with risk of rosacea, However, it remains uncertain whether this association is causal or it is a result of reverse causation, and whether this association is affected by drinking behaviors. Methods:This study utilized the summary-level data from the largest genome-wide association study (GWAS) for smoking, alcohol consumption, and rosacea. The objective was to investigate the effect of genetically predicted exposures to smoking and alcohol consumption on the risk of developing rosacea. Two-sample bidirectional Mendelian randomization (MR) was applied, accompanied by sensitive analyses to validate the robustness of findings. Furthermore, multivariable MR was conducted to evaluate the direct impact of smoking on rosacea. Results:A decreased risk of rosacea was observed in individuals with genetically predicted lifetime smoking [odds ratio (OR) = 0.53; 95% confidence interval (CI), 0.318-0.897; = 0.017], and number of cigarettes per day (OR = 0.55; 95% CI, 0.358-0.845; = 0.006). However, no significant associations were found between initiation of regular smoking, smoking cessation, smoking initiation, alcohol consumption and rosacea. Reverse MR analysis did not show any associations between genetic liability toward rosacea and smoking or alcohol drinking. Importantly, the effect of lifetime smoking and the number of cigarettes per day on rosacea remained significant even after adjusting for alcohol consumption in multivariable MR analysis. Conclusion:Smoking was causally related to a lower risk of rosacea, while alcohol consumption does not appear to be associated with risk of rosacea.
10.3389/fpubh.2024.1320932
Deciphering the role of oxidative stress genes in idiopathic pulmonary fibrosis: a multi-omics mendelian randomization approach.
Genes and immunity
Oxidative stress (OS) is crucial in idiopathic pulmonary fibrosis (IPF) pathogenesis, with its genes potentially acting as both causes and consequences of the disease. We identified OS-related genes from GeneCards and performed a meta-analysis on pulmonary transcriptome datasets to discover differentially expressed genes (DEGs) related to OS in IPF. We integrated this data with the largest available IPF GWAS summaries, expression quantitative trait loci (eQTLs), and DNA methylation QTLs (mQTLs) from blood. This approach aimed to identify blood OS genes and regulatory elements linked to IPF risk, incorporating the latest pulmonary eQTLs and bronchoalveolar lavage fluid microbial QTLs (bmQTLs) for a comprehensive view of gene-lung microbiota interactions through SMR and colocalization analyses. Sensitivity analyses were conducted using two additional mendelian randomization (MR) methods. Meta-analysis revealed 1090 differentially expressed OS genes between IPF patients and controls. Integration with IPF GWAS, eQTL, and mQTL data identified key genes and regulatory elements involved in IPF pathogenesis, highlighting the role of specific genes such as KCNMA1 and SLC22A5 in modulating IPF risk through epigenetic mechanisms. Colocalization analysis further identified potential interactions between gene expression and lung microbiota. Our findings elucidate the complex interplay between OS genes and IPF, suggesting potential therapeutic targets and highlighting the importance of considering epigenetic and microbial interactions in the disease's etiology and progression.
10.1038/s41435-024-00292-5
The Role of the Gut-Joint Axis in the Care of Psoriatic Arthritis: A Two-Sample Bidirectional Mendelian Randomization Study.
Dermatology and therapy
INTRODUCTION:Observational studies and clinical trials have supported the association between gut microbiota and psoriatic arthritis. However, the causal link between gut microbiota and psoriatic arthritis is still unclear. METHODS:A two-sample bi-directional Mendelian randomization analysis was performed using the summary statistics of gut microbiota from the largest available genome-wide association study meta-analysis (n = 13,266) conducted by the MiBioGen consortium. The summary statistics of psoriatic arthritis were extracted directly from the FinnGen consortium, which consists of 3186 psoriatic arthritis patients and 24,086 controls. Sensitivity analyses were conducted to assess the validity of our findings. Enrichment analyses were used to investigate the biofunction and pathways. RESULTS:Inverse variance weighted (IVW) estimates suggested that family Rikenellaceae (P = 0.032) and genus Ruminococcaceae UCG011 (P = 0.014) had a detrimental effect on psoriatic arthritis. We also noticed the negative association between the class Methanobacteria (P = 0.032), order Methanobacteriales (P = 0.032), family Methanobacteriaceae (P = 0.032), genus Eubacterium fissicatena group (P = 0.010), genus Methanobrevibacter (P = 0.031), and genus Butyricicoccus (P = 0.041) with psoriatic arthritis. Sensitivity analyses showed that genus Butyricicoccus had pleiotropy and heterogeneity. According to the results of reverse MR analysis, the causal effect of psoriatic arthritis was found on six taxa, respectivelyc family Clostridiaceae1, family Defluviitaleaceae, genus Butyrivibrio, genus Defluviitaleaceae UCG011, genus Clostridium sensu stricto1, and genus Ruminococcaceae UCG011. CONCLUSION:This two-sample bidirectional Mendelian randomization analysis suggested that the gut microbiota had a causal effect on psoriatic arthritis and implied the potential role of probiotics in the management and prevention of psoriatic arthritis.
10.1007/s13555-024-01121-3
Association of educational attainment with hypertension and type-2 diabetes: A Mendelian randomization study.
SSM - population health
BACKGROUNDDue to the long time interval between exposure and outcome, it is difficult to infer the causal relationship between educational attainment (EA) and common chronic diseases. Therefore, we utilized Mendelian randomization (MR) to predict the causal relationships of EA with hypertension and type-2 diabetes (T2DM). METHODSA two-sample MR analysis was conducted using genome-wide association studies (GWASs) combined with inferential measurements. A GWAS meta-analysis including 1,131,881 European individuals was used to identify instruments for EA. Hypertension and T2DM data were obtained from a Finnish database. MR analyses were performed using inverse-variance weighted meta-analysis (IVW), weighted median regression, MR‒Egger regression, simple mode regression, weighted mode regression and the MR-Pleiotropy RESidual Sum and Outlier test. Sensitivity analyses were further performed using the leave-one-out method to test the robustness of our findings. RESULTSUsing the MR approach, our results showed that EA was significantly associated with a reduced risk of hypertension (OR = 0.63; P = 2.94 × 10; [95% CI: 0.59, 0.67]) and type-2 diabetes (OR = 0.59; P = 1.25 × 10; [95% CI: 0.52, 0.67]). CONCLUSIONSThis study showed that EA is causally linked to the risk of chronic diseases, including high blood pressure and T2DM.
10.1016/j.ssmph.2023.101585
Effects of particulate matter exposure on the risk of type 2 diabetes: a Mendelian randomization study.
European review for medical and pharmacological sciences
OBJECTIVE:The impact of particulate matter (PM) on the risk of type 2 diabetes (T2D) remains inconclusive. The purpose of this study was to assess the causal relationship between PM and T2D using Mendelian randomization (MR) analysis. MATERIALS AND METHODS:Single nucleotide polymorphisms (SNPs) for PM2.5, PM10, and T2D were obtained from the UK Biobank and FinnGen datasets. Inverse variance weighted, MR-Egger, and weighted median were utilized to examine the causal relationship between exposure and outcome. MR-Egger intercept analysis, Cochran's Q test, and leave-one-out sensitivity analysis were used to assess horizontal pleiotropy, heterogeneity, and robustness of the results, respectively. RESULTS:The MR analysis revealed a significant association between PM2.5 and increased risk of T2D (OR: 1.159, 95% CI: 1.003 to 1.339, p = 0.045), while no significant association was found between PM10 and T2D risk (OR: 1.031, 95% CI: 0.788 to 1.350, p = 0.822). MR-Egger intercept analysis and Cochran's Q test indicated no evidence of horizontal pleiotropy or heterogeneity in these results. Sensitivity analysis demonstrated the robustness of the results. CONCLUSIONS:This MR analysis suggests that PM2.5, rather than PM10, is associated with an increased risk of T2D. The use of air purifiers and anti-smog masks may potentially help reduce the risk of T2D. Further research is needed to elucidate the specific effects and underlying mechanisms of PM2.5 and PM10 on T2D.
10.26355/eurrev_202405_36297
Genetic Evidence for the Causal Link Between Coagulation Factors and the Risk of Ovarian Cancer: A Two-Sample Mendelian Randomization Study.
International journal of women's health
Background:Prior investigations have suggested a significant association between coagulation factors and ovarian cancer; however, the precise nature of the causal relationship remains elusive. Our objective is to thoroughly investigate this causal link and delineate the influence of coagulation factors on the risk of ovarian cancer through a rigorous two-sample Mendelian randomization (MR) analysis. Methods:Genetic instrumental variables representing coagulation factors were sourced from four distinct data repositories. Summary statistics pertaining to ovarian cancer were obtained from two extensive Genome-Wide Association Studies (GWAS) for primary and replication analyses, respectively. The primary Mendelian randomization (MR) analysis utilized the inverse-variance weighted (IVW) method. To fortify the reliability of our findings, additional analyses were conducted, including the weighted-median method, MR-Egger regression, MR pleiotropy residual sum and outlier test, Cochran's Q statistic test, MR-Egger intercept analysis, and leave-one-out method, among others. Results:We identified four coagulation factors that were associated with the risk of ovarian cancer in the primary analysis, [odds ratio (OR): 1.365, 95% confidence interval (CI): 1.209-1.542, P <0.001 for von Willebrand factor measurement(vWF); OR: 1.060, 95% CI: 1.018-1.104, P = 0.005 for A disintegrin and metalloproteinase with thrombospondin motifs 13 (ADATMS13); OR: 1.317, 95% CI: 1.002-1.730, P = 0.048 for activated partial thromboplastin time (aPTT); OR: 1.139, 95% CI: 1.063-1.221, P <0.001 for coagulation Factor VIII (FVIII)]. In the meta-analysis, we found that higher levels of coagulation factor VII measurement(FVII) (OR=1.0007, 95% CI: 1.0001-1.0013, =1.0007) was associated with increased ovarian cancer risk. The results of sensitivity analyses for these coagulation factors were consistent (<0.05). Conclusion:Our systematic analyses have furnished evidence suggesting a plausible causal association between FVII and the susceptibility to ovarian cancer. Further investigations are warranted to delineate the mechanistic pathways through which coagulation factors influence the progression of ovarian cancer.
10.2147/IJWH.S482359
Association of metabolic signatures of air pollution with MASLD: Observational and Mendelian randomization study.
Journal of hepatology
BACKGROUND & AIMS:Air pollution is a significant public health issue and an important risk factor for metabolic dysfunction-associated steatotic liver disease (MASLD), though the underlying mechanisms of this association are unknown. Herein, we aimed to identify metabolic signatures associated with exposure to ambient air pollution and to explore their associations with the risk of MASLD. METHODS:We utilized data from the UK Biobank cohort. Annual mean concentrations of PM, PM, NO and NO were assessed for each participant using bilinear interpolation. The elastic net regression model was used to identify metabolites associated with four air pollutants and to construct metabolic signatures. Associations between air pollutants, metabolic signatures and MASLD were analyzed using Cox models. Mendelian randomization (MR) analysis was used to examine potential causality. Mediation analysis was employed to examine the role of metabolic signatures in the association between air pollutants and MASLD. RESULTS:A total of 244,842 participants from the UK Biobank were included in this analysis. We identified 87, 65, 76, and 71 metabolites as metabolic signatures of PM, PM, NO, and NO, respectively. Metabolic signatures were associated with risk of MASLD, with hazard ratios (HRs) and 95% CIs of 1.10 (1.06-1.14), 1.06 (1.02-1.10), 1.24 (1.20-1.29) and 1.14 (1.10-1.19), respectively. The four pollutants were associated with increased risk of MASLD, with HRs (95% CIs) of 1.03 (1.01-1.05), 1.02 (1.01-1.04), 1.01 (1.01-1.02) and 1.01 (1.00-1.01), respectively. MR analysis indicated an association between PM, NO and NO-related metabolic signatures and MASLD. Metabolic signatures mediated the association of PM, PM, NO and NO with MASLD. CONCLUSION:PM, PM, NO and NO-related metabolic signatures appear to be associated with MASLD. These signatures mediated the increased risk of MASLD associated with PM, PM, NO and NO. IMPACT AND IMPLICATIONS:Air pollution is a significant public health issue and an important risk factor for metabolic dysfunction-associated steatotic liver disease (MASLD), however, the mechanism by which air pollution affects MASLD remains unclear. Our study used integrated serological metabolic data of 251 metabolites from a large-scale cohort study to demonstrate that metabolic signatures play a crucial role in the elevated risk of MASLD caused by air pollution. These results are relevant to patients and policymakers because they suggest that air pollution-related metabolic signatures are not only potentially associated with MASLD but also involved in mediating the process by which PM, PM, NO, and NO increase the risk of MASLD. Focusing on changes in air pollution-related metabolic signatures may offer a new perspective for preventing air pollution-induced MASLD and serve as protective measures to address this emerging public health challenge.
10.1016/j.jhep.2024.09.033
Mitochondrial biological function and risk of atrial fibrillation and atrial flutter: A 2-sample Mendelian randomization study.
Medicine
Current research suggests that mitochondrial dysfunction can be a contributing factor in the development of cardiac arrhythmias. In pursuit of elucidating the causal link between the biological functions of mitochondria and the occurrence of atrial fibrillation/flutter, we conducted a 2-sample Mendelian randomization (MR) study. Mitochondrial proteins were selected for exposure in this study. To enhance the accuracy of our study, we selected data on AF/AFL from the FinnGen study and the UK Biobank for MR analysis, respectively. The inverse variance-weighted method was utilized as the primary analysis technique for MR. In addition, we performed a series of sensitivity analyses to detect heterogeneity and horizontal pleiotropy. MR results indicated a significant positive association between NAD-dependent protein deacylase sirtuin-5 and AF/AFL (odds ratio = 1.084, 95% confidence interval: 1.037-1.133, P = 3.679 × 10-4, Adjusted P = .024), with consistent outcomes observed in replication analysis (odds ratio = 1.002, 95% confidence interval: 1.001-1.003, P = 4.808 × 10-4, Adjusted P = .032). NAD-dependent protein deacylase sirtuin-5 can significantly promote the occurrence of AF/AFL, and its specific mechanisms warrant further investigation.
10.1097/MD.0000000000038631
Antioxidants and the risk of sleep disorders: results from NHANES and two-sample Mendelian randomization study.
Frontiers in nutrition
Background:Sleep disorders have emerged as a major public health concern. Observational research indicates that antioxidants might mitigate the risk of sleep disturbances, yet the causal relationship remains uncertain. Materials and methods:This study utilized data from the National Health and Nutrition Examination Survey (NHANES) spanning 2011 to 2018, focusing on adults who reported sleep disorders. The analysis included 25,178 American adults. We examined the association between the Composite Dietary Antioxidant Index (CDAI) and the prevalence of sleep disorders. Additionally, a two-sample Mendelian randomization analysis was conducted to explore the potential causal link between CDAI and the risk of sleep disorders. Results:Analysis of data from the 2011-2018 NHANES survey revealed a significant negative association between CDAI and sleep disorders (OR = 0.854, 95% CI 0.821-0.888, < 0.001). A multivariable logistic regression model showed that each unit increase in CDAI corresponded to a 14.6% reduction in sleep disorder risk, exhibiting a nonlinear trend where the risk decreased until reaching the inflection point of -0.134. Additionally, MR analysis demonstrated that genetically determined selenium reduces the risk of OSA (OR = 0.992, 95% CI 0.860-0.989, = 0.023). Furthermore, vitamin E (γ-tocopherol) and vitamin C were protective against sleep-wake disorders (OR = 0.016, 95% CI 0.001-0.674, = 0.03) and (OR = 0.049, 95% CI 0.007-0.346, = 0.002), respectively. Conclusion:Dietary antioxidants may help prevent sleep disorders. However, further studies are required to clarify the pathways through which antioxidants exert this protective effect.
10.3389/fnut.2024.1453064
Causal influences of testosterone on brain structure change rate: A sex-stratified Mendelian randomization study.
The Journal of steroid biochemistry and molecular biology
The impact of testosterone levels on changes in brain structure has been reported. However, it is still unclear which specific brain region could be affected. This study approached Mendelian randomization method to reveal the causal relationship between testosterone levels and the rate of longitudinal structural changes in the brain. The testosterone-related GWAS data were determined from 425,097 European participants. The GWAS data on the rate of longitudinal structural changes in the brain came from the ENIGMA consortium, which included 15,640 all-age participants from 40 longitudinal cohorts. The inverse variance weighted was considered as the main estimate, MR Egger and weighted median methods were used to supplement IVW. A positive correlation was found between total testosterone levels and bioavailable testosterone levels in women and age-independent longitudinal changes in cerebral WM and surface area. The sex hormone-binding globulin levels were found a negative correlation with age-dependent longitudinal structural changes of cortical GM in men. Additionally, we also found that the bioavailable testosterone level in males was negatively associated with the quadratic age-dependent longitudinal change rate in the globus pallidum. We also found estradiol levels and sex hormone-binding globulin levels were negatively associated with the quadratic age-dependent longitudinal change rate of total brain in men. Moreover, we found a positive correlation between total testosterone levels and linear age-dependent longitudinal changes in the hippocampus in both males and females. The testosterone levels in different genders may have varying degrees of causal effects on the structural changes of brain regions. These findings provide evidence for the influence of the brain glandular axis on brain structure, particularly during female brain development.
10.1016/j.jsbmb.2024.106629
Epigenetic age acceleration and risk of aortic valve stenosis: a bidirectional Mendelian randomization study.
Clinical epigenetics
BACKGROUND:Aortic valve stenosis (AVS) is the most prevalent cardiac valve lesion in developed countries, and pathogenesis is closely related to aging. DNA methylation-based epigenetic clock is now recognized as highly accurate predictor of the aging process and associated health outcomes. This study aimed to explore the causal relationship between epigenetic clock and AVS by conducting a bidirectional Mendelian randomization (MR) analysis. METHODS:Summary genome-wide association study statistics of epigenetic clocks (HannumAge, HorvathAge, PhenoAge, and GrimAge) and AVS were obtained and assessed for significant instrumental variables from Edinburgh DataShare (n = 34,710) and FinnGen biobank (cases = 9870 and controls = 402,311). The causal association between epigenetic clock and AVS was evaluated using inverse variance weighted (IVW), weighted median (WM), and MR-Egger methods. Multiple analyses (heterogeneity analysis, pleiotropy analysis, and sensitivity analysis) were performed for quality control assessment. RESULTS:The MR analysis showed that the epigenetic age acceleration of HorvathAge and PhenoAge was associated with an increased risk of AVS (HorvathAge: OR = 1.043, P = 0.016 by IVW, OR = 1.058, P = 0.018 by WM; PhenoAge: OR = 1.058, P = 0.005 by IVW, OR = 1.053, P = 0.039 by WM). Quality control assessment proved our findings were reliable and robust. However, there was a lack of evidence supporting a causal link from AVS to epigenetic aging. CONCLUSION:The present MR analysis unveiled a causal association between epigenetic clocks, especially HorvathAge and PhenoAge, with AVS. Further research is required to elucidate the underlying mechanisms and develop strategies for potential interventions.
10.1186/s13148-024-01647-5
Mendelian randomization analysis of psoriasis and psoriatic arthritis associated with risks of ulcerative colitis.
Skin research and technology : official journal of International Society for Bioengineering and the Skin (ISBS) [and] International Society for Digital Imaging of Skin (ISDIS) [and] International Society for Skin Imaging (ISSI)
OBJECTIVE:This study is designed to explore the potential causal relationship between psoriasis and psoriatic arthritis (PsA) while investigating the genetic basis shared by these inflammatory diseases. METHODS:Significant single nucleotide polymorphisms (SNPs) associated with UC, psoriasis, and PsA were selected as genetic instrumental variables using Genome-Wide Association Study (GWAS) datasets. Additionally, Mendelian randomization (MR) methods, including inverse-variance weighting (IVW), MR-Egger regression, and Weighted Median (WME), were utilized to evaluate the causal relationships between these diseases. Moreover, sensitivity analysis and heterogeneity testing were conducted to validate the stability of the results. RESULTS:A total of 123 significant SNPs associated with psoriasis, PsA, and UC were identified as genetic instrumental variables based on GWAS datasets. The analysis revealed a 36% increased risk of UC with psoriasis (odds ratio [OR] = 1.350, 95% confidence interval [CI] = 1.065-1.729, P = 0.012) and a 32.9% increased risk of UC with PsA (OR = 1.329, 95% CI = 1.176-1.592, P < 0.001). Further analysis showed a 43.5% increased risk of psoriasis with UC (OR = 1.435, 95% CI = 1.274-1.831, P < 0.001) and a 45.8% increased risk of PsA with UC (OR = 1.458, 95% CI = 1.166-1.822, P = 0.0013). In addition, sensitivity analysis and heterogeneity testing demonstrated the high stability of these results. Particularly, neither MR-Egger regression analysis nor leave-one-out analysis revealed significant heterogeneity or pleiotropy bias, indicating the reliability of these causal estimates. Moreover, the use of the MR-PRESSO further confirmed the positive correlation between psoriasis and UC, and the corrected estimates remained consistent with IVW analysis results after excluding potential outlier SNPs, enhancing the credibility of the analysis. CONCLUSIONS:This study strengthens the understanding of the genetic and causal relationships among UC, psoriasis, and PsA through GWAS and MR methods, revealing the genetic basis they may share. These findings not only provide a novel perspective on the comorbidity mechanisms of these diseases but also offer a valuable reference for the development of future treatment strategies and intervention measures.
10.1111/srt.13795
Evaluating causal influence of serum uric acid on psoriasis via observational study and transethnic Mendelian randomization analyses.
Scientific reports
Psoriasis mimics uric acid in terms of inflammation, but the association has not been well defined. This study aimed to identify the causal link between serum uric acid (SUA) and psoriasis in an observational study using the National Health and Nutrition Examination Survey (NHANES, 2004-2006, and 2011-2014) and transethnic Mendelian randomization (MR) analyses. We utilized weighted multivariable-adjusted logistic regression and transethnic MR in European and East Asian populations to assess the association. Inverse variance weighted (IVW) was the main analysis. To test the robustness and pleiotropy, further sensitivity analyses were also conducted. Weighted regression analysis suggested that SUA positively related to psoriasis risk (OR = 1.339, 95% CI: 1.092-1.642, P = 0.006) in women. For all participants and males, neither association was significant. IVW showed that SUA levels were not significantly associated with psoriasis in Europeans (OR = 1.099, 95% CI: 0.963-1.254, P = 0.159) or East Asians (OR = 1.297, 95% CI: 0.576-2.918, P = 0.528). Furthermore, sensitivity analyses confirmed the robustness of the present MR results. In females, SUA and psoriasis were significantly correlated; findings from transethnic MR analysis did not indicate a causal relationship between SUA and psoriasis.
10.1038/s41598-024-77222-y
Association of dietary and circulating antioxidant vitamins with metabolic syndrome: an observational and Mendelian randomization study.
Frontiers in endocrinology
Aims:The objective of this study was to investigate the associations of dietary and circulating antioxidant vitamins with metabolic syndrome (MetS), and to assess causality using Mendelian randomization (MR). Methods:This study included 10,308 participants from the National Health and Nutrition Examination Survey. The associations of vitamins A, C, E and carotenoids with MetS were assessed using multivariable weighted logistic regression analysis. Subsequently, the MR approach was employed to test the causal associations, with inverse variance weighted (IVW) serving as the primary analysis. Results:Observationally, dietary vitamin A (OR=0.852, 95%CI: 0.727-0.999), C (OR=0.802, 95%CI: 0.675-0.952), carotene (OR=0.832, 95%CI: 0.706-0.982), and β-carotene (OR=0.838, 95%CI: 0.706-0.995) in quartile 4 had lower incidents of MetS, when compared to quartile 1. Circulating vitamin C and carotene were also present inversely associated with MetS, while the vitamin A and E both increased this risk. IVW-MR confirmed the associations of dietary vitamin A (OR=0.920, 95%CI: 0.861-0.984), vitamin C (OR=0.905, 95%CI: 0.836-0.979) and carotene (OR=0.918, 95%CI: 0.865-0.974) with MetS. However, there was only circulating β-carotene (OR=0.909, 95%CI: 0.857-0.965) was found to be causally associated with MetS. Conclusions:Observational and MR studies have shown that adequate dietary intake of vitamin A, C and carotenoids may help to reduce the risk of MetS.
10.3389/fendo.2024.1446719
Causal effects of sepsis on structural changes in cerebral cortex: A Mendelian randomization investigation.
Medicine
Previous research has shown a strong correlation between sepsis and brain structure. However, whether this relationship represents a causality remains elusive. In this study, we employed Mendelian randomization (MR) to probe the associations of genetically predicted sepsis and sepsis-related death with structural changes in specific brain regions. Genome-wide association study (GWAS) data for sepsis phenotypes (sepsis and sepsis-related death) were obtained from the IEU OpenGWAS. Correspondingly, GWAS data for brain structural traits (volume of the subcortical structure, cortical thickness, and surface area) were derived from the ENIGMA consortium. Inverse variance weighted was mainly utilized to assess the causal effects, while weighted median and MR-Egger regression served as complementary methods. Sensitivity analyses were implemented with Cochran Q test, MR-Egger regression, and MR-PRESSO. In addition, a reverse MR analysis was carried out to assess the possibility of reverse causation. We identified that genetic liability to sepsis was normally significantly associated with a reduced surface area of the postcentral gyrus (β = -35.5280, SE = 13.7465, P = .0096). The genetic liability to sepsis-related death showed a suggestive positive correlation with the surface area of fusiform gyrus (β = 11.0920, SE = 3.6412, P = .0023) and posterior cingulate gyrus (β = 3.6530, SE = 1.6684, P = .0286), While it presented a suggestive negative correlation with surface area of the caudal middle frontal gyrus (β = -11.4586, SE = 5.1501, P = .0261) and frontal pole (β = -1.0024, SE = 0.4329, P = .0206). We also indicated a possible bidirectional causal association between genetic liability to sepsis-related death and the thickness of the transverse temporal gyrus. Sensitivity analyses verified the robustness of the above associations. These findings suggested that genetically determined liability to sepsis might influence the specific brain structure in a causal way, offering new perspectives to investigate the mechanism of sepsis-related neuropsychiatric disorders.
10.1097/MD.0000000000039404
Mendelian randomization study highlights hypothyroidism as a causal determinant of alopecia areata.
Frontiers in endocrinology
Background:Although observational studies have found an association between hypothyroidism and alopecia areata, the causality of this relationship remains unclear. Objectives:This study aimed to investigate the genetic variants associated with hypothyroidism and their potential impact on the risk of developing alopecia areata. Methods:genome-wide association study summary statistics for hypothyroidism (30,155 cases and 379,986 controls) and alopecia areata (289 cases and 211,139 controls) were obtained from the IEU OpenGwas project. The inverse variance-weighted method was used as the primary analysis method to evaluate the causality between hypothyroidism and alopecia areata, supplemented by the weighted median, MR-Egger, simple mode and weighted mode. Furthermore, the function of causal SNPs was evaluated by gene ontology (GO) analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis, and protein-protein interaction networks. Result:Utilizing two-sample Mendelian randomization analysis, we found that the single-nucleotide polymorphisms (SNPs) of hypothyroidism (OR = 1.40, 95% CI: 1.12-1.75, = 3.03×10) significantly increased the risk of alopecia areata ( 289 cases and 211,139 controls ). KEGG pathway analysis showed that the candidate genes were mainly enriched in virion-herpesvirus, Th1 and Th2 cell differentiation, Th17 cell differentiation, T-cell receptor signaling pathway, PD-L1/PD-1 checkpoint pathway in cancer and Toll-like receptor signaling pathway. Protein-protein interaction networks results showed that CTLA4, STAT4, IL2RA, TYK2, IRF7, SH2B3, BACH2, TLR3, NOD2, and FLT3. Conclusion:This study provided compelling genetic evidence supporting a causative association between hypothyroidism and alopecia areata, which could potentially inform the development of more efficacious treatment strategies for patients afflicted by alopecia areata.
10.3389/fendo.2023.1309620
A Mendelian randomization study of the entire phenome to explore the causal links between epilepsy.
Brain and behavior
OBJECTIVE:The causes and triggering factors of epilepsy are still unknown. The results of genome-wide association studies can be utilized for a phenome-wide association study using Mendelian randomization (MR) to identify potential risk factors for epilepsy. METHODS:This study utilizes two-sample MR analysis to investigate whether 316 phenotypes, including lifestyle, environmental factors, blood biomarker, and more, are causally associated with the occurrence of epilepsy. The primary analysis employed the inverse variance weighted (IVW) model, while complementary MR analysis methods (MR Egger, Wald ratio) were also employed. Sensitivity analyses were also conducted to evaluate heterogeneity and pleiotropy. RESULTS:There was no evidence of a statistically significant causal association between the examined phenotypes and epilepsy following Bonferroni correction (p < 1.58 × 10) or false discovery rate correction. The results of the MR analysis indicate that the frequency of tiredness or lethargy in the last 2 weeks (p = 0.042), blood uridine (p = 0.003), blood propionylcarnitine (p = 0.041), and free cholesterol (p = 0.044) are suggestive causal risks for epilepsy. Lifestyle choices, such as sleep duration and alcohol consumption, as well as biomarkers including steroid hormone levels, hippocampal volume, and amygdala volume were not identified as causal factors for developing epilepsy (p > 0.05). CONCLUSIONS:Our study provides additional insights into the underlying causes of epilepsy, which will serve as evidence for the prevention and control of epilepsy. The associations observed in epidemiological studies may be partially attributed to shared biological factors or lifestyle confounders.
10.1002/brb3.3602
Associations of 50 modifiable risk factors with atrial fibrillation using Mendelian randomization analysis.
European journal of clinical investigation
BACKGROUND:Substantial focus has been placed on atrial fibrillation (AF) treatment and associated stroke prevention rather than preventing AF itself. We employed Mendelian randomization (MR) approach to examine the causal relationships between 50 modifiable risk factors (RFs) and AF. METHODS:Instrumental variables for genetically predicted exposures were derived from corresponding genome-wide association studies (GWASs). Summary-level statistical data for AF were obtained from a GWAS meta-analysis (discovery dataset, N = 1,030,836) and FinnGen (validation dataset, N = 208,594). Univariable and multivariable MR analyses were performed, primarily using inverse variance weighted method with a series of robust sensitivity analyses. RESULTS:Genetic predisposition to insomnia, daytime naps, apnea, smoking initiation, moderate to vigorous physical activity and obesity traits, including body mass index, waist-hip ratio, central and peripheral fat/fat-free mass, exhibited significant associations with an increased risk of AF. Coffee consumption and ApoB had suggestive increased risks. Hypertension (odds ratio (OR) 95% confidence interval (CI): 5.26 (4.42, 6.24)), heart failure (HF) (OR 95% CI, 4.77 (2.43, 9.37)) and coronary artery disease (CAD) (OR 95% CI: 1.20 (1.16, 1.24)) were strongly associated with AF, while college degree, higher education attachment and HDL levels were associated with a decreased AF risk. Reverse MR found a bidirectional relationship between genetically predicted AF and CAD, HF and ischemic stroke. Multivariable analysis further indicated that obesity-related traits, systolic blood pressure and lower HDL levels independently contributed to the development of AF. CONCLUSIONS:This study identified several lifestyles and cardiometabolic factors that might be causally related to AF, underscoring the importance of a holistic approach to AF management and prevention.
10.1111/eci.14194
Causal Associations of DNA Methylation and Cardiovascular Disease: A Two-Sample Mendelian Randomization Study.
Global heart
Background:There is growing evidence that concentrations of DNA methylation are associated with cardiovascular disease; however, it is unclear whether this association reflects a causal relationship. Methods:We utilized a two-sample Mendelian randomization (MR) approach to investigate whether DNA methylation can affect the risk of developing cardiovascular disease in human life. We primarily performed the inverse variance weighted (IVW) method to analyze the causal effect of DNA methylation on multiple cardiovascular diseases. Additionally, to ensure the robustness of our findings, we conducted several sensitivity analyses using alternative methodologies. These analysis methods included maximum likelihood, MR-Egger regression, weighted median method, and weighted model methods. Results:Inverse variance weighted estimates suggested that an SD increase in DNA methylation Hannum age acceleration exposure increased the risk of cardiac arrhythmias (OR = 1.03, 95% CI 1.00-1.05, = 0.0290) and atrial fibrillation (OR = 1.03, 95% CI 1.00-1.05, = 0.0022). We also found that an SD increase in DNA methylation PhenoAge acceleration exposure increased the risk of heart failure (OR = 1.01, 95% CI 1.00-1.03, = 0.0362). Exposure to DNA methylation-estimated granulocyte proportions was found to increase the risk of hypertension (OR = 1.00, 95% CI 1.00-1.0001, p = 0.0291). Exposure to DNA methylation-estimated plasminogen activator inhibitor-1 levels was found to increase the risk of heart failure (OR = 1.00, 95% CI 1.00-1.00, = 0.0215). Conclusion:This study reveals a causal relationship between DNA methylation and CVD. Exposed to high levels of DNA methylation Hannum age acceleration inhabitants with an increased risk of cardiac arrhythmias and atrial fibrillation. DNA methylation PhenoAge acceleration levels exposure levels were positively associated with the increased risk of developing heart failure. This has important implications for the prevention of cardiovascular diseases.
10.5334/gh.1324
Exploring the role of mitochondrial proteins SIRT5 and MRPL33 through Mendelian randomization in primary biliary cholangitis.
Clinics and research in hepatology and gastroenterology
BACKGROUND:Primary biliary cholangitis (PBC) is an autoimmune liver disease characterized by elevated serum antimitochondrial antibody levels in 90-95 % of cases. However, the exact causal relationship between mitochondrial proteins and PBC remains unclear. This study aims to investigate and clarify this relationship. METHODS:Genome-wide association data for mitochondrial proteins and PBC were obtained from public databases. The assessment of causal relationships between exposures and outcomes employed the Inverse Variance Weighted (IVW) method, MR Egger regression, and Weighted Median. Sensitivity analyses were systematically carried out to appraise the robustness of the Mendelian Randomization (MR) findings. RESULTS:The analysis revealed two mitochondrial proteins exhibiting a causal relationship with PBC. Elevated SIRT5 levels demonstrated a positive correlation with an augmented susceptibility to PBC in the IVW approach (odds ratio, OR: 1.2907, 95 % CI: 1.062-1.568, p = 0.0102). Conversely, increased MRPL33 levels were associated with a decreased risk of PBC (OR: 0.8957, 95 % CI: 0.807-0.993, p = 0.0376). Sensitivity analysis corroborated these findings consistently. CONCLUSION:This investigation advances the notion of a potential causal association between elevated SIRT5 levels and an increased risk of PBC, alongside a decreased risk of PBC linked to elevated MRPL33 levels. The identified mitochondrial proteins may serve as viable biomarkers, offering pertinent insights for the understanding and addressing of PBC.
10.1016/j.clinre.2024.102394
Identification of Potential Causal Genes for Neurodegenerative Diseases by Mitochondria-Related Genome-Wide Mendelian Randomization.
Molecular neurobiology
Current research lacks comprehensive investigations into the potential causal link between mitochondrial-related genes and the risk of neurodegenerative diseases (NDDs). We aimed to identify potential causative genes for five NDDs through an examination of mitochondrial-related gene expression levels. Through the integration of summary statistics from expression quantitative trait loci (eQTL) datasets (human blood and brain tissue), mitochondrial DNA copy number (mtDNA-CN), and genome-wide association studies (GWAS) datasets of five NDDs from European ancestry, we conducted a Mendelian randomization (MR) analysis to explore the potential causal relationship between mitochondrial-related genes and Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and Lewy body dementia (LBD). Sensitivity analysis and Bayesian colocalization were employed to validate this causal relationship. Through MR analysis, we have identified potential causal relationships between 12 mitochondria-related genes and AD, PD, ALS, and FTD overlapping with motor neuron disease (FTD_MND) in human blood or brain tissue. Bayesian colocalization analysis further confirms 9 causal genes, including NDUFS2, EARS2, and MRPL41 for AD; NDUFAF2, MALSU1, and METTL8 for PD; MYO19 and MRM1 for ALS; and FASTKD1 for FTD_MND. Importantly, in both human blood and brain tissue, NDUFS2 exhibits a significant pathogenic effect on AD, while NDUFAF2 demonstrates a robust protective effect on PD. Additionally, the mtDNA-CN plays a protected role in LBD (OR = 0.62, p = 0.031). This study presents evidence establishing a causal relationship between mitochondrial dysfunction and NDDs. Furthermore, the identified candidate genes may serve as potential targets for drug development aimed at preventing NDDs.
10.1007/s12035-024-04528-3
Sex hormones and risk of lung and colorectal cancers in women: a Mendelian randomization study.
Research square
The roles of sex hormones such as estradiol, testosterone, and sex hormone-binding globulin (SHBG) in the etiology of lung and colorectal cancers in women, among the most common cancers after breast cancer, are unclear. This Mendelian randomization (MR) study evaluated such potential causal associations in women of European ancestry. We used summary statistics data from genome-wide association studies (GWASs) on sex hormones and from the Trøndelag Health (HUNT) Study and large consortia on cancers. There was suggestive evidence of genetically predicted 1-standard deviation increase in total testosterone levels being associated with a lower risk of lung non-adenocarcinoma (hazard ratio (HR) 0.60, 95% CI 0.37-0.98) in the HUNT Study. However, this was not confirmed by using data from a larger consortium. In general, we did not find convincing evidence to support a causal role of sex hormones on risk of lung and colorectal cancers in women of European ancestry.
10.21203/rs.3.rs-4083598/v1
Exploring causal associations of antioxidants from supplements and diet with attention deficit/hyperactivity disorder in European populations: a Mendelian randomization analysis.
Frontiers in nutrition
Background:Antioxidants from both supplements and diet have been suggested to potentially reduce oxidative stress in individuals with ADHD. However, there is a lack of studies utilizing the Mendelian randomization (MR) method to explore the relationship between dietary and supplemental antioxidants with ADHD. Methods:This study employed two-sample mendelian randomization. Various specific antioxidant dietary supplements (such as coffee, green tea, herbal tea, standard tea, and red wine intake per week), along with diet-derived circulating antioxidants including Vitamin C (ascorbate), Vitamin E (-tocopherol), Vitamin E (-tocopherol), carotene, Vitamin A (retinol), zinc, and selenium ( = 2,603-428,860), were linked to independent single nucleotide polymorphisms (SNPs). Data on ADHD was gathered from six sources, comprising 246,888 participants. The primary analytical method utilized was inverse variance weighting (IVW), with sensitivity analysis conducted to assess the robustness of the main findings. Results:In different diagnostic periods for ADHD, we found that only green tea intake among the antioxidants was significantly associated with a reduced risk of ADHD in males (OR: 0.977, CI: 0.963-0.990, < 0.001, FDR = 0.065), with no evidence of pleiotropy or heterogeneity observed in the results. Additionally, a nominal causal association was found between green tea intake and childhood ADHD (OR: 0.989, 95% CI: 0.979-0.998, = 0.023, FDR = 0.843). No causal relationships were detected between the intake of other antioxidant-rich diets and ADHD. Conclusion:Our study found a significant inverse association between green tea intake and male ADHD, suggesting that higher green tea consumption may reduce ADHD risk in males. Further research is needed to explore optimal doses and underlying mechanisms.
10.3389/fnut.2024.1415793
Causal relationship between the gut microbiome and basal cell carcinoma, melanoma skin cancer, ease of skin tanning: evidence from three two-sample mendelian randomisation studies.
Frontiers in immunology
Objectives:The present study used publicly available genome-wide association study (GWAS) summary data to perform three two-sample Mendelian randomization (MR) studies, aiming to examine the causal links between gut microbiome and BCC, melanoma skin cancer, ease of skin tanning. Methods:SNPs associated with exposures to basal cell carcinoma, melanoma skin cancer and ease of skin tanning from the genome-wide association study data of UK Biobank and MRC-IEU (MRC Integrative Epidemiology Unit), and the meta-analysis data from Biobank and MRC-IEU were used as instrumental variables (IVs). The casual estimates were assessed with a two-sample Mendelian randomisation test using the inverse-variance-weighted (IVW) method, Wald ratio, MR-Egger method, maximum likelihood, weighted median, simple mode, and weighted mode. Results:After the application of MR analysis, diffirent effects of multiple groups of gut microbiota was observed for BCC, melanoma skin cancer and ease of skin tanning. The relationships between the gut microbiome and BCC, melanoma skin cancer, ease of skin tanning were supported by a suite of sensitivity analyses, with no statistical evidence of instrument heterogeneity or horizontal pleiotropy. Further investigation is required to explore the relationship between between the gut microbiome and BCC, melanoma skin cancer, ease of skin tanning. Conclusion:Our study initially identified potential causal roles between the gut microbiome and BCC, melanoma skin cancer, ease of skin tanning, and highlighted the role of gut microbiome in the progression of basal cell carcinoma, melanoma skin cancer, ease of skin tanning.
10.3389/fimmu.2024.1279680
Causal Roles of Lifestyle, Psychosocial Characteristics, and Sleep Status in Sarcopenia: A Mendelian Randomization Study.
The journals of gerontology. Series A, Biological sciences and medical sciences
BACKGROUND:Many studies reported that lifestyle, psychosocial characteristics, and sleep status related to sarcopenia, although few studies provided evidence of causal relationships between them. METHODS:The data used in our study were from UK Biobank, FinnGen Release 8, and large genome-wide association study meta-analyses. Two-sample Mendelian randomization was conducted to identify the causal associations of 21 traits of lifestyle, psychosocial characteristics, and sleep status with 6 traits of sarcopenia. Benjamini-Hochberg correction was performed to reduce the bias caused by multiple tests. Risk factor analyses were performed to explore the potential mechanism behind the exposures. RESULTS:Mendelian randomization analyses after adjustment proved the causal roles of coffee intake, education years, smoking, leisure screen time, and moderate-to-vigorous intensity physical activity during leisure time in sarcopenia was proven although providing no significant evidence for causal roles for carbohydrates intake, protein intake, alcohol, and sleep status in sarcopenia. CONCLUSIONS:Our results strongly support that coffee intake, education years, smoking, leisure screen time, and moderate-to-vigorous intensity physical activity during leisure time played significantly causal roles in sarcopenia, which may provide new intervention strategies for preventing the development of sarcopenia.
10.1093/gerona/glad191
The role of mitochondrial DNA copy number in cardiometabolic disease: a bidirectional two-sample mendelian randomization study.
Cardiovascular diabetology
BACKGROUND:This study used a bidirectional 2-sample Mendelian randomization study to investigate the potential causal links between mtDNA copy number and cardiometabolic disease (obesity, hypertension, hyperlipidaemia, type 2 diabetes [T2DM], coronary artery disease [CAD], stroke, ischemic stroke, and heart failure). METHODS:Genetic associations with mtDNA copy number were obtained from a genome-wide association study (GWAS) summary statistics from the UK biobank (n = 395,718) and cardio-metabolic disease were from largest available GWAS summary statistics. Inverse variance weighting (IVW) was conducted, with weighted median, MR-Egger, and MR-PRESSO as sensitivity analyses. We repeated this in the opposite direction using instruments for cardio-metabolic disease. RESULTS:Genetically predicted mtDNA copy number was not associated with risk of obesity (P = 0.148), hypertension (P = 0.515), dyslipidemia (P = 0.684), T2DM (P = 0.631), CAD (P = 0.199), stroke (P = 0.314), ischemic stroke (P = 0.633), and heart failure (P = 0.708). Regarding the reverse directions, we only found that genetically predicted dyslipidemia was associated with decreased levels of mtDNA copy number in the IVW analysis (β= - 0.060, 95% CI - 0.044 to - 0.076; P = 2.416e-14) and there was suggestive of evidence for a potential causal association between CAD and mtDNA copy number (β= - 0.021, 95% CI - 0.003 to - 0.039; P = 0.025). Sensitivity and replication analyses showed the stable findings. CONCLUSIONS:Findings of this Mendelian randomization study did not support a causal effect of mtDNA copy number in the development of cardiometabolic disease, but found dyslipidemia and CAD can lead to reduced mtDNA copy number. These findings have implications for mtDNA copy number as a biomarker of dyslipidemia and CAD in clinical practice.
10.1186/s12933-023-02074-1
The impact of serum uric acid on psoriasis: NHANES 2005-2014 and Mendelian randomization.
Frontiers in genetics
Background:Psoriasis is a chronic systemic inflammatory disease, and hyperuricemia is a common comorbidity in patients with psoriasis. However, the exact relationship between uric acid levels and psoriasis remains unclear. This study aimed to explore the association between uric acid levels and psoriasis. Methods:Observational study participant data (≥16 years, n = 23,489) from NHANES 2003-2014. We conducted analyses using a weighted multiple logistic regression model. Genetic data sets for uric acid levels and psoriasis were obtained from the IEU database. We selected genetically independent loci closely associated with serum uric acid levels as instrumental variables and performed Mendelian randomization analyses using five complementary methods: inverse variance weighting (IVW), MR-Egger, weighted median, simple mode, and weighted mode. Results:After adjusting for other covariates, the results revealed no significant association between serum uric acid levels and psoriasis (b = 0.999, 95% CI: 0.998, 1.001, = 0.275). Subgroup analyses stratified by gender and ethnicity showed no significant association between sUA and psoriasis in any of the subgroups. Furthermore, the MR analysis involved the selection of 227 SNPs that were associated with both sUA and psoriasis. IVW results demonstrated no causal relationship between sUA and psoriasis (OR = 0.282, 95% CI: -0.094-0.657, = 0.142). Conclusion:Our study suggests that uric acid levels are not significantly causally related to psoriasis. This finding provides valuable insights for the treatment and prevention of psoriasis, indicating that merely reducing uric acid levels may not be an effective strategy to reduce the risk of psoriasis onset.
10.3389/fgene.2024.1334781
Causal effect of psoriasis on aortic valve stenosis: a two-sample Mendelian randomization study.
Journal of geriatric cardiology : JGC
Background:Epidemiological studies have suggested a potential connection between psoriasis and an increased risk of aortic valve stenosis (AS), though the impact of psoriasis on AS progression remains uncertain. The study aims to investigate the causal relationship between psoriasis and AS using Mendelian randomization (MR) analysis, as well as to uncover potential mechanisms underlying this association. Methods:A two-sample MR analysis was conducted using publicly available summary statistics from genome-wide association studies (GWAS) of psoriasis and AS. Cis-eQTL and significant genes were identified for each causal single-nucleotide polymorphisms (SNPs), followed by pathway enrichment and protein-protein interaction (PPI) analysis for functional evaluation. Hub genes were pinpointed by Cytospace. The transcriptional profile of AS population was acquired, and interconnected genes networks were clustered using Molecular Complex Detection (MCODE). Results:Our results demonstrate a significant causal relationship between psoriasis and AS, with a genetic predisposition to psoriasis associated with a higher AS risk (odds ratio: 1.46). Pathway and PPI analyses unveiled 15 hub genes, including HLA-C, HLA-B, ISG15, IFIT3, and MX2, along with immune-related pathways linking psoriasis and AS. Moreover, the transcriptional profiling of the AS database highlighted the significant involvement of adaptive immune cells in AS development. Notably, among the 15 hub genes, ISG15, MX2, OAS3, OASL, IFI6, and EPSTI1 exhibited higher expression in the AS population. Conclusion:Our study provides compelling evidence supporting a causal relationship between psoriasis and AS. Furthermore, the identified hub genes and immune-related pathways may play an important role in the development of both diseases.
10.26599/1671-5411.2024.09.002
Sodium-glucose cotransporter 1/2 inhibition and risk of neurodegenerative disorders: A Mendelian randomization study.
Brain and behavior
INTRODUCTION:This study aims to evaluate the effects of sodium-glucose cotransporter 1 inhibitors (SGLT1i) and sodium-glucose cotransporter 2 inhibitors (SGLT2i) on neurodegenerative disorders and to investigate the role of hemoglobin A1c (HbA1c) levels. METHODS:Utilizing drug target Mendelian randomization, we employed single nucleotide polymorphisms (SNPs) proximal to the SLC5A1 and SLC5A2 genes to analyze the influence of SGLT1i and SGLT2i on Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), frontotemporal dementia (FTD), Lewy body dementia (LBD), and amyotrophic lateral sclerosis (ALS), with type 2 diabetes (T2D) as a positive control. An additional analysis examined the impact of HbA1c levels on the same disorders. RESULTS:SGLT1i exhibited a significant association with decreased risk for ALS and MS. Conversely, SGLT2i were linked to an increased risk of AD, PD, and MS. Elevated HbA1c levels, independent of SGLT1 and SGLT2 effects, were associated with an increased risk of PD. Sensitivity analyses supported the robustness of these findings. CONCLUSION:Our study suggests that SGLT1i may confer protection against ALS and MS, whereas SGLT2i could elevate the risk of AD, PD, and MS. Additionally, elevated HbA1c levels emerged as a risk factor for PD. These findings underscore the importance of personalized approaches in the utilization of SGLT inhibitors, considering their varying impacts on the risks of neurodegenerative diseases.
10.1002/brb3.3624
Causal Effect of Selenium Levels on Osteoporosis: A Mendelian Randomization Study.
Nutrients
Prior research has demonstrated equivocal associations between selenium (Se) concentrations and osteoporosis (OP), yielding inconclusive findings. The purpose of the current study was to examine the potential correlation between Se levels and the risk of OP by using the Mendelian randomization (MR) study design. The genetic variants related to Se levels were obtained from a meta-analysis of a Genome-Wide Association Study (GWAS) conducted on toenail Se levels ( = 4162) and blood Se levels ( = 5477). The data summary for OP and bone mineral density (BMD) was obtained by utilizing the GWAS database. To examine the association between Se levels and BMD and OP, we employed three statistical methods: inverse variance weighted, weighted median, and MR-Egger. The reliability of the analysis was verified by sensitivity testing. All three methods of MR analysis revealed that Se levels had no effect on OP risk. In addition, the sensitivity analysis revealed no heterogeneity or pleiotropy, and the significance of the overall effect remained unaffected by single-nucleotide polymorphisms (SNPs), as determined by the leave-one-out analysis, indicating that our findings are relatively reliable. The results of our study indicate that there is no causal association between Se levels and the risk of OP. However, additional investigation is necessary to ascertain whether there is a potential association between these variables.
10.3390/nu15245065
Mendelian Randomization Analysis of Systemic Iron Status and Risk of Different Types of Kidney Disease.
Nutrients
With rapid increases in incidence, diverse subtypes, and complicated etiologies, kidney disease remains a global public health problem. Iron, as an essential trace element, has pleiotropic effects on renal function and the progression of kidney diseases. A two-sample Mendelian randomization (MR) analysis was implemented to determine the potential causal effects between systemic iron status on different kidney diseases. Systemic iron status was represented by four iron-related biomarkers: serum iron, ferritin, transferrin saturation (TfSat), and total iron binding capacity (TIBC). For systemic iron status, 163,511, 246,139, 131,471, and 135,430 individuals were included in the genome-wide association study (GWAS) of serum iron, ferritin, TfSat, and TIBC, respectively. For kidney diseases, 653,143 individuals (15,658 cases and 637,485 controls), 657,076 individuals (8160 cases and 648,916 controls), and 659,320 individuals (10,404 cases and 648,916 controls) were included for immunoglobulin A nephropathy (IgAN), acute kidney disease (AKD), and chronic kidney disease (CKD), respectively. Our MR results showed that increased serum iron [odds ratio (OR): 1.10; 95% confidence interval (95% CI): 1.04, 1.16; < 0.0042], ferritin (OR: 1.30; 95% CI: 1.14, 1.48; < 0.0042), and TfSat (OR: 1.07; 95% CI: 1.04, 1.11; < 0.0042)] and decreased TIBC (OR: 0.92; 95% CI: 0.88, 0.97; < 0.0042) were associated with elevated IgAN risk. However, no significant associations were found between systemic iron status and AKD or CKD. In our MR study, the genetic evidence supports elevated systemic iron status as a causal effect on IgAN, which suggests a potential protective effect of iron chelation on IgAN patients.
10.3390/nu16131978
Roles of negative emotions and personality traits in psoriasis vulgaris: A mendelian randomization study.
Skin research and technology : official journal of International Society for Bioengineering and the Skin (ISBS) [and] International Society for Digital Imaging of Skin (ISDIS) [and] International Society for Skin Imaging (ISSI)
BACKGROUND:Many studies have indicated that negative emotions and personality traits are related to psoriasis, though few have provided causal evidence. METHODS:Our analysis utilized 15 genome-wide association study datasets to identify instrumental variables associated with negative emotions, personality traits and psoriasis vulgaris. Two-sample Mendelian randomization was conducted to identify the causal associations of negative emotions and personality traits with psoriasis vulgaris. To mitigate bias from multiple tests, we adjusted p-values using the Benjamini-Hochberg method. RESULTS:Our study revealed causal links between negative emotions and psoriasis vulgaris, including depressed affect, worry too long, feeling hurt, guilty feelings, mood swings, unenthusiasm, miserableness, fed-up feelings. However, there was no significant evidence of a causal relationship between feeling lonely and psoriasis vulgaris. Additionally, personality traits including neuroticism and openness to experience were found to have causal effects on psoriasis vulgaris. However, no significant evidence supported a causal relationship between agreeableness, conscientiousness, and extraversion with psoriasis vulgaris. CONCLUSION:Our findings suggest that experiencing negative emotions including depressed affect, worrying excessively, feeling hurt, guilty feelings, mood swings, lack of enthusiasm, miserableness and fed-up feelings may pose risks for psoriasis vulgaris. Additionally, neuroticism is associated with a risk of psoriasis vulgaris. Conversely, the openness trait may serve a protective role against psoriasis vulgaris.
10.1111/srt.13702
DMRdb: a disease-centric Mendelian randomization database for systematically assessing causal relationships of diseases with genes, proteins, CpG sites, metabolites and other diseases.
Nucleic acids research
Exploring the causal relationships of diseases with genes, proteins, CpG sites, metabolites and other diseases is fundamental to the life sciences. However, large-scale research using Mendelian randomization (MR) analysis is currently lacking. To address this, we introduce DMRdb (http://www.inbirg.com/DMRdb/), a disease-centric Mendelian randomization database, designed to systematically assess causal relationships of diseases with genes, proteins, CpG sites, metabolites and other diseases. The database consists of three main components: (i) 6640 high-quality disease genome-wide association studies (GWASs) from public sources that were subjected to rigorous quality filtering and standardization; (ii) over 497 billion results from MR analyses involving 6640 disease GWAS datasets, 16 238 expression quantitative trait loci (eQTLs) data, 2564 protein quantitative trait loci (pQTLs) data, 12 000 methylation quantitative trait locus (meQTLs) data and 825 metabolites data and (iii) over 380 000 causal relationship pairs from 1223 literature sources relevant to MR analyses. A user-friendly online database was developed to allow users to query, search, and download all the results. In summary, we anticipate that DMRdb will be a valuable resource for advancing our understanding of disease mechanisms and identifying new biomarkers and therapeutic targets.
10.1093/nar/gkae853
Two-sample Mendelian randomization analysis of causal relationship between eczema and autoimmune diseases.
Zhong nan da xue xue bao. Yi xue ban = Journal of Central South University. Medical sciences
OBJECTIVES:The causal relationship between eczema and autoimmune diseases has not been previously reported. This study aims to evaluate the causal relationship between eczema and autoimmune diseases. METHODS:The two-sample Mendelian randomization (MR) method was used to assess the causal effect of eczema on autoimmune diseases. Summary data from the Genome-Wide Association Study Catalog (GWAS) were obtained from the Integrative Epidemiology Unit (IEU) database. For eczema and autoimmune diseases, genetic instrument variants (GIVs) were identified according to the significant difference (<5×10). Causal effect estimates were generated using the inverse-variance weighted (IVW) method. MR Egger, maximum likelihood, MR-PRESSO, and MR-RAPS methods were used for alternative analyses. Sensitivity tests, including heterogeneity, horizontal pleiotropy, and leave-one-out analyses, were performed. Finally, reverse causality was assessed. RESULTS:Genetic susceptibility to eczema was associated with an increased risk of Crohn's disease (=1.444, 95% 1.199 to 1.738, <0.001) and ulcerative colitis (=1.002, 95% 1.001 to 1.003, =0.002). However, no causal relationship was found for the other 6 autoimmune diseases, including systemic lupus erythematosus (SLE) (=0.932, =0.401), bullous pemphigoid (BP) (=1.191, =0.642), vitiligo (=1.000, =0.327), multiple sclerosis (MS) (=1.000, =0.965), ankylosing spondylitis (AS) (=1.001, =0.121), rheumatoid arthritis (RA) (=1.000, =0.460). Additionally, no reverse causal relationship was found between autoimmune diseases and eczema. CONCLUSIONS:Eczema is associated with an increased risk of Crohn's disease and ulcerative colitis. No causal relationship is found between eczema and SLE, MS, AS, RA, BP, or vitiligo.
10.11817/j.issn.1672-7347.2024.240103
Mediators of the association between educational attainment and carpal tunnel syndrome: A 2-sample, 2-step Mendelian randomization study.
Medicine
To clarify the causal relationship and potential mediators between educational attainment and carpal tunnel syndrome (CTS), as well as to evaluate whether educational attainment, cognition, and intelligence independently exert causal effects on CTS, we employed univariable Mendelian randomization (MR), multivariable MR, reverse MR, and 2-step MR approaches. Our research demonstrates that educational attainment exerts an independent causal effect on CTS, with this causal relationship being unidirectional. Five mediators were identified as significant influencers within the causal pathways connecting educational attainment and CTS. Targeting these mediators may be beneficial in the prevention of CTS.
10.1097/MD.0000000000040302
Alcohol intake and endogenous sex hormones in women: Meta-analysis of cohort studies and Mendelian randomization.
Cancer
BACKGROUND:The mechanisms underlying alcohol-induced breast carcinogenesis are not fully understood but may involve hormonal changes. METHODS:Cross-sectional associations were investigated between self-reported alcohol intake and serum or plasma concentrations of estradiol, estrone, progesterone (in premenopausal women only), testosterone, androstenedione, dehydroepiandrosterone sulfate, and sex hormone binding globulin (SHBG) in 45 431 premenopausal and 173 476 postmenopausal women. Multivariable linear regression was performed separately for UK Biobank, European Prospective Investigation into Cancer and Nutrition, and Endogenous Hormones and Breast Cancer Collaborative Group, and meta-analyzed the results. For testosterone and SHBG, we also conducted Mendelian randomization and colocalization using the ADH1B (alcohol dehydrogenase 1B) variant (rs1229984). RESULTS:Alcohol intake was positively, though weakly, associated with all hormones (except progesterone in premenopausal women), with increments in concentrations per 10 g/day increment in alcohol intake ranging from 1.7% for luteal estradiol to 6.6% for postmenopausal dehydroepiandrosterone sulfate. There was an inverse association of alcohol with SHBG in postmenopausal women but a small positive association in premenopausal women. Two-sample randomization identified positive associations of alcohol intake with total testosterone (difference per 10 g/day increment: 4.1%; 95% CI, 0.6-7.6) and free testosterone (7.8%; 4.1-11.5), and an inverse association with SHBG (-8.1%; -11.3% to -4.9%). Colocalization suggested a shared causal locus at ADH1B between alcohol intake and higher free testosterone and lower SHBG (posterior probability for H4, 0.81 and 0.97, respectively). CONCLUSIONS:Alcohol intake was associated with small increases in sex hormone concentrations, including bioavailable fractions, which may contribute to its effect on breast cancer risk.
10.1002/cncr.35391
Prediagnostic Amino Acid Metabolites and Risk of Gout, Accounting for Serum Urate: Prospective Cohort Study and Mendelian Randomization.
Arthritis care & research
OBJECTIVE:Our objective was to prospectively investigate prediagnostic population-based metabolome for risk of hospitalized gout (ie, most accurate, severe, and costly cases), accounting for serum urate. METHODS:We conducted prediagnostic metabolome-wide analyses among 249,677 UK Biobank participants with nuclear magnetic resonance metabolomic profiling (N = 168 metabolites, including eight amino acids) from baseline blood samples (2006-2010) without a history of gout. We calculated multivariable hazard ratios (HRs) for hospitalized incident gout, before and after adjusting for serum urate levels; we included patients with nonhospitalized incident gout in a sensitivity analysis. Potential causal effects were evaluated with two-sample Mendelian randomization. RESULTS:Correcting for multiple testing, 107 metabolites were associated with incidence of hospitalized gout (n = 2,735) before urate adjustment, including glycine and glutamine (glutamine HR 0.64, 95% confidence interval [CI] 0.54-0.75, P = 8.3 × 10; glycine HR 0.69, 95% CI 0.61-0.78, P = 3.3 × 10 between extreme quintiles), and glycoprotein acetyls (HR 2.48, 95% CI 2.15-2.87, P = 1.96 × 10). Associations remained significant and directionally consistent following urate adjustment (HR 0.83, 95% CI 0.70-0.98; HR 0.86, 95% CI 0.76-0.98; HR 1.41, 95% CI 1.21-1.63 between extreme quintiles), respectively; corresponding HRs per SD were 0.91 (95% CI 0.86-0.97), 0.94 (95% CI 0.91-0.98), and 1.10 (95% CI 1.06-1.14). Findings persisted when including patients with nonhospitalized incident gout. Mendelian randomization corroborated their potential causal role on hyperuricemia or gout risk; with change in urate levels of -0.05 mg/dL (95% CI -0.08 to -0.01) and -0.12 mg/dL (95% CI -0.22 to -0.03) per SD of glycine and glutamine, respectively, and odds ratios of 0.94 (95% CI 0.88-1.00) and 0.81 (95% CI 0.67-0.97) for gout. CONCLUSION:These prospective findings with causal implications could lead to biomarker-based risk prediction and potential supplementation-based interventions with glycine or glutamine.
10.1002/acr.25420
Causal association of basal metabolic rate on systemic sclerosis: a bidirectional mendelian randomization study.
Archives of dermatological research
Prior evidence suggests that altered energy metabolism plays a crucial role in the development of fibrotic diseases. Recent research indicates that systemic sclerosis (SSc) patients have potentially benefited from energy management, implying that basal metabolic rate (BMR), a vital energy metabolic parameter, may be related to SSc. However, the causal effect of BMR on SSc remains unknown. Thus, we aimed to elucidate the causal links between BMR and SSc. Based on summary statistics from the genome-wide association studies (GWAS) database, two-sample Mendelian randomization (MR) was applied to explore causality between BMR and SSc. The causal relationships were assessed employing inverse variance weighted (IVW), MR-Egger, and weighted median (WM) methods. Meanwhile, several sensitivity analyses were carried out to ensure the robustness of the findings. There was an underlying genetic association of BMR on SSc (OR = 0.505, 95% CI: 0.272-0.936, P = 0.030). Moreover, no significant causal effect between SSc and BMR was observed in the reverse MR analysis (OR = 0.999, 95% CI: 0.997-1.001, P = 0.292). According to the sensitivity analysis, the presence of heterogeneity and genetic pleiotropy was not detected. Our findings, derived from a genetic perspective, provide robust evidence of a causal connection between BMR and SSc. To verify these results and clarify the potential mechanisms, further research is warranted.
10.1007/s00403-024-03248-x
Roles of gut microbiota in androgenetic alopecia: insights from Mendelian randomization analysis.
Frontiers in microbiology
Background:Androgenetic alopecia (AGA) is the most common type of androgen-associated hair loss. Previous studies have indicated an association between the gut microbiota and AGA. To delve deeper, we executed a two-sample Mendelian randomization (MR) analysis to investigate the potential causal relationship between the gut microbiota and AGA. Methods:A two-sample MR investigation was utilized to delve into the intricate interplay between gut microbiota and AGA. Information regarding 211 gut microbial taxa was sourced from the MiBioGen consortium. The summary statistics of the genome-wide association studies (GWAS) for AGA were obtained from the FinnGen biobank, which included 195 cases and 201,019 controls. Various analytical approaches, including Inverse Variance Weighting (IVW), Weighted Median, MR-Egger, Weighted Mode, and Simple Mode were employed to evaluate the causal impact of gut microbiota on AGA. Sensitivity analyses were subsequently conducted to affirm the robustness of the findings. Results:A two-sample MR investigation unveiled the genus , genus , and genus were identified as risk factors associated with AGA. In contrast, the family and genus , along with the genus 9, demonstrated a protective effect. The sensitivity analyses provided additional assurance that the findings of the current study were less susceptible to the influence of confounding variables and biases. Conclusion:The MR study has established a link between specific gut microbiota and AGA, offering evidence for the identification of more precisely targeted probiotics. This discovery has the potential to aid in the prevention, control, and reversal of AGA progression.
10.3389/fmicb.2024.1360445
Robust use of phenotypic heterogeneity at drug target genes for mechanistic insights: Application of cis-multivariable Mendelian randomization to GLP1R gene region.
Genetic epidemiology
Phenotypic heterogeneity at genomic loci encoding drug targets can be exploited by multivariable Mendelian randomization to provide insight into the pathways by which pharmacological interventions may affect disease risk. However, statistical inference in such investigations may be poor if overdispersion heterogeneity in measured genetic associations is unaccounted for. In this work, we first develop conditional F statistics for dimension-reduced genetic associations that enable more accurate measurement of phenotypic heterogeneity. We then develop a novel extension for two-sample multivariable Mendelian randomization that accounts for overdispersion heterogeneity in dimension-reduced genetic associations. Our empirical focus is to use genetic variants in the GLP1R gene region to understand the mechanism by which GLP1R agonism affects coronary artery disease (CAD) risk. Colocalization analyses indicate that distinct variants in the GLP1R gene region are associated with body mass index and type 2 diabetes (T2D). Multivariable Mendelian randomization analyses that were corrected for overdispersion heterogeneity suggest that bodyweight lowering rather than T2D liability lowering effects of GLP1R agonism are more likely contributing to reduced CAD risk. Tissue-specific analyses prioritized brain tissue as the most likely to be relevant for CAD risk, of the tissues considered. We hope the multivariable Mendelian randomization approach illustrated here is widely applicable to better understand mechanisms linking drug targets to diseases outcomes, and hence to guide drug development efforts.
10.1002/gepi.22551
Associations of inflammatory cytokines with palmoplantar pustulosis: a bidirectional Mendelian randomization study.
Frontiers in medicine
Background:Variations in circulatory cytokine levels have been observed during the onset and course of palmoplantar pustulosis (PPP); however, whether these changes are due to etiological or secondary factors is unclear. To clarify the causal relationship, we conducted a summarized-level bidirectional Mendelian randomization (MR) analysis in this study. Methods:A FinnGen biobank genome-wide association study (GWAS) of 212,766 individuals (524 PPP patients and 212,242 controls) provided summary data for PPP, whereas genetic instrumental variables (IVs) linked to circulation cytokine levels were gathered from a GWAS of 14,824 European individuals. The inverse-variance weighted (IVW), weighted median (WME), simple mode, and MR-Egger methods were used to ascertain the changes in PPP pathogenic cytokine taxa. Sensitivity analysis, which included horizontal pleiotropy analysis, was then conducted. The reliability of the results was assessed using the leave-one-out approach and the MR Steiger test, which evaluated the strength of a causal relationship. To evaluate the reverse causality between PPP and circulating cytokine levels, a reverse MR analysis was carried out. Results:Our study demonstrated positive associations between C-X-C motif chemokine 6 (CXCL6) and PPP (odds ratio, OR 1.257, 95%CI: 1.001-1.570, 0.043). C-C motif chemokine 19 (CCL19) and interleukin-6 (IL-6) were suggested to be protectively associated with the development of PPP (OR: 0.698,95% CI: 0.516-0.944, 0.020; OR: 0.656, 95%CI:0.437-0.985, 0.042). The results were steady after sensitivity and heterogeneity analyses. Conclusion:At the genetic prediction level, we identified causally connected inflammation-related variables that contributed to the onset and development of PPP. The therapeutic options for some refractory PPP have expanded due to tailored cytokine therapy, generating fresh concepts for PPP diagnostics and mechanism investigation.
10.3389/fmed.2024.1387210
Genetic perspectives on the influence of circulating cytokines on acne: A Mendelian randomization study.
Medicine
Previous studies have reported that the occurrence and development of acne are closely associated with immune-inflammatory responses. Mendelian randomization was performed to further assess the causal correlation between 41 inflammatory cytokines and acne. Mendelian two-sample randomization utilized genetic variants for acne from a large open genome-wide association study (1299 cases and 211,139 controls of European ancestry) and inflammatory cytokines from a genome-wide association study abstract containing 8293 healthy participants. The causal relationship between exposure and outcome was explored primarily using an inverse variance weighting approach. In addition, multiple sensitivity analyses including MR-Egger, weighted median, simple model, weighted model, and MR-PRESSO were applied simultaneously to enhance the final results. The results suggest that il-10, MIP-1A, and SCGF-β are suggestive of the risk of acne in clinical practice (OR = 0.799, 95% CI = 0.641-0.995, P = .045; OR = 0.55, 95% CI = 0.388-0.787, P = .001; OR = 1. 152, 95% CI = 1.001-1.325, P = .048). Our study conclusively identified a causal relationship between il-10 and circulating levels of acne risk and a suggestive link between MIP-1A and SCGF-β and acne. Our study may provide greater insight into the pathogenesis of acne and develop effective management strategies for the clinic. We believe that IL-10, MIP-1A, and SCGF-β could be potential therapeutic targets for acne development.
10.1097/MD.0000000000036639
Association between levels of sex hormones and risk of multiple sclerosis: a mendelian randomization study.
Acta neurologica Belgica
BACKGROUND:This research aimed to examine the causal connections between multiple sclerosis (MS) and a range of sex hormone-related traits, such as bioavailable testosterone (BT), sex hormone-binding globulin (SHBG), testosterone, and estradiol (E2). METHODS:A bidirectional two-sample Mendelian randomization (MR) analysis using summary statistics from genome-wide association studies (GWAS) was conducted to investigate the relationship between sex hormone-related traits and MS. Moreover, the Inverse-variance weighted (IVW) method was employed as the primary analysis approach. RESULTS:The MR analysis, using the IVW method, found a significant correlation between genetically determined SHBG levels and MS (OR = 1.634, 95% CI: 1.029-2.599, p = 0.038). Similarly, the reverse MR analysis suggested a causal link between MS and SHBG (OR = 1.005, 95% CI: 1.001-1.009, P = 0.003). However, no association was observed between MS risk and E2, testosterone, or BT levels. CONCLUSION:Our MR analysis demonstrated that genetically predicted higher SHBG may be positively correlated with the risk of MS. Moreover, the role of SHBG in MS could be further investigated.
10.1007/s13760-024-02613-x
Identification of potential therapeutic targets for systemic lupus erythematosus based on GEO database analysis and Mendelian randomization analysis.
Frontiers in genetics
Background:Systemic lupus erythematosus (SLE) is a complex autoimmune disease. Current treatments mainly rely on immunosuppressants, which lack specificity and pose challenges during treatment. This study aims to deeply explore the molecular pathogenic mechanism of SLE through gene expression databases (GEO) and bioinformatics analysis methods, combined with Mendelian randomization analysis, to provide key clues for new therapeutic targets. Methods:In this study, the SLE-related gene chip dataset GSE65391 was selected from the GEO database, and the data were preprocessed and statistically analyzed using R language and bioinformatics tools. Differential expression analysis, weighted gene co-expression network analysis (WGCNA), GO, and KEGG enrichment analysis were used to screen differentially expressed genes (DEGs) for functional annotation and pathway localization. Furthermore, Mendelian randomization analysis was conducted to identify core genes closely related to SLE risk, and immune cell infiltration analysis and compound molecular docking studies were performed on the core gene ISG15. Results:The study successfully screened 3,456 DEGs and identified core gene modules highly related to SLE through WGCNA analysis, including key genes closely related to the pathogenesis of SLE, such as STAT1, DDX58, ISG15, IRF7, and IFIH1. In particular, this study found a significant positive correlation between the ISG15 gene and SLE, suggesting that it may be a potential risk factor for SLE. Additionally, through molecular docking technology, it was discovered that the ISG15 gene can effectively bind to two compounds, genistein, and flavopiridol, which have anti-inflammatory and immunosuppressive effects, respectively. This provides new potential drug targets for SLE treatment. Discussion:As an immunomodulatory cytokine, ISG15 plays a crucial role in the pathogenesis of SLE. This study found that variations in the ISG15 gene may increase the risk of SLE and exacerbate inflammatory responses and tissue damage through multiple mechanisms. Furthermore, molecular docking revealed that genistein and flavopiridol can effectively bind to ISG15, offering a new approach for SLE treatment. These two compounds, with their anti-inflammatory and immunosuppressive properties, have the potential to slow the progression of SLE by influencing the expression and function of ISG15. Conclusion:Through comprehensive bioinformatics analysis and Mendelian randomization analysis, this study deeply explored the molecular pathogenic mechanism of SLE and successfully identified ISG15 as a potential therapeutic target for SLE. Simultaneously, molecular docking technology revealed that two compounds, genistein and flavopiridol, have potential therapeutic effects with ISG15, providing new potential drugs for SLE treatment. These discoveries not only enhance our understanding of the pathogenesis of SLE but also provide important clues for developing new treatment strategies.
10.3389/fgene.2024.1454486
Causal Effects of Rheumatoid Arthritis, Ankylosing Spondylitis, Juvenile Idiopathic Arthritis on Psoriasis: A Mendelian Randomization Study.
Clinical, cosmetic and investigational dermatology
Background:It is well-documented that rheumatoid arthritis (RA), ankylosing spondylitis (AS), and juvenile idiopathic arthritis (JIA) often exhibit skin manifestations, with psoriasis typically occurring around the time of diagnosis. Thus, it is essential to investigate the potential causal relationship between these forms of arthritis and psoriasis. Methods:The OpenGWAS provided traitIDs for exposure factors (RA (bbj-A-74), AS (ebi-A-GCST005529), and JIA (finn-b-JUVEN-ARTHR)) and outcome (psoriasis, finn-b-L12-PSORIASIS). bbj-A-74 had 19,190 samples (9,739,303 SNPs), ebi-A-GCST005529 had 22,647 samples (99,962 SNPs), finn-b-JUVEN-ARTHR had 173,622 samples (16,380,296 SNPs), and psoriasis had 216,752 samples (16,380,464 SNPs). Initially, 57 RA SNPs, 25 AS SNPs, and 5 JIA SNPs were acquired. Causal links were explored via univariate Mendelian Randomization (UVMR) analysis, with sensitivity analyses ensuring reliability. Additionally, multivariate MR (MVMR) analysis was conducted to further estimate the effect of each exposure factor on psoriasis. Results:Significant causal links (P < 0.05, OR > 1) were found between bbj-A-74, ebi-A-GCST005529, finn-b-JUVEN-ARTHR, and finn-b-L12-PSORIASIS, indicating associations of RA, AS, and JIA with psoriasis. Sensitivity analyses ensured the reliability of these finding, showing no heterogeneity, horizontal pleiotropy, or SNP locus oversensitivity in UVMR results. Furthermore, MVMR analysis revealed AS and JIA as psoriasis risk factors, while RA showed non-significant protective effects. This suggests AS and JIA may contribute to psoriasis onset or exacerbation when coexisting. Conclusion:MR analyses were conducted to investigate the causal links between RA, AS, JIA, and psoriasis, enhancing our grasp of the underlying mechanisms of psoriasis.
10.2147/CCID.S490250
Association of air pollutants with psychiatric disorders: a two-sample Mendelian randomization.
Ecotoxicology and environmental safety
BACKGROUND:The link between air pollution and increased risk of psychiatric disorders has been growing in evidence. However, the causal relationship between air pollution and psychiatric disorders remains poorly understood. METHODS:Single-nucleotide polymorphisms associated with air pollutants (including NOx, NO, PM, PM, and PM) from the UK Biobank were used as instrumental variables. Summary-level data for psychiatric disorders (major depressive disorder, anxiety, bipolar disorder, schizophrenia, post-traumatic stress disorder, attention deficit hyperactivity disorder, autism spectrum disorder, anorexia nervosa, and obsessive-compulsive disorder) were procured from the Psychiatric Genomics Consortium and FinnGen consortium. Two-sample Mendelian randomization (MR) analysis was conducted to analyze the causal associations. RESULTS:The MR analysis revealed significant associations between certain air pollutants and specific types of psychiatric disorders. The inverse-variance weighted model of preliminary analysis indicated that genetically predicted NO was associated with increased risks of major depressive disorder (odds ratio [OR]: 1.13, 95 % confidence intervals [CI]: 1.00-1.28, P = 0.041), bipolar disorder (OR: 1.26, 95 % CI: 1.00-1.58, P = 0.0497), schizophrenia (OR: 1.57, 95 % CI: 1.23-2.00, P < 0.001), attention deficit hyperactivity disorder (OR: 1.61, 95 % CI: 1.25-2.09, P < 0.001) and autism spectrum disorder (OR: 1.39, 95 % CI: 1.01-1.91, P = 0.044). Genetically predicted PM showed a positive association with the risk of major depressive disorder (OR: 1.21, 95 % CI: 1.06-1.39, P = 0.006), bipolar disorder (OR: 1.32, 95 % CI: 1.03-1.69, P = 0.030) and attention deficit hyperactivity disorder (OR: 1.57, 95 % CI: 1.16-2.12, P = 0.004). In addition, our results also indicated that NOx (OR: 1.64, 95 % CI: 1.21-2.21, P = 0.0012) and PM (OR: 1.70, 95 % CI: 1.23-2.36, P = 0.0014) could increase the risk of attention deficit hyperactivity disorder. CONCLUSIONS:The MR analysis provides evidence for the causality of different air pollutants on specific psychiatric disorders, underscoring the importance of mitigating air pollution to reduce the risk of psychiatric disorders.
10.1016/j.ecoenv.2024.117105
Serum lipids may causally affect the occurrence of alopecia areata: A Mendelian randomization study.
Skin research and technology : official journal of International Society for Bioengineering and the Skin (ISBS) [and] International Society for Digital Imaging of Skin (ISDIS) [and] International Society for Skin Imaging (ISSI)
PURPOSE:The etiology of alopecia areata (AA) in relation to serum lipids remains unclear, thereby prompting our intention to do Mendelian study on this subject. DESIGN:Two-sample Mendelian randomization (MR) analysis was performed in the study. The inverse variance-weighted method was used as the primary method. METHODS:In our study, we integrated a set of 123 single-nucleotide polymorphisms (SNPs) into our analysis. These SNPs have been extensively studied and are known to exhibit associations with serum lipids. We sourced these SNPs from a variety of relevant studies and consortia that specifically focus on lipid-related research, such as the MRC Integrative Epidemiology Unit. These carefully curated SNPs were then utilized as instrumental variables in our analysis, allowing us to explore and evaluate the causal relationships between these genetic variants and serum lipids. By incorporating this comprehensive set of SNPs, we aimed to enhance the precision and robustness of our findings, shedding light on the intricate interplay between genetics and serum lipids. RESULTS:In the MR analysis, a higher total lipid concentration in large low-density lipoprotein (LDL) particles (odds ratio [OR] = 1.502; 95% confidence interval [CI] = 1.086-1.953; p = 0.006), a greater ratio of cholesteryl esters to total lipids in chylomicrons and extremely large very LDL (VLDL) particles (OR = 2.174; 95% CI = 1.300-2.500; p = 0.010), and a greater ratio of cholesterol to total lipids in chylomicrons and extremely large VLDL particles (OR = 2.363;95% CI = 1.556-4.438; p = 0.004), were genetically predicted to be causally associated with an increased risk of AA, while patients with a higher triglyceride to total lipids ratio in chylomicrons and extremely large VLDL particles had a lower risk of AA (OR = 0.481; 95% CI = 0.191-1.270; p = 0.002). CONCLUSION:This study found that serum lipids may be causally implicated in AA.
10.1111/srt.13785
Oily fish reduces the risk of acne by lowering fasting insulin levels: A Mendelian randomization study.
Food science & nutrition
Meat intake, particularly from oily fish, has been associated with various chronic diseases. However, its relationship with acne has always been controversial. Therefore, we have adopted Mendelian randomization (MR) analysis to investigate the causal relationship between different types of meat intake and acne. The exposure and outcome datasets for this study were obtained from the Integrative Epidemiology Unit (IEU) Open GWAS project. Seven datasets on meat intake were included, which consisted of non-oily fish, oily fish, lamb/mutton, poultry, pork, beef, and processed meat. The main methods used for MR analysis were inverse variance weighted, weighted median, and MR-egger. To ensure the accuracy of the results, heterogeneity, pleiotropy, and Mendelian randomization pleiotropy residual sum and outlier (MR-PRESSO) analyses were conducted. Additionally, an analysis of four risk factors (fasting insulin, insulin resistance, total testosterone level, and estradiol level) was performed to investigate the underlying mechanisms linking statistically significant meat intake to acne. Oily fish intake was found to be a protective factor for acne (OR: 0.22, 95% CI: 0.10-0.49, < .001), and it was also observed that oily fish intake can reduce the level of fasting insulin by the IVW method (OR: 0.89, 95% CI: 0.81-0.98, = .02). No causal relationship was identified between other types of meat intake and acne. The intake of oily fish reduces the risk of acne by lowering fasting insulin levels.
10.1002/fsn3.4054
Mendelian randomization study to assess causality between diet and phenotype of aging.
Asia Pacific journal of clinical nutrition
BACKGROUND AND OBJECTIVES:Observational research findings have demonstrated correlations between diet and the process of aging. Nevertheless, there remains uncertainty regarding possible disruption caused by confounding variables. To elucidate the connections between diet and aging, we employed the Mendelian randomization analysis. METHODS AND STUDY DESIGN:The exposure factor was the daily diet, whereas accelerated aging was measured through telomere length, facial aging (FA), frailty index (FI), and senescence-associated secretory phenotypes (SASPs), representing the outcome factors. The primary analysis employed IVW analysis, with additional MR-Egger and Weighted Median analyses conducted to assess the reliability of the findings. Furthermore, we analyzed the heterogeneity and pleiotropy of the results. RESULTS:The results revealed that the consumption of salad/raw vegetables and oily fish exhibited a negative correlation with FA, whereas coffee intake showed a positive correlation with FA. On the other hand, the intake of cheese, oily fish, dried fruit, and cereal showed negative associations with FI. Additionally, coffee, alcohol, and pork intake were positively associated with FI. Lastly, the intake of bread exhibited a positively correlated with SASPs, while the intake of cheese and coffee showed a negative correlation with SASPs. CONCLUSIONS:Our study revealed that the consumption of cheese, vegetables, oily fish, dried fruit, bread, coffee, and alcohol was associated with the aging process. Interestingly, our findings suggest that coffee intake may accelerate aging, whereas intake of oily fish may delay the aging process. However, it is important to note that further well-designed prospective studies are required to validate our findings in the future.
10.6133/apjcn.202409_33(3).0008
Genetic insights into kidney stone formation: a Mendelian randomization study of protein quantitative trait loci.
Urolithiasis
Kidney stones are a common urological condition caused by a complex interaction of genetic, metabolic, and environmental factors. Recent genomic research has shed light on the genetic basis of kidney stone susceptibility.This study aims to identify protein quantitative trait loci (pQTL) associated with kidney stone formation and explore their causal relationships using Mendelian randomization.We conducted two-sample Mendelian Randomization (MR) analyses utilizing Genome-Wide Association Study (GWAS) summary data to assess the causal impact of pQTL on kidney stone formation. Data sources included the UK Biobank dataset "ukb-b-8297" and an external validation dataset "ukb-b-13537". We employed inverse variance weighting (IVW) as the primary MR method, supplemented by sensitivity analyses such as MR-PRESSO, Leave-One-Out, and Cochran Q tests to validate the robustness of our findings.Our analyses identified significant associations between several pQTL and kidney stones. Key proteins such as CD27, CXCL9, and TNFRSF1A exhibited significant centrality in the protein-protein interaction (PPI) network, suggesting their critical roles in kidney stone pathogenesis. The KEGG pathway enrichment analysis revealed significant pathways, including cytokine-cytokine receptor interaction and osteoclast differentiation, highlighting the involvement of immune response and inflammatory processes in kidney stone formation.This study underscores the significance of pQTL in kidney stone research, identifying key proteins and pathways that may serve as biomarkers or therapeutic targets. The findings provide insights into the genetic and molecular mechanisms underlying kidney stone formation, offering potential avenues for future research and therapeutic interventions.
10.1007/s00240-024-01667-z
Causality of genetically proxied immunophenotypes on cardiovascular diseases: a Mendelian randomization study.
Frontiers in immunology
Background:Cardiovascular diseases (CVDs) stand as the foremost global cause of mortality, prompting a growing interest in using the potential of immune cells for heart injury treatment. This study aims to assess the causal association between immune cells and CVDs. Methods:A total of 731 immune cells were derived from a previously published genome-wide association study (GWAS), which included approximately 22 million genetic variants among 3,757 individuals of Sardinian ancestry. Genetic associations with atrial fibrillation (AF), heart failure, coronary artery disease, myocardial infarction and stroke were extracted from large-scale GWAS. A two-sample Mendelian randomization (MR) analysis was used to assess the causal association between immune cells and CVDs. Replication MR analysis based on FinnGen dataset and meta-analysis are sequentially conducted to validate causal relationships. Results:Collectively, genetically predicted 4 immune cell traits were associated with AF and 5 immune cell traits were associated with stroke. Increased levels of IgD- CD38dim absolute count were associated with a higher susceptibility to AF, while increased expression of CD14+ CD16+ monocytes, CD62L on CD62L+ myeloid dendritic cells, and CD16 on CD14- CD16+ monocytes were linked to a decreased susceptibility to AF. Additionally, an elevated susceptibility to stroke was linked to an increase in the percentage of CD39+ resting Tregs and heightened CD27 expression on IgD- CD38+ cells. Conversely, a decreased susceptibility to stroke was associated with increased CD40 expression on monocytes, particularly on CD14+ CD16+ and CD14+ CD16- monocytes, with the latter two showing the most compelling evidence. Conclusion:This study identified several immune cell traits that have a causal relationship with CVDs, thus confirming that immune cells play an important role in the pathogenesis of these diseases.
10.3389/fimmu.2024.1344773
Sex hormones and risk of lung and colorectal cancers in women: a Mendelian randomization study.
Scientific reports
The roles of sex hormones such as estradiol, testosterone, and sex hormone-binding globulin (SHBG) in the etiology of lung and colorectal cancers in women, among the most common cancers after breast cancer, are unclear. This Mendelian randomization (MR) study evaluated such potential causal associations in women of European ancestry. We used summary statistics data from genome-wide association studies on sex hormones and from the Trøndelag Health Study (HUNT) and large consortia on cancers. There was suggestive evidence of 1-standard deviation increase in total testosterone levels being associated with a lower risk of lung non-adenocarcinoma (hazard ratio 0.60, 95% confidence interval 0.37-0.98) in the HUNT Study. However, this was not confirmed by using data from a larger consortium. In general, we did not find convincing evidence to support a causal role of sex hormones on risk of lung and colorectal cancers in women of European ancestry.
10.1038/s41598-024-75305-4
Associations of dietary sources of antioxidant intake and NAFLD: NHANES 2017-2020 and Mendelian randomization.
Frontiers in nutrition
Purpose:To determine the association between dietary antioxidant sources and non-alcoholic fatty liver disease (NAFLD). Methods:In this observational study, we utilized NHANES 2017-2020 data to identify the factors associated with NAFLD in dietary antioxidant sources via weighted multivariate logistic regression models. Then, Mendelian randomization (MR) was applied to investigate the effect of dietary antioxidant sources on NAFLD at the genetic level. Results:Of the six dietary sources of antioxidants, only vitamin E (Vit E) was significantly associated with NAFLD (OR = 0.98; 95% CI: 0.97-0.99; = 0.001). Upon adjusting for all covariates, it was determined that the highest quartile of dietary Vit E intake was associated with a decreased NAFLD occurrence compared with the lowest quartile of dietary Vit E intake ( < 0.001). The results of IVW-MR analysis revealed an association between Vit E and NAFLD (OR = 0.028; = 0.039). Conclusion:Our research indicates a negative and linear relationship between daily vitamin E intake and NAFLD.
10.3389/fnut.2024.1447524
Appraising the causal role of smoking in idiopathic pulmonary fibrosis: a Mendelian randomization study.
Thorax
Smoking has been considered a risk factor for idiopathic pulmonary fibrosis (IPF) in observational studies. To assess whether smoking plays a causal role in IPF, we performed a Mendelian randomization study using genetic association data of 10 382 cases with IPF and 968 080 controls. We found that genetic predisposition to smoking initiation (based on 378 variants) and lifetime smoking (based on 126 variants) were associated with a higher risk of IPF. Our study suggests a potential causal effect of smoking on increasing IPF risk from a genetic perspective.
10.1136/thorax-2023-220012
Causal Relationship between Sex Hormones and Risk of Developing Common Neurodegenerative Diseases: A Mendelian Randomization Study.
Journal of integrative neuroscience
BACKGROUND:Neurodegenerative diseases are a group of unexplained disorders of the central nervous system, and studies have shown that a large number of genetic and environmental factors are associated with these diseases. Since these diseases show significant gender differences in epidemiology, sex hormones are thought to be strongly associated with these diseases. In this study, we used Mendelian randomization to explore the causal relationship between sex hormones and the risk of developing neurodegenerative diseases. METHODS:We obtained genetic instrumental variables for sex hormones (sex hormone-binding globulin [SHBG], estradiol levels [EL], and bioavailable testosterone [BT]) separately through the Integrative Epidemiology Unit (IEU) database (https://gwas.mrcieu.ac.uk/). We analyzed the causal relationship of each with the risk of developing neurodegenerative diseases (Amyotrophic Lateral Sclerosis [ALS], Parkinson's disease [PD], and Alzheimer's disease [AD]) using inverse variance weighted (IVW) in Mendelian randomization. Data were then analyzed for sensitivity. RESULTS:BT was negatively associated with the risk of developing ALS (odds ratio [OR] = 0.794; 95% confidence interval [95% CI] = 0.672-0.938; = 0.006). EL and SHBG were not associated with a risk for developing neurodegenerative diseases (ALS, PD, AD). CONCLUSIONS:Elevated BT is associated with a reduced risk of developing ALS. Further research is needed to investigate the underlying mechanisms of action for this correlation and how it can be used as a potential target of action to reduce the risk of developing ALS.
10.31083/j.jin2304078
Analyzing the causal role of blood cells in aging: a Mendelian randomization study.
Biogerontology
Blood cells are crucial components of the human body, closely linked to the aging process. This study aims to explore the causal relationship between 91 blood cell phenotypes and aging through Mendelian randomization (MR) analysis. Exposure data from genome-wide association studies (GWAS) was extracted from the GWAS of blood cell perturbation phenotypes in 2,600 European individuals. Initial analysis utilized GWAS data related to aging from the GWAS Catalog database GCST90014288, with inverse-variance weighting as the primary method for causal analysis. Sensitivity analyses included Cochran's Q test, MR-Egger intercept test, MR-PRESSO, and leave-one-out analysis. For significant associations, replication and meta-analysis were conducted using independent aging GWAS data from GCST90014300. Initial analysis revealed that environmental peroxide-impacted red blood cells and ciprofloxacin-impacted reticulocytes accelerated aging. Additionally, elevated neutrophil levels were found to accelerate aging, while LiCl-impacted neutrophils reduced aging risk. Replication and meta-analysis showed consistent results: ciprofloxacin-impacted reticulocytes and elevated neutrophil levels increased the risk of aging, while LiCl-impacted neutrophils reduced the risk. RBCs showed no significant impact on aging progression. Sensitivity analyses confirmed the robustness and reliability of these positive findings. Our study provides evidence of a causal relationship between three blood cell disturbance phenotypes and human aging.
10.1007/s10522-024-10148-0
The effect of epigenetic aging on neurodegenerative diseases: a Mendelian randomization study.
Frontiers in endocrinology
Background:Aging has always been considered as a risk factor for neurodegenerative diseases, but there are individual differences and its mechanism is not yet clear. Epigenetics may unveil the relationship between aging and neurodegenerative diseases. Methods:Our study employed a bidirectional two-sample Mendelian randomization (MR) design to assess the potential causal association between epigenetic aging and neurodegenerative diseases. We utilized publicly available summary datasets from several genome-wide association studies (GWAS). Our investigation focused on multiple measures of epigenetic age as potential exposures and outcomes, while the occurrence of neurodegenerative diseases served as potential exposures and outcomes. Sensitivity analyses confirmed the accuracy of the results. Results:The results show a significant decrease in risk of Parkinson's disease with GrimAge (OR = 0.8862, 95% CI 0.7914-0.9924, = 0.03638). Additionally, we identified that HannumAge was linked to an increased risk of Multiple Sclerosis (OR = 1.0707, 95% CI 1.0056-1.1401, = 0.03295). Furthermore, we also found that estimated plasminogen activator inhibitor-1(PAI-1) levels demonstrated an increased risk for Alzheimer's disease (OR = 1.0001, 95% CI 1.0000-1.0002, = 0.04425). Beyond that, we did not observe any causal associations between epigenetic age and neurodegenerative diseases risk. Conclusion:The findings firstly provide evidence for causal association of epigenetic aging and neurodegenerative diseases. Exploring neurodegenerative diseases from an epigenetic perspective may contribute to diagnosis, prognosis, and treatment of neurodegenerative diseases.
10.3389/fendo.2024.1372518
Causal role of immune cells in psoriasis: a Mendelian randomization analysis.
Frontiers in immunology
Background:A growing body of evidence has shown that immune cells are linked to psoriasis. It is, however, still unclear if these associations reflect a relationship of cause and effect. Objective:We employed a two-sample Mendelian randomization (MR)-based study to elucidate the probable causative connection between immune cells and psoriasis. Methods:Summary information for psoriasis (Ncase = 5,427, Ncontrol = 479,171) was obtained from the European Bioinformatics Institute. Summarized statistical information on 731 immune cell features, including morphological parameters (MP; n = 32), relative cell number (n = 192), median fluorescence intensity (MFI) of surface antigens (n = 389), and absolute cell number (n = 118), was obtained from the genome-wide association studies (GWAS) catalog. The research consisted of forward MR analysis, in which immune cell traits were used as the exposure factor, and psoriasis was the outcome, as well as reverse MR analysis, in which psoriasis was used as the exposure factor, and immune cell traits were the outcome. We ran numerous sensitivity analyses to ascertain the study results for robustness, heterogeneity, and potential multiple-biological effects. Result:This research determined a probable causative connection between immune cells and psoriasis. In particular, we identified 36 distinct types of immune cells that are potentially causally linked to psoriasis. Conclusion:Our findings indicate strong causal correlations between 36 immunological phenotypes and psoriasis, thus, directing future clinical trials.
10.3389/fimmu.2024.1326717
Causal association of epigenetic aging and osteoporosis: a bidirectional Mendelian randomization study.
BMC medical genomics
BACKGROUND:The relationship between aging and osteoporosis is well established. However, the relationship between the body's physiological age, i.e. epigenetic age, and osteoporosis is not known. Our goal is to analyze the bidirectional causal relationship between epigenetic clocks and osteoporosis using a bidirectional Mendelian randomization study. METHODS:We used SNPs closely associated with GrimAge, Hannum, PhenoAge, and HorvathAge in epigenetic age and SNPs closely associated with femoral neck bone mineral density, lumbar spine bone mineral density, and forearm bone mineral density as instrumental variables, respectively, using the inverse variance weighting method and several other MR methods to assess the bidirectional causal relationship between epigenetic age and osteoporosis. RESULT:There was no evidence of a clear causal relationship of epigenetic age (GrimAge, Hannum, PhenoAge, and HorvathAge) on femoral neck bone mineral density, lumbar spine bone mineral density, and forearm bone mineral density. In reverse Mendelian randomization analysis showed a significant causal effect of lumbar spine bone mineral density on GrimAge: odds ratio (OR) = 0.692, 95% confidence interval (CI) = (0.538-0.890), p = 0.004. The results suggest that a decrease in lumbar spine bone mineral density promotes an acceleration of GrimAge. CONCLUSION:There was no significant bidirectional causal relationship between epigenetic age and osteoporosis A decrease in lumbar spine bone density may lead to an acceleration of the epigenetic clock "GrimAge". Our study provides partial evidence for a bidirectional causal effect between epigenetic age and Osteoporosis.
10.1186/s12920-023-01708-3
Is diet related to skin condition? A Mendelian randomization study.
Archives of dermatological research
Observational studies have revealed associations between various dietary factors and skin conditions. However, the causal relationship between diet and skin condition is still unknown. Data on 17 dietary factors were obtained from the UK Biobank. Data on four skin conditions were derived from the UK Biobank and another large-scale GWAS study. Genetic predictions suggested that the intake of oily fish was associated with a lower risk of skin aging (OR: 0.962, P = 0.036) and skin pigmentation (OR: 0.973, P = 0.033); Tea intake was associated with a lower risk of skin pigmentation (OR: 0.972, P = 0.024); Salad/raw vegetables intake was associated with a lower risk of keratinocyte skin cancer (OR: 0.952, P = 0.007). Coffee intake was associated with increased risk of skin aging (OR: 1.040, P = 0.028); Pork intake was associated with increased risk of skin aging (OR: 1.134, P = 0.020); Beef intake was associated with increased risk of cutaneous melanoma (OR: 1.013, P = 0.016); Champagne plus white wine intake was associated with increased risk of cutaneous melanoma (OR: 1.033, P = 0.004); Bread intake was associated with increased risk of keratinocyte skin cancer (OR: 1.026, P = 0.013). Our study results indicate causal relationships between genetically predicted intake of oily fish, tea, salad/raw vegetables, coffee, pork, beef, champagne plus white wine, and bread and skin conditions.
10.1007/s00403-024-03103-z
Causal Factors for Osteoarthritis: A Scoping Review of Mendelian Randomization Studies.
Arthritis care & research
OBJECTIVE:Mendelian randomization (MR) has increasingly been utilized as a tool for establishing causal relations between modifiable exposures and osteoarthritis (OA). The goal of this review was to summarize available MR studies of OA that evaluate the causal role of modifiable risk factors on OA. METHODS:This review was performed following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) Extension for Scoping Reviews model. We performed a literature search for relevant studies published before December 2021 across multiple databases using the search terms "osteoarthritis" and ("Mendelian randomization" or "polygenic risk score"). We reported the MR estimates of causal associations between exposures and OA and then assessed methodologic quality of abstracted studies according to their efforts to validate the three key MR assumptions. RESULTS:Our search identified 45 studies reporting on 141 exposure-association analyses. All studies performed a formal instrumental variable analysis to estimate the causal effect of exposure on OA. Causal associations (P < 0.05) were reported in 60 of these analyses representing 36 unique publications, and MR-Egger sensitivity analyses were performed in 45 of these analyses. MR studies provided support for causal associations of OA with increased levels of adiposity, coffee consumption, bone mineral density, and sleep disturbance, and decreased levels of serum calcium and low-density lipoprotein cholesterol. CONCLUSION:These results highlight the potential benefits of weight reduction and improvement of sleep quality to reduce the risk of OA and call for a better understanding of the relations of coffee consumption and serum calcium to OA risk.
10.1002/acr.25252
The role of circulating metabolites and gut microbiome in hypertrophic scar: a two-sample Mendelian randomization study.
Archives of dermatological research
Hypertrophic scarring is a fibro-proliferative disorder caused by abnormal cutaneous wound healing. Circulating metabolites and the gut microbiome may be involved in the formation of these scars, but high-quality evidence of causality is lacking. To assess whether circulating metabolites and the gut microbiome contain genetically predicted modifiable risk factors for hypertrophic scar formation. Two-sample Mendelian randomization (MR) was performed using MR-Egger, inverse-variance weighting (IVW), Mendelian Randomization Pleiotropy RESidual Sum and Outlier, maximum likelihood, and weighted median methods. Based on the genome-wide significance level, genetically predicted uridine (P = 0.015, odds ratio [OR] = 1903.514, 95% confidence interval [CI] 4.280-846,616.433) and isovalerylcarnitine (P = 0.039, OR = 7.765, 95% CI 1.106-54.512) were positively correlated with hypertrophic scar risk, while N-acetylalanine (P = 0.013, OR = 7.98E-10, 95% CI 5.19E-17-0.012) and glycochenodeoxycholate (P = 0.021, OR = 0.021 95% CI 0.003-0.628) were negatively correlated. Gastranaerophilales and two unknown gut microbe species (P = 0.031, OR = 0.378, 95% CI 0.156-0.914) were associated with an decreased risk of hypertrophic scarring. Circulating metabolites and gut microbiome components may have either positive or negative causal effects on hypertrophic scar formation. The study provides new insights into strategies for diagnosing and limiting hypertrophic scarring.
10.1007/s00403-024-03116-8
Causal associations of particulate matter 2.5 and cardiovascular disease: A two-sample mendelian randomization study.
PloS one
BACKGROUND:According to epidemiological studies, particulate matter 2.5 (PM2.5) is a significant contributor to cardiovascular disease (CVD). However, making causal inferences is difficult due to the methodological constraints of observational studies. In this study, we used two-sample Mendelian randomization (MR) to examine the causal relationship between PM 2.5 and the risk of CVD. METHODS:Genome-wide association study (GWAS) statistics for PM2.5 and CVD were collected from the FinnGen and UK Biobanks. Mendelian randomization analyses were applied to explore the causal effects of PM2.5 on CVD by selecting single-nucleotide polymorphisms(SNP) as instrumental variables. RESULTS:The results revealed that a causal effect was observed between PM2.5 and coronary artery disease(IVW: OR 2.06, 95% CI 1.35, 3.14), and hypertension(IVW: OR 1.07, 95% CI 1.03, 1.12). On the contrary, no causal effect was observed between PM2.5 and myocardial infarction(IVW: OR 0.73, 95% CI 0.44, 1.22), heart failure(IVW: OR 1.54, 95% CI 0.96, 2.47), atrial fibrillation(IVW: OR 1.03, 95% CI 0.71, 1.48), and ischemic stroke (IS)(IVW: OR 0.98, 95% CI 0.54, 1.77). CONCLUSION:We discovered that there is a causal link between PM2.5 and coronary artery disease and hypertension in the European population, using MR methods. Our discovery may have the significance of public hygiene to improve the understanding of air quality and CVD risk.
10.1371/journal.pone.0301823
Genetic insight into putative causes of xanthelasma palpebrarum: a Mendelian randomization study.
Frontiers in immunology
Xanthelasma palpebrarum (XP) is the most common form of cutaneous xanthoma, with a prevalence of 1.1%~4.4% in the population. However, the cause of XP remains largely unknown. In the present study, we used Mendelian randomization to assess the genetic association between plasma lipids, metabolic traits, and circulating protein with XP, leveraging summary statistics from large genome-wide association studies (GWAS). Genetically predicted plasma cholesterol and LDL-C, but not HDL-C or triglyceride, were significantly associated with XP. Metabolic traits, including BMI, fasting glucose, type 2 diabetes, systolic and diastolic blood pressure, were not significantly associated with XP. Furthermore, we found genetically predicted 12 circulating proteins were associated with XP, including FN1, NTM, FCN2, GOLM1, ICAM5, PDE5A, C5, CLEC11A, CXCL1, CCL2, CCL11, CCL13. In conclusion, this study identified plasma cholesterol, LDL-C, and 12 circulating proteins to be putative causal factors for XP, highlighting the role of plasma cholesterol and inflammatory response in XP development.
10.3389/fimmu.2024.1347112
Identification of potential drug targets for diabetic polyneuropathy through Mendelian randomization analysis.
Cell & bioscience
BACKGROUND:Diabetic polyneuropathy (DPN) is a common diabetes complication with limited treatment options. We aimed to identify circulating plasma proteins as potential therapeutic targets for DPN using Mendelian Randomization (MR). METHODS:The protein quantitative trait loci (pQTLs) utilized in this study were derived from seven previously published genome-wide association studies (GWASs) on plasma proteomics. The DPN data were obtained from the IEU OpenGWAS project. This study employed two-sample MR using MR-Egger and inverse-variance weighted methods to evaluate the causal relationship between plasma proteins and DPN risk, with Cochran's Q test, and I statistics, among other methods, used to validate the robustness of the results. RESULTS:Using cis-pQTLs as genetic instruments, we identified 62 proteins associated with DPN, with 33 increasing the risk and 29 decreasing the risk of DPN. Using cis-pQTLs + trans-pQTLs, we identified 116 proteins associated with DPN, with 44 increasing the risk and 72 decreasing the risk of DPN. Steiger directionality tests indicated that the causal relationships between circulating plasma proteins and DPN were consistent with expected directions. CONCLUSION:This study identified 96 circulating plasma proteins with genetically determined levels that affect the risk of DPN, providing new potential targets for DPN drug development, particularly ITM2B, CREG1, CD14, and PLXNA4.
10.1186/s13578-024-01323-4
Identification of drug targets for Sjögren's syndrome: multi-omics Mendelian randomization and colocalization analyses.
Frontiers in immunology
Background:Targeted therapy for Sjögren's syndrome (SS) has become an important focus for clinicians. Multi-omics-wide Mendelian randomization (MR) analyses have provided new ideas for identifying potential drug targets. Methods:We conducted summary-data-based Mendelian randomization (SMR) analysis to evaluate therapeutic targets associated with SS by integrating DNA methylation, gene expression and protein quantitative trait loci (mQTL, eQTL, and pQTL, respectively). Genetic associations with SS were derived from the FinnGen study (discovery) and the GWAS catalog (replication). Colocalization analyses were employed to determine whether two potentially relevant phenotypes share the same genetic factors in a given region. Moreover, to delve deeper into potential regulation among DNA methylation, gene expression, and protein abundance, we conducted MR analysis to explore the causal relationship between candidate gene methylation and expression, as well as between gene expression and protein abundance. Drug prediction and molecular docking were further employed to validate the pharmacological activity of the candidate drug targets. Results:Upon integrating the multi-omics data, we identified three genes associated with SS risk: TNFAIP3, BTN3A1, and PLAU. The methylation of cg22068371 in BTN3A1 was positively associated with protein levels, consistent with the negative effect of cg22068371 methylation on the risk of SS. Additionally, positive correlations were observed between the gene methylation of PLAU (cg04939496) and expression, as well as between expression and protein levels. This consistency elucidates the promotional effects of PLAU on SS risk at the DNA methylation, gene expression, and protein levels. At the protein level, genetically predicted TNFAIP3 (OR 2.47, 95% CI 1.56-3.92) was positively associated with SS risk, while BTN3A1 (OR 2.96E-03, 95% CI 2.63E-04-3.33E-02) was negatively associated with SS risk. Molecular docking showed stable binding for candidate drugs and target proteins. Conclusion:Our study reveals promising therapeutic targets for the treatment of SS, providing valuable insights into targeted therapy for SS. However, further validation through future experiments is warranted.
10.3389/fimmu.2024.1419363
Investigating the Impact of Sun/UV Protection and Ease of Skin Tanning on the Risk of Pseudoexfoliation Glaucoma: A Mendelian Randomization Study.
Investigative ophthalmology & visual science
Purpose:To investigate the potential causal associations between the use of sun/ultraviolet (UV) protection and ease of skin tanning and the risk of pseudoexfoliation glaucoma (PXG) in European populations. Methods:Single nucleotide polymorphisms (SNPs) associated with the use of sun/UV protection and ease of skin tanning were selected from the UK Biobank genome-wide association study database consisting of 498,751 European participants. SNPs of PXG were obtained from the FinnGen study including 3424 PXG cases and 326,434 controls. Two-sample Mendelian randomization (MR) analyses were performed to assess the association between the use of sun/UV protection and ease of skin tanning and risk of PXG. Results:Inverse variance weighted regression of genetic susceptibility predicted that both use of sun/UV protection and ease of skin tanning were potentially positively associated with the decreased risk of PXG in the European ancestry (use of sun/UV protection: odds ratio [OR] = 0.47; 95% confidence interval [CI], 0.24-0.92; P = 0.028; ease of skin tanning: OR = 0.81; 95% CI, 0.67-0.97; P = 0.025). Conclusions:We found genetic evidence supporting a potential causal association between UV protection and a decreased risk of PXG in European population. Further research will help elucidate the underlying mechanisms and promote UV protection for eyes, especially in people with a high risk of PXG.
10.1167/iovs.64.13.4
Causal effects of genetically determined metabolites on androgenetic alopecia: A two-sample Mendelian randomization analysis.
Skin research and technology : official journal of International Society for Bioengineering and the Skin (ISBS) [and] International Society for Digital Imaging of Skin (ISDIS) [and] International Society for Skin Imaging (ISSI)
BACKGROUND:Androgenic alopecia (AGA) is the most common non-scarring alopecia disorder. Given its increasing incidence and onset during adolescence, AGA significantly impacts both the physical and psychological well-being of affected individuals. Emerging evidence suggests a pivotal role of metabolites in AGA. This study aims to elucidate the causal relationship between metabolites and AGA using Mendelian randomization (MR) analysis. METHODS:We conducted a two-sample Mendelian randomization (TSMR) analysis based on a genome-wide association study (GWAS) to assess the causality of 452 metabolites on AGA. The main approach employed for inferring causal effects was inverse variance weighted (IVW), which was complemented by MR-Egger regression, weighted median, as well as MR pleiotropy residual sum and outlier (MR-PRESSO) approaches. Additionally, sensitivity analyses were performed to ensure result robustness. Single nucleotide polymorphisms (SNPs) were selected as instrumental variables (IVs) in GWAS dataset comprising 452 metabolites. RESULTS:Notably, we identified Scyllo-inositol and Alpha-ketoglutarate as the most potent protective factors against AGA, while Heme* and 2-palmitoylglycerophosphocholine* emerged as significant risk factors for AGA. Furthermore, sensitivity analysis revealed no heterogeneity in these findings. CONCLUSIONS:Overall, our research suggests a potential causal link between metabolites and AGA, offering a more comprehensive insight into the pathogenesis of AGA and present additional strategies for prevention and treatment.
10.1111/srt.13732
Systemic Immune Factors and Risk of Allergic Contact Dermatitis: A Bidirectional Mendelian Randomization Study.
International journal of molecular sciences
Skin inflammation and immune regulation have been suggested to be associated with allergic contact dermatitis (ACD) progression, but whether the system's immune regulation is a cause or a potential mechanism is still unknown. This study aims to assess the upstream and downstream of systemic immune factors on ACD within a bidirectional Mendelian-randomization design. A bidirectional two-sample MR analysis was employed to implement the results from genome-wide association studies for 52 system immune factors and ACD. Genetic associations with systemic immune factors and ACD were obtained from the IEU Open GWAS project database. The inverse-variance weighted (IVW) method was adopted as the primary MR analysis, MR-Egger, weighted median, MR-pleiotropy residual sum, and outlier (MR-PRESSO) was also used as the sensitivity analyses. Only Tumor necrosis factor ligand superfamily member 11 (TNFS11) from among 52 systemic immune factors was associated with a protective effect of ACD. However, ACD was associated with a decrease in Interleukin-9 (IL9) and an increase in C-X-C motif chemokine 1 (GROα), Tumor necrosis factor ligand superfamily member 10 (TRAIL), C4, and complement factor B of the assessed systemic immune factors. This study identified TNFS11 as the upstream regulator and IL9, GROα, TRAIL, C4, and complement factor B as the downstream regulator of ACD, providing opportunities for new therapeutic exploitation of ACD. Nonetheless, these associations of systemic immune factors need to be verified in vivo.
10.3390/ijms251910436
Contribution of Telomere Length to Systemic Sclerosis Onset: A Mendelian Randomization Study.
International journal of molecular sciences
Although previous studies have suggested a relationship between telomere shortening and systemic sclerosis (SSc), the association between these two traits remains poorly understood. The objective of this study was to assess the causal relationship between telomere length in leukocytes (LTL) and SSc using the two-sample Mendelian randomization approach, with the genome-wide association study data for both LTL and SSc. The results of inverse-variance weighted regression (OR = 0.716 [95% CI 0.528-0.970], = 0.031) and the Mendelian randomization pleiotropy residual sum and outlier method (OR = 0.716 [95% CI 0.563-0.911], = 0.035) indicate an association between telomere length and SSc. Specifically, longer genetically predicted LTL is associated with a reduced risk of SSc. Sensitivity tests highlight the significant roles of the variants rs10936599 and rs2736100 annotated to the and genes, respectively. Our findings suggest an influence of telomere length in leukocytes on the development of SSc.
10.3390/ijms242115589
Association of lipid-lowering drug targets with risk of cutaneous melanoma: a mendelian randomization study.
BMC cancer
BACKGROUND:Melanoma proliferation is partly attributed to dysregulated lipid metabolism. The effectiveness of lipid-lowering drugs in combating cutaneous melanoma (CM) is a subject of ongoing debate in both in vitro and clinical studies. METHOD:This study aims to evaluate the causal relationship between various lipid-lowering drug targets, namely 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR, targeted by statins), Proprotein convertase subtilisin/kexin type 9 (PCSK9, targeted by alirocumab and evolocumab), and Niemann-Pick C1-like 1 (NPC1L1, targeted by ezetimibe), and the outcomes of cutaneous melanoma. To mimic the effects of lipid-lowering drugs, we utilized two genetic tools: analysis of polymorphisms affecting the expression levels of drug target genes, and genetic variations linked to low-density lipoprotein cholesterol levels and drug target genes. These variations were sourced from genome-wide association studies (GWAS). We applied Summary-data-based Mendelian Randomization (SMR) and Inverse Variance Weighted Mendelian Randomization (IVW-MR) to gauge the effectiveness of these drugs. RESULTS:Our findings, with SMR results showing an odds ratio (OR) of 1.44 (95% CI: 1.08-1.92; P = 0.011) and IVW-MR results indicating an OR of 1.56 (95% CI: 1.10-2.23; P = 0.013), demonstrate a positive correlation between PCSK9 expression and increased risk of CM. However, no such correlations were observed in other analyses. CONCLUSION:The study concludes that PCSK9 plays a significant role in the development of CM, and its inhibition is linked to a reduced risk of the disease.
10.1186/s12885-024-12366-8
Impact of systemic lupus erythematosus on cardiovascular morphologic and functional phenotypes: a Mendelian randomization analysis.
Frontiers in cardiovascular medicine
Background:Previous studies have established a correlation between systemic lupus erythematosus (SLE) and cardiovascular health, but the potential causal effects of SLE on heart function and structure remain poorly understood. Cardiovascular magnetic resonance imaging (CMR), a novel non-invasive technique, provides a unique assessment of cardiovascular structure and function, making it an essential tool for evaluating the risk of heart disease. In this study, we performed a Mendelian randomization analysis to determine the causal relationship between SLE and CMR traits. Methods:Genetic variants independently linked to SLE were selected from a genome-wide association study (GWAS) containing 5,201 cases and 9,066 controls as instrumental variables. A set of 82 CMR traits was obtained from a recent GWAS, serving as preclinical indicators and providing preliminary insights into the morphology and function of the four cardiac chambers and two aortic segments. Primary analysis employed a two-sample Mendelian randomization study using the inverse-variance weighted method. Heterogeneity testing, sensitivity analyses, and instrumental variable strength assessments confirmed the robustness of the findings. Results:SLE exhibited a correlation with increased stroke volume (β = 0.007, = 0.045), regional peak circumferential strain (β = 0.013, = 0.002; β = 0.009, = 0.043; β = 0.013, = 0.006), and global peak circumferential strain of the LV (β = 0.010, = 0.022), as well as decreased regional radial strain (β = -0.010, = 0.017). Conclusions:This research presents evidence of a potential causal association between traits of SLE and alterations in cardiac function, guiding cardiac examinations and disease prevention in lupus patients.
10.3389/fcvm.2024.1454645
Causal relationship and mediation effects of immune cells and plasma metabolites in atopic dermatitis: A Mendelian randomization study.
Medicine
Atopic dermatitis (AD) is a chronic inflammatory skin condition with complex etiology involving genetic, environmental, and immunological factors. This study employs Mendelian randomization to explore the causal relationships between immune cell phenotypes and AD, and the mediating effects of plasma metabolites. Using data from European cohorts, we identified 7 immune cell phenotypes significantly associated with AD. Mediation analysis revealed that the alpha-ketobutyrate to 4-methyl-2-oxopentanoate ratio negatively regulates CCR2 on monocytes, while the glycerol to carnitine ratio positively regulates HLA-DR on CD14- CD16- cells. These findings underscore the critical role of metabolic pathways in modulating immune responses and suggest potential dietary and therapeutic interventions for AD management. Further research should consider more diverse populations to validate these findings.
10.1097/MD.0000000000039932
Mendelian randomization evidence for the causal effect of mental well-being on healthy aging.
Nature human behaviour
Mental well-being relates to multitudinous lifestyle behaviours and morbidities and underpins healthy aging. Thus far, causal evidence on whether and in what pattern mental well-being impacts healthy aging and the underlying mediating pathways is unknown. Applying genetic instruments of the well-being spectrum and its four dimensions including life satisfaction, positive affect, neuroticism and depressive symptoms (n = 80,852 to 2,370,390), we performed two-sample Mendelian randomization analyses to estimate the causal effect of mental well-being on the genetically independent phenotype of aging (aging-GIP), a robust and representative aging phenotype, and its components including resilience, self-rated health, healthspan, parental lifespan and longevity (n = 36,745 to 1,012,240). Analyses were adjusted for income, education and occupation. All the data were from the largest available genome-wide association studies in populations of European descent. Better mental well-being spectrum (each one Z-score higher) was causally associated with a higher aging-GIP (β [95% confidence interval (CI)] in different models ranging from 1.00 [0.82-1.18] to 1.07 [0.91-1.24] standard deviations (s.d.)) independent of socioeconomic indicators. Similar association patterns were seen for resilience (β [95% CI] ranging from 0.97 [0.82-1.12] to 1.04 [0.91-1.17] s.d.), self-rated health (0.61 [0.43-0.79] to 0.76 [0.59-0.93] points), healthspan (odds ratio [95% CI] ranging from 1.23 [1.02-1.48] to 1.35 [1.11-1.65]) and parental lifespan (1.77 [0.010-3.54] to 2.95 [1.13-4.76] years). Two-step Mendelian randomization mediation analyses identified 33 out of 106 candidates as mediators between the well-being spectrum and the aging-GIP: mainly lifestyles (for example, TV watching and smoking), behaviours (for example, medication use) and diseases (for example, heart failure, attention-deficit hyperactivity disorder, stroke, coronary atherosclerosis and ischaemic heart disease), each exhibiting a mediation proportion of >5%. These findings underscore the importance of mental well-being in promoting healthy aging and inform preventive targets for bridging aging disparities attributable to suboptimal mental health.
10.1038/s41562-024-01905-9
Validation of TYK2 and exploration of PRSS36 as drug targets for psoriasis using Mendelian randomization.
Scientific reports
Psoriasis is a chronic inflammatory skin disorder with multiple causes, including genetic and environmental factors. Despite advances in treatment, there remains a need to identify novel therapeutic targets. A Mendelian randomization (MR) analysis was conducted to identify therapeutic targets for psoriasis. Data on cis-expression quantitative trait loci were obtained from the eQTLGen Consortium (n = 31,684). Summary statistics for psoriasis (outcome) were sourced from the GWAS Catalog with a sample size of 484,598, including 5,427 cases and 479,171 controls. Colocalization analysis was used to assess whether psoriasis risk and gene expression were driven by shared single nucleotide polymorphisms. Drug prediction and molecular docking were utilized to validate the pharmacological value of the drug targets. The MR analysis found that 81 drug targets were significantly associated, and two (TYK2 and PRSS36) were supported by colocalization analysis (PP.H4 > 0.80). Phenome-wide association studies did not show any associations with other traits at the gene level. Biologically, these genes were closely related to immune function. Molecular docking revealed strong binding with drugs and proteins, as supported by available structural data. This study validated TYK2 as a drug target for psoriasis, in line with its existing clinical use, including the development of decucravacitinib. PRSS36 is a potential novel target requiring further investigation.
10.1038/s41598-024-74148-3
Genetic Susceptibility of Thrombin Measurement Levels and the Risk of Colon Adenocarcinoma: A Mendelian Randomization Study.
British journal of hospital medicine (London, England : 2005)
This investigation sought to establish a possible correlation between thrombin measurement levels and the risk of developing colon adenocarcinoma (COAD). Thrombin measurement levels were sourced from a study by Pietzner M (2020, PMID: 33328453) and integrated into the IEU database. Data on COAD were obtained from the FinnGen database (2021, C3_COLON_ADENO). Various analytical methods were used to assess the relationship, including inverse variance weighting (IVW), mendelian randomization-Egger (MR-Egger) regression, as well as weighted median and mode techniques. Sensitivity analyses were performed, including Cochran's Q test, MR-Egger intercept test, mendelian randomization Pleiotropy RESidual Sum and Outlier (MR-PRESSO), along with leave-one-out analysis, to ensure the robustness of the results. The IVW analysis indicated a significant inverse association between elevated thrombin levels and the risk of COAD (odds ratio (OR) = 0.76, 95% CI = 0.66-0.88, = 0.0003). These findings were supported by the weighted median analysis (OR = 0.78, 95% CI = 0.68-0.90, = 0.0006) and the weighted mode analysis (OR = 0.78, 95% CI = 0.68-0.88, = 0.0017). This research identified an inverse causal relationship between thrombin measurement levels and the incidence of COAD, suggesting that higher thrombin levels are associated with a reduced risk of developing COAD.
10.12968/hmed.2024.0220
Exploration of the causality of frailty index on psoriasis: A Mendelian randomization study.
Skin research and technology : official journal of International Society for Bioengineering and the Skin (ISBS) [and] International Society for Digital Imaging of Skin (ISDIS) [and] International Society for Skin Imaging (ISSI)
BACKGROUND:Frailty is associated with a variety of diseases, but the relationship between frailty and psoriasis remains unclear. METHODS:First, we conducted a two-sample Mendelian randomization based on genome-wide association studies (GWAS) to investigate genetic causality between frailty index and common diseases in dermatology. Inverse variance weighted was used to estimate causality. Second, expression quantitative trait locus (eQTLs) analysis was conducted to identify the genes affected by Single nucleotide polymorphisms (SNPs). Third, we performed function and pathway enrichment, transcriptome-wide association studies (TWAS) analysis based on eQTLs. RESULTS:It was shown that the rise of frailty index could increase the risk of psoriasis (IVW, beta = 0.916, OR = 2.500, 95%CI:1.418-4.408, p = 0.002) through Mendelian randomization (MR), and there was no heterogeneity and pleiotropy. There was no causality between the frailty index and other common diseases in dermatology. We found 31 eQTLs based on strongly correlated SNPs in the causality. TWAS analysis found that the expressions of four genes were closely related to psoriasis, including HLA-DQA1, HLA-DQA2, HLA-DRB1 and HLA-DQB1. CONCLUSION:It suggested that the frailty index had a significant positive causality on the risk of psoriasis, which was well documented by combined genomic, transcriptome, and proteome analyses.
10.1111/srt.13641
Multivariate Mendelian randomization provides no evidence for causal associations among both psoriasis and psoriatic arthritis, and skin cancer.
Frontiers in immunology
Background:Some retrospective studies reported that psoriasis (PsO) and psoriatic arthritis (PsA) may have been associated with an elevated risk of skin cancer. The causal associations among them remain unclear. Objectives:To evaluate the causal association of among both PsO and PsA, and skin cancer. Methods:We performed large-scale two-sample and Multivariate Mendelian randomization analyses to examine whether there is a causal relationship between PsO and PsA, and skin cancer, encompassing basal cell carcinoma (BCC), cutaneous squamous cell carcinoma (cSCC), and cutaneous melanoma (CM). Results:Genetically predicted PsO, per log-odds ratio increase, showed no significant association with the risk of BCC, cSCC, and CM. The odds ratios (with corresponding 95% confidence intervals) for BCC, cSCC, and CM were 1.00 (0.99,1.01) (P = 0.990), 0.94(0.89, 1.00) (P = 0.065), and 0.99 (0.98, 1.01) (P = 0.239), respectively. PsA showed a significant association with a decreased risk of BCC, with odds ratios (with corresponding 95% confidence intervals) of 1.00 (1.00, 1.00) (P = 0.214) and 1.00 (1.00, 1.00) (P = 0.477), respectively. Univariate analysis of the FinnGen database demonstrated PsA did exhibit a significant association with the decrease risk of BCC, with an odds ratio of 0.94(0.90,0.99) (P = 0.016). However, this association disappeared after other risk factors were adjusted. Conclusions:Our findings suggest no causal association between PsO and PsA and the genetic risk of skin cancer. Further observational studies are required to elucidate the relationship among PsO, PsA, and skin cancer.
10.3389/fimmu.2023.1252720
Genetically predicted levels of circulating cytokines and the risk of six immune skin diseases: a two-sample Mendelian randomization study.
Frontiers in immunology
Background:Circulating cytokines play a crucial role in the onset and progression of immune skin diseases. However, the causal relationships and the direction of causal effects require further investigation. Methods:Two-sample Mendelian randomization (MR) analyses were conducted to assess the causal relationships between 41 circulating cytokines and six immune skin diseases including alopecia areata, chloasma, hidradenitis suppurativa (HS), lichen planus (LP), seborrheic dermatitis, and urticaria, using summary statistics from genome-wide association studies. Reverse MR analyses was performed to test for the reverse causation. Pleiotropy and heterogeneity tests were conducted to assess the robustness of the findings. Results:Twelve unique cytokines showed a suggestive causal relationship with the risk of six immune skin diseases. Among them, the causal effects between 9 unique cytokines and immune skin diseases have strong statistical power. Additionally, the concentrations of six cytokines might be influenced by LP and urticaria. After Bonferroni correction, the following associations remained significant: the causal effect of beta-nerve growth factor on HS (odds ratio [OR] = 1.634, 95% confidence interval [CI] = 1.226-2.177, p = 7.97e-04), interleukin (IL)-6 on LP (OR = 0.615, 95% CI = 0.481-0.786, p = 1.04e-04), IL-4 on LP (OR = 1.099. 95% CI = 1.020-1.184, p = 1.26e-02), and IL-2 on urticaria (OR = 0.712, 95% CI = 0.531-0.955, p = 2.33e-02). Conclusion:This study provides novel perspectives on the relationship between circulating cytokines and immune skin diseases, potentially providing valuable insights into their etiology, diagnostic approaches, and treatment.
10.3389/fimmu.2023.1240714
Mendelian Randomization Analysis Supports Causal Effect of Type II Diabetes Mellitus on Onychomycosis.
Skin appendage disorders
Introduction:Onychomycosis is common among adults with diabetes mellitus (DM). We used two-sample Mendelian randomization to estimate the causal effect of genetic risk for DM on onychomycosis and tinea skin infections in the All of Us Research Program. Methods:Onychomycosis and tinea corporis, pedis, manus, and cruris cases were identified using electronic health record data, and genetic instrument variables and summary statistics were collected from a type II DM (T2DM) genome-wide association study (GWAS) meta-analysis. Results:Inverse variance weighted regression showed positive effect of T2DM genetic risk on onychomycosis (beta = 0.135, = 1.86E-2), and weighted median regression produced a comparable estimate of effect size (beta = 0.148). There was no significant effect of T2DM on skin dermatophytosis. Conclusions:Our results suggest that T2DM has a positive causal effect on onychomycosis but not tinea skin infection risk. As onychomycosis may impair occupational function and increase risk for secondary soft tissue infections, patients with diabetes should be screened for onychomycosis and counseled on mitigating infection risk.
10.1159/000535921
Causal association of sleep traits with the risk of thyroid cancer: A mendelian randomization study.
BMC cancer
BACKGROUND:This study was to explore the causal associations of sleep traits including sleep duration, snoring, chronotype, sleep disorders, getting up in the morning, sleeplessness/insomnia and nap during day with the risk of thyroid cancer based on Mendelian randomization (MR) analysis. METHOD:Summary single nucleotide polymorphism (SNP)-phenotype association data were obtained from published genome-wide association studies (GWASs) using the FinnGen and UK Biobank databases. A series of screening processes were performed to select qualified SNPs strongly related to exposure. We applied the inverse variance weighted (IVW), the Mendelian Randomization robust adjusted profile score (MR-RAPS), the Mendelian randomization pleiotropy residual sum and outlier (MR-PRESSO), and the Weighted Median to estimate the causal links between sleep traits and the risk of thyroid cancer. Odds ratio (OR) and 95% confidence interval (CI) were calculated. RESULTS:The IVW results showed that getting up in the morning (OR = 0.055, 95%CI: 0.004-0.741) and napping during day (OR = 0.031, 95%CI: 0.002-0.462) were associated with decreased risk of thyroid cancer in the Italian population. A 1.30-h decrease of sleep duration was associated with 7.307-fold of thyroid cancer risk in the Finnish population (OR = 7.307, 95%CI: 1.642-32.519). Cronotype could decrease the risk of thyroid cancer in the Finnish population (OR = 0.282, 95%CI: 0.085-0.939). Sleep disorders increased the risk of thyroid cancer in the Finnish population (OR = 2.298, 95%CI: 1.194-4.422). The combined results revealed that sleep duration was correlated with increased risk of thyroid cancer (OR = 5.600, 95%CI: 1.458-21.486). CONCLUSION:Decreased sleep duration was associated with increased risk of thyroid cancer, which indicated the importance of adequate sleep for the prevention of thyroid cancer.
10.1186/s12885-024-12376-6
Evaluating the causality between skin tanning, radiated disorders, and basal cell carcinoma: a multivariable Mendelian randomization analysis.
Environmental science and pollution research international
The causality of ease of skin tanning and radiation-related disorders of the skin and subcutaneous tissue with basal cell carcinoma (BCC) remains unclear. Our objective was to investigate whether ease of skin tanning and radiation-related disorders of the skin and subcutaneous tissue have a relation with the occurrence and development of BCCs. In this work, independent genetic variants strongly associated (P < 5e-08) with ease of skin tanning and radiation-related disorders of the skin and subcutaneous tissue were selected as instrumental variables from corresponding genome-wide association studies (GWASs). Summary-level data for BCC was obtained from the European Bioinformatics Institute (EBI). Two-sample univariable and multivariable Mendelian randomization (MR) were performed. Sensitivity analyses were preformed via MR-Egger regression, heterogeneity test, pleiotropy test, and leave-one-out sensitivity test. We observed positive causal effect both for ease of skin tanning [odds ratio (OR) = 2.102, 95% confidence interval (CI) = 1.915-2.306, P = 2.71e-55] and radiation-related disorders of the skin and subcutaneous (OR = 1.603, 95% CI = 1.483-1.734, P = 3.41e-32) on occurrence of BCCs based on univariable MR analyses. In the multivariable mendelian randomization (MVMR) analysis of BCC risk, we also observed a direct causal effect of ease of skin tanning (ORMVMR = 1.623, 95% CI = 1.445-1.824, PMVMR =3.41e-16) and radiation-related disorders of the skin and subcutaneous (ORMVMR = 1.208, 95% CI = 1.107-1.319, PMVMR = 2.46e-05) on BCCs. The findings suggest that the high risk of BCCs can be attributed to ease of skin tanning and radiation-related disorders of the skin and subcutaneous tissue.
10.1007/s11356-023-27420-4
The causal effects of atopic dermatitis on the risk of skin cancers: A two-sample Mendelian randomization study.
Journal of the European Academy of Dermatology and Venereology : JEADV
BACKGROUND:Observational and epidemiological studies show conflicting results on the relationship between atopic dermatitis and skin cancer. Additionally, observational studies are susceptible to the reverse causation and confounders, thus, may not interpret true causal relationships. The causal effects of atopic dermatitis on the risk of skin cancers remains unclear. OBJECTIVES:To investigate the causal relationship between atopic dermatitis and skin cancer including cutaneous malignant melanoma, cutaneous squamous cell carcinoma, basal cell carcinoma and actinic keratosis. METHODS:We performed a two-sample Mendelian randomization analysis based on summary datasets of public genome-wide association studies of European ancestry. The inverse variance-weighted approach was applied as the main analysis. MR-Egger and weighted median methods were used to complement the inverse variance-weighted results. A series of sensitivity analyses were used to ensure the robustness of the causality estimates. RESULTS:Inverse variance-weighted method showed that genetically predicted dermatitis patients were significantly associated with an increased incidence of basal cell carcinoma (OR, 1.20; 95% CI, 1.10-1.31; p = 4.07E-05) and cutaneous squamous cell carcinoma (OR, 1.14; 95% CI, 1.10-1.19; p = 1.05E-11). However, we did not find a significant causality for atopic dermatitis on melanoma neither did we find actinic keratosis. Subsequent sensitive analyses supported these results. CONCLUSIONS:Our study identified the causality between atopic dermatitis basal cell carcinoma and squamous cell carcinoma. Accordingly, regular skin cancer screening is recommended for patients with atopic dermatitis.
10.1111/jdv.19674
Childhood sunburn and risk of melanoma and non-melanoma skin cancer: a Mendelian randomization study.
Environmental science and pollution research international
Previous evidence has suggested that childhood sunburn could be a risk factor for cutaneous malignant melanoma (MM) and non-melanoma skin cancer (NMSC). However, existing observational studies could not reveal the causal associations genetically. This study aimed to investigate whether there was a genetic causal relationship between childhood sunburn and skin cancers. Univariable Mendelian randomization (MR) and Causal Analysis Using Summary Effect analysis was carried out for causal estimates and evaluation for the horizontal pleiotropy. Multivariable MR and the mediation effects analysis were used to test whether the causal associations were mediated by potential confounders. A suggestively significant causal association between childhood sunburn and MM was indicated (OR = 4.74; 95% CI: 1.31-17.19; p = 1.79E-02). Genetically predicted childhood sunburn was significantly associated with increased risk of overall melanoma in situ (MIS) (OR = 4.02; 95% CI: 2.00-8.08; p = 9.40E-05), MIS of face (OR = 18.28; 95% CI: 5.28-63.35; p = 4.59E-06), and MIS of trunk (OR = 7.05; 95% CI: 2.06-24.13; p = 1.88E-03). Similar trends were found for childhood sunburn and NMSC (OR = 8.16; 95% CI: 6.07-10.99; p = 1.53E-20), including both basal cell carcinoma (BCC) (OR = 3.76; 95% CI:2.96-4.77; p = 2.19E-08) and squamous cell carcinoma (SCC) (OR = 7.44; 95% CI: 5.09-10.87; p = 2.19E-08). After adjustment for hair and skin color, facial ageing, vitamin D levels, body mass index, alcohol consumption, and smoking status, childhood sunburn showed an independent association with MIS, MIS of face, MIS of trunk, as well as NMSC, including both BCC and SCC. Mediation analysis showed no significant mediation effect. This study demonstrated a causal relationship between childhood sunburn and the risk of both MM and NMSC, which suggested that enhanced screening and prevention for childhood sunburn could contribute to the early detection and decreased risk of MM and NMSC.
10.1007/s11356-023-30535-3
The associations between gut microbiota and inflammatory skin diseases: a bi-directional two-sample Mendelian randomization study.
Frontiers in immunology
Background:Accumulating evidence shows that dysregulation of intestinal flora is associated with inflammatory skin diseases, specifically atopic dermatitis (AD), psoriasis (PSO), and rosacea (ROS). However, the causality is still unclear. Objectives:To study the underlying causality between gut microbiota (GM) and AD, PSO, and ROS, a bi-directional two-sample Mendelian randomization (2SMR) analysis was conducted. Methods:Summary statistics of gut microbiota, AD, PSO, and ROS were extracted from large-scale genome-wide association studies (GWASs). In 2SMR analysis, in addition to the inverse variance weighted as the principal method for evaluating causal association, four different methods were also used. Sensitivity analysis and reverse 2SMR study were implemented to evaluate the robustness of 2SMR results or reverse causal relationship, respectively. Results:A total of 24 specific gut microbiota species related to AD, PSO, and ROS were identified by 2SMR analysis. After using the Bonferroni method for multiple testing correction, family (ID: 1957) [OR = 1.28 (1.13, 1.45), = 9.26e-05] and genus (ID: 14373) [OR = 1.20 (1.09, 1.33), = 1.65e-04] were associated with an increased risk for AD and PSO, respectively. The genus showed a negative association, suggesting a protective role against both atopic dermatitis and rosacea. Our reverse 2SMR analysis indicated no reverse causality between these inflammatory skin diseases and the identified gut microbiota. Conclusions:In summary, this study provided evidence for the causality between GM and inflammatory skin diseases. These findings suggested that supplementing specific bacterial taxa may be an effective therapy for AD, PSO, and ROS.
10.3389/fimmu.2024.1297240
Mendelian Randomization Analysis reveals Inverse Genetic Risks between Skin Cancers and Vitiligo.
JID innovations : skin science from molecules to population health
Several observational studies have demonstrated a consistent pattern of decreased melanoma risk among patients with vitiligo. More recently, this finding has been supported by a suggested genetic relationship between the two entities, with certain variants significantly associated with an increased risk of melanoma, basal cell carcinoma, and squamous cell carcinoma but a decreased risk of vitiligo. We compared 48 associated variants from a recently published GWAS and identified three variants-located in the , , and loci- that correlated with an increased risk for melanoma, basal cell carcinoma, and squamous cell carcinoma and a decreased risk for vitiligo. We then used results of skin cancers and vitiligo GWAS to compare the shared genetic properties between these two traits through an unbiased Mendelian randomization analysis. Our results suggest that the inverse genetic relationship between common skin cancers and vitiligo is broader than previously reported owing to the influence of shared genome-wide significant associations.
10.1016/j.xjidi.2023.100217
Lipid-lowering medications and risk of malignant melanoma: a Mendelian randomization study.
Frontiers in oncology
Background:The relationship between blood lipids, lipid-modifying medications, and cancer risk has been under investigation for some time. Recent studies suggest that lipid-lowering medications might influence melanoma outcomes, though findings remain controversial. Our study aims to clarify the potential causal relationship between lipid-lowering drugs commonly used and melanoma incidence through a comprehensive Mendelian randomization (MR) analysis. Methods:Genetic variations within an LDL-related drug target gene (LDL-cholesterol from a genome-wide association study) served as proxies for exposure to lipid-lowering drugs. We conducted a two-sample Mendelian randomization analysis using inverse variance weighting (IVW), MR-Egger, and weighted median approaches. The MR-PRESSO test and pleiotropy_test were utilized to identify and adjust for horizontal pleiotropy. Stability and reliability of the Mendelian randomization findings were assessed using the leave-one-out method, Cochran's Q test, and funnel plot analysis. Odds ratios (OR) were employed to evaluate the causal relationship between genetic proxies of lipid-lowering drugs and melanoma risk. Results:IVW analysis revealed that HMGCR gene expression is linked to a decreased risk of melanoma [OR: 0.624(0.439-0.888); = 0.008]. Conversely, PCSK9 gene expression is tied to an elevated risk of melanoma [OR: 1.233(1.026-1.484); = 0.025]. No significant association was observed between NPC1L1 and melanoma. Conclusions:HMGCR inhibitors (statins) may increase melanoma risk, while PCSK9 inhibitors (evolocumab, alirocumab) could potentially decrease melanoma risk.
10.3389/fonc.2024.1408972
A two-step, two-sample Mendelian randomization analysis investigating the interplay between gut microbiota, immune cells, and melanoma skin cancer.
Medicine
This study aims to rigorously explore the potential causal relationships among gut microbiota (GM), immune cells, and melanoma skin cancer among participants from Europe, where this disease exhibits significant prevalence and profound societal impact. Using the genome-wide association analysis database, a double-sample Mendelian randomization (MR) analysis was drawn upon to investigate GM, immune cells, and melanoma skin cancer. The inverse variance weighted approach was applied to estimate the causal connections among these variables. A two-step MR analysis was employed to quantitatively gauge the impact of immune cells mediated GM on melanoma skin cancer. To address potential sources of bias, such as pleiotropy and heterogeneity, multiple analytical techniques were integrated. The MR analysis pinpointed 6 GM taxa related to either an augmented or declined risk of late-stage melanoma skin cancer. In the same vein, 32 immune cell phenotypes were noticed as correlates with modified risk of melanoma skin cancer. Our study also implies that the probable association between GM and melanoma could be facilitated by 5 immune cell phenotypes. The findings of our study underline certain GM taxa and immune cells as potential influencers on the onset and development of melanoma skin cancer. Importantly, our results spotlight 5 immune cell phenotypes as potential agents mediating this association.
10.1097/MD.0000000000040432
Investigating causal relationships between the gut microbiota and inflammatory skin diseases: A Mendelian randomization study.
The Australasian journal of dermatology
BACKGROUND:Numerous inflammatory skin diseases are associated with the gut microbiota. Studies of the association between gut microbiota and inflammatory skin diseases have yielded conflicting results owing to confounding factors, and the causal relationship between them remains undetermined. METHODS:Two-sample Mendelian randomization (MR) was used to examine the association between gut microbiota and four common inflammatory skin diseases: acne, psoriasis, urticaria and atopic dermatitis. The summary statistics of the gut microbiota from the largest available genome-wide association study meta-analysis (n = 13,266) conducted by the MiBioGen consortium along with the summary statistics of the four diseases were obtained from the FinnGen consortium. Causal relationships were assessed using the inverse variance weighted (IVW), weighted median, MR-Egger and maximum likelihood methods, and several sensitivity analyses were performed to ensure the accuracy of the results. Finally, reverse and multivariable MR analyses were performed to verify the robustness of the results. RESULTS:We found causal associations of Bacteroidaceae [odds ratio (OR), 2.25; 95% confidence interval (CI), 1.48-3.42; p = 0.0001], Allisonella (OR, 1.42; 95% CI, 1.18-1.70; p = 0.0002) and Bacteroides (OR, 2.25; 95% CI, 1.48-3.42; p = 0.0001) with acne, the Eubacterium fissicatena group with psoriasis (OR, 1.22; 95% CI, 1.10-1.35; p = 0.0002) and Intestinibacter with urticaria (OR, 1.28; 95% CI, 1.13-1.45; p = 0.0001). These results were corrected for a false discovery rate. Sensitivity analyses were performed to validate the robustness of the associations and reverse MR confirmed that the results were not influenced by the reverse effect. CONCLUSION:Our study revealed that some gut microbiota are risk factors for inflammatory skin diseases, providing new information on potential therapeutic targets. Additionally, a possible association with the gut-skin axis was confirmed. Further research is required to elucidate the mechanisms underlying these relationships.
10.1111/ajd.14231
Decoding skin mysteries: Unveiling the link between microbiota and keloid scars through a Mendelian randomization study.
Medicine
The cause of keloids remains unclear, but studies suggest a link between skin microbiota and keloid formation. However, the causal relationship has not been confirmed. This study utilized Genome-Wide Association Studies (GWAS) data from 2 population-based German cohorts, comprising a total of 1656 skin samples. To bolster the reliability of our results, we incorporated GWAS data from 3 keloid cohorts, encompassing 2555 patients and 870,556 controls (GWAS ID: keloid1, ebi-a-GCST90018874; keloid2, bbj-a-131; keloid3, ebi-a-GCST90018654). Subsequently, we employed bidirectional 2-sample Mendelian randomization (MR) analysis to probe the causal relationship between the variables. The primary method employed was the inverse-variance weighted (IVW) method, supported by heterogeneity analysis, horizontal pleiotropy testing, outlier detection, and "leave-one-out" sensitivity analysis. By synthesizing the results from 3 groups of MR analyses, we discovered a negative causal association between a.ASV063 [Finegoldia (unc.)] located on the volar forearm and keloid disease (IVW (keloid1) odds ratio (OR): 0.939, 95% confidence interval (CI): 0.886-0.994, P = .032; IVW (keloid2) OR: 0.897, 95% CI: 0.813-0.990, P = .031; IVW (keloid3) OR: 0.900, 95% CI: 0.825-0.981, P = .017). Similarly, a negative causal relationship may also exist between the genus: Bacteroides from the antecubital fossa and keloid disease (IVW (keloid1) OR: 0.928, 95% CI: 0.884-0.973, P = .002; IVW (keloid2) OR: 0.891, 95% CI: 0.820-0.968, P = .007; IVW (keloid3) OR: 0.918, 95% CI: 0.849-0.992, P = .030). Additionally, no reverse causation was found, with all analyses showing no signs of horizontal pleiotropy or heterogeneity. This study offers new insights for the prevention and treatment of keloids.
10.1097/MD.0000000000040004
Natural hair color and skin cancers: A two-sample Mendelian randomization study.
Gene
Previous observational studies have indicated an association between hair color and the risk of melanoma and keratinocyte skin cancer (KSC); however, different hair colors show inconsistent effects on skin cancers. Here, we conducted a two-sample Mendelian randomization (MR) study to evaluate the causal relationship between natural hair color and skin cancers by using 211 single nucleotide polymorphisms as genetic instruments from a genome-wide meta-analysis of 360,270 individuals of European ancestry. Light hair colors (red, blonde, and light brown) were associated with high levels of cutaneous melanoma (CM) and KSC (CM-inverse variance weighted [IVW] odds ratio [OR]-red: 1.034, 95% confidence interval [CI]: 1.025-1.044, P < 0.001; OR-blonde: 1.008, 95% CI: 1.003-1.014, P = 0.003; OR-light brown: 1.006, 95% CI: 1.002-1.011, P = 0.009; KSC-IVW OR-red: 1.078, 95% CI: 1.053-1.103, P < 0.001; OR-blonde: 1.024, 95% CI: 1.009-1.040, P = 0.002; OR-light brown: 1.018, 95% CI: 1.004-1.033, P = 0.01). However, dark brown hair showed an inverse causal relationship with skin cancers (CM IVW OR: 0.987, 95% CI: 0.984-0.990, P < 0.001; KSC IVW OR: 0.979, 95% CI: 0.970-0.988, P < 0.001). Black hair was associated with a decreased risk of KSC (IVW OR: 0.954, 95% CI: 0.913-0.997, P = 0.036) but showed no causal relationship with CM. The present study provides strong MR evidence of a causal association between hair color and skin cancer. Secondary MR analyses enhances result robustness by replicating findings, exploring gender-specific effects, and providing a more comprehensive understanding of the complex relationship between hair color and skin cancers. More large-scale MR studies or randomized controlled trials are required to further investigate the mechanisms of the association between hair color and skin cancers.
10.1016/j.gene.2023.147940
Causal relationship between genetically determined plasma metabolites and skin cancer: a two-sample Mendelian randomization study.
Archives of dermatological research
We aimed to unveil the underlying pathogenic mechanisms of skin cancer in relation to metabolic factors and pathway mechanisms. This study utilized the TwoSample Mendelian randomization (MR) method to investigate the causal relationship between 1400 plasma metabolites and skin cancer. The primary method employed was the inverse variance weighting (IVW). Through IVW analysis, we found 105 plasma metabolites associated with Basal Cell Carcinoma (BCC), with the highest association observed for Prolylglycine levels (OR [95% CI]: 1.1902 [1.0274, 1.3788]). For Malignant Melanoma of Skin (MSS), 68 plasma metabolites were linked, with the highest causal relationship seen for 3-Hydroxybutyrate levels (OR [95% CI]: 1.0030 [1.0013, 1.0048]). Regarding actinic keratosis (AK), and the highest association observed for Hexadecadienoate (16:2n6) levels (OR [95% CI]: 1.3302 [1.0333, 1.7125]). Glycerol to palmitoylcarnitine (16: n6) levels (OR [95% CI]: 1.3302 [1.0333, 1.125]) were found to be significant for BCC and AK. Palmitoylcarnitine (C16) had the most positive causal effect for BCC (OR [95% CI]: 1.1777 [1.0493, 1.3218]), while 5-hydroxy-2-methylpyridine sulfate levels had the highest effect for AK (OR [95% CI]: 1.1788 [1.0295, 1.3498]). And 4-guanidinobutanoate levels had the largest positive causal effect (OR [95% CI]: 1.0857 [1.0417, 1.1317]) for BCC, and X-11880 levels for MSS (OR [95% CI]: 1.0013 [1.0000, 1.0025]). The study revealed a positive association between hereditary Glycerol to palmitoylcarnitine (C16) and 5-hydroxy-2-methylpyridine sulfate levels with the risk of developing BCC and AK. Additionally, 4-guanidinobutanoate levels and X 11880 levels were found to be positively associated with the risk of BCC and MMS.
10.1007/s00403-024-03011-2
The causal effects of inflammatory and autoimmune skin diseases on thyroid diseases: evidence from Mendelian randomization study.
Frontiers in endocrinology
Background:To clarify the controversy between inflammatory or autoimmune skin diseases and thyroid diseases, we performed two-sample Mendelian randomization (MR) analyses. Participants:Genetic data on factors associated with atopic dermatitis (AD, n=40,835), seborrheic dermatitis (SD, n=339,277), acne (n=363,927), rosacea (n=299,421), urticaria (n=374,758), psoriasis (n=373,338), psoriasis vulgaris (n=369,830), systemic lupus erythematosus (SLE, n=14,267), vitiligo (n=353,348), alopecia areata (AA, n=361,822), pemphigus (n=375,929), bullous pemphigoid (BP, n=376,274), systemic sclerosis (SSc, n=376,864), localized scleroderma (LS, n=353,449), hypothyroidism (n=314,995 or n=337,159), and hyperthyroidism (n=281,683 or n=337,159) were derived from genome-wide association summary statistics of European ancestry. Main measures:The inverse variance weighted method was employed to obtain the causal estimates of inflammatory or autoimmune skin diseases on the risk of thyroid diseases, complemented by MR-Egger, weighted median, and MR-pleiotropy residual sum and outlier (MR-PRESSO). Key results:AD, SLE, SD, and psoriasis vulgaris were associated with an increased risk of hypothyroidism, whereas BP was associated with a lower risk of hypothyroidism (all with p < 0.05). The multivariable MR analyses showed that AD (OR = 1.053; 95%CI: 1.015-1.092; p = 0.006), SLE (OR = 1.093; 95%CI: 1.059-1.127; p < 0.001), and SD (OR = 1.006; 95%CI: 1.002-1.010; p = 0.006) independently and predominately contributed to the genetic causal effect on hypothyroidism after adjusting for smoking. The results showed no causal effects of inflammatory or autoimmune skin diseases on hyperthyroidism. Conclusion:The findings showed a causal effect of AD, SLE, SD on hypothyroidism, but further investigations should be conducted to explore the pathogenic mechanisms underlying these relationships.
10.3389/fendo.2024.1388047
The causal effects of inflammatory bowel disease on skin carcinoma: A two-sample Mendelian randomization study.
Medicine
Observational studies have indicated that inflammatory bowel disease (IBD) patients have higher incidence of skin carcinoma (SC), including melanoma skin carcinoma (MSC) and nonmelanoma skin carcinoma (NMSC) than healthy people. However, whether there is a causal relationship between the 2 is unclear. The purpose of this study was to evaluate the causality of IBD on SC using the Mendelian randomization (MR) analysis. We performed a two-sample MR analysis using publicly available genome-wide association study data. Eligible instrumental variables were selected based on the 3 core assumptions of MR analysis. The inverse-variance weighted (IVW) approach served as the primary analytical method. Supplementary analyses were conducted using MR-Egger regression, the weighted median, the weighted mode, and MR pleiotropy residual sum and outlier methods. Genetically predicted IBD (IVW odds ratio [OR] = 1.07, 95% confidence interval [CI]: 1.02-1.13, P = .011) and ulcerative colitis (UC; IVW OR = 1.09, 95% CI: 1.03-1.16, P = .003) were associated with an increased risk of MSC. Results of complementary methods were consistent with those of the IVW method with the exception of the weighted mode. In addition, Crohn disease (CD; IVW OR = 1.04, 95% CI: 0.99-1.08, P = .128) did not have a causal effect on MSC. Moreover, IBD (IVW OR = 1.03, 95% CI: 1.00-1.07, P = .034) and CD (IVW OR = 1.03, 95% CI: 1.00-1.06, P = .045) were associated with an increased risk of NMSC. However, UC (IVW OR = 1.00, 95% CI: 0.97-1.04, P = .803) was not significantly associated with an increased risk of NMSC. Our study revealed genetically predicted associations between IBD and the risks of MSC and NMSC in European populations. Furthermore, UC was associated with an increased risk of MSC, while CD was associated with a higher risk of NMSC. However, the potential influence of immunosuppressive agents or biologics cannot be excluded.
10.1097/MD.0000000000039997
Relationship between circulating white blood cell count and inflammatory skin disease: a bidirectional mendelian randomization study.
Archives of dermatological research
Observational studies have shown a strong association between circulating white blood cell counts (WBC) and inflammatory skin diseases such as acne and psoriasis. However, the causal nature of this relationship is unclear. We performed a two-way two-sample Mendelian randomization (MR) analysis to investigate potential causal relationships between leukocytes and inflammatory skin diseases. The circulating white blood cell count, basophil cell count, leukocyte cell count, lymphocyte cell count, eosinophil cell count, and neutrophil cell count data were obtained from the Blood Cell Consortium (BCX). The data for inflammatory skin disorders, including acne, atopic dermatitis (AD), hidradenitis suppurativa (HS), psoriasis, and seborrheic dermatitis (SD), were obtained from the FinnGen Consortium R10. The primary analysis utilized inverse variance weighting (IVW) along with additional methods such as MR-Egger, weighted mode, and weighted median estimator. To assess heterogeneity among instrument variables, Cochran's Q test was employed, while MR-Egger intercept and MR-PRESSO were used to test for horizontal pleiotropy. IVW demonstrated that an elevated monocyte count was significantly associated with a decreased risk of psoriasis (OR = 0.897, 95% CI: 0.841-0.957, P = 0.001, FDR = 0.016). Additionally, an increased eosinophil count was causally associated with a higher risk of AD (OR = 1.188, 95% CI: 1.093-1.293, P = 0.000, FDR = 0.002). No inverse causal relationship between inflammatory skin disease and circulating white blood cell count was found. In conclusion, this study provides evidence that increased monocyte count is associated with a reduced risk of psoriasis and that there is a causal relationship between increased eosinophil counts and an increased risk of AD. These findings help us understand the potential causal role of specific white blood cell counts in the development of inflammatory skin diseases.
10.1007/s00403-024-03241-4
Genetic insights into the gut microbiota and risk of facial skin aging: A Mendelian randomization study.
Skin research and technology : official journal of International Society for Bioengineering and the Skin (ISBS) [and] International Society for Digital Imaging of Skin (ISDIS) [and] International Society for Skin Imaging (ISSI)
BACKGROUND:A growing number of experimental studies have shown an association between the gut microbiota (GM) and facial skin aging. However, the causal relationship between GM and facial skin aging remains unclear to date. METHODS:We conducted a two-sample Mendelian randomization (MR) analysis to investigate the potential causal relationship between GM and facial skin aging. MR analysis was mainly performed using the inverse-variance weighting (IVW) method, complemented by the weighted median (MW) method, MR-Egger regression, and weighted mode, and sensitivity analysis was used to test the reliability of MR analysis results. RESULTS:Eleven GM taxa associated with facial skin aging were identified by IVW method analysis, Family Victivallaceae (p = 0.010), Genus Eubacterium coprostanoligenes group (p = 0.038), and Genus Parasutterella (p = 0.011) were negatively associated with facial skin aging, while Phylum Verrucomicrobia (p = 0.034), Family Lactobacillaceae (p = 0.017) and its subgroups Genus Lactobacillus (p = 0.038), Genus Parabacteroides (p = 0.040), Genus Eggerthella (p = 0.049), Genus Family XIII UCG001 (p = 0.036), Genus Phascolarctobacterium (p = 0.027), and Genus Ruminococcaceae UCG005 (p = 0.012) were positively associated with facial skin aging. At Class and Order levels, we did not find a causal relationship between GM and facial skin aging. Results of sensitivity analyses did not show evidence of pleiotropy and heterogeneity. CONCLUSION:Our findings confirm the causal relationship between GM and facial skin aging, providing a new perspective on delaying facial aging.
10.1111/srt.13636
Exploring the Association between Gut Microbiota and Inflammatory Skin Diseases: A Two-Sample Mendelian Randomization Analysis.
Microorganisms
Emerging research underscores the substantial link between gut flora and various inflammatory skin diseases. We hypothesize that there exists a complex gut-skin axis, possibly affecting the progression of conditions such as eczema, acne, psoriasis, and rosacea. However, the precise nature of the causal connection between gut flora and skin diseases remains unestablished. In this study, we started by compiling summary data from genome-wide association studies (GWAS) featuring 211 unique gut microbiota and four types of skin conditions. We scrutinized these data across different taxonomic strata. Subsequently, we leveraged Mendelian randomization (MR) to ascertain if there is a causal link between gut microbiota and these skin conditions. We also performed a bidirectional MR analysis to identify the causality's direction. By utilizing Mendelian randomization, we identified 26 causal connections between the gut microbiome and four recognized inflammatory skin conditions, including 9 positive and 17 negative causal directions. Additional sensitivity analyses of these results revealed no evidence of pleiotropy or heterogeneity. Our MR analysis suggests a causal connection between gut microbiota and skin diseases, potentially providing groundbreaking perspectives for future mechanistic and clinical studies on microbiota-affected skin conditions.
10.3390/microorganisms11102586
Role of Ubiquitin-conjugating enzyme E2 (UBE2) in two immune-mediated inflammatory skin diseases: a mendelian randomization analysis.
Archives of dermatological research
Psoriasis vulgaris (PV) and Atopic dermatitis (AD) are the two major types of immune-mediated inflammatory skin disease (IMISD). Limited studies reported the association between Ubiquitin-conjugating enzyme E2 (UBE2) and IMISD. We employed a two-sample Mendelian randomization (MR) study to assess the causality between UBE2 and PV & AD. UBE2 association genome-wide association study (GWAS) data were collected. The inverse variance weighted (IVW) method was utilized as the principal method in our Mendelian randomization (MR) study, with additional using the MR-Egger, weighted median, simple mode, and weighted mode methods. The MR-Egger intercept test, Cochran's Q test, MR-Pleiotropy RESidual Sum and Outlier (MR-PRESSO) and leave-one-out analysis were conducted to identify heterogeneity and pleiotropy, colocalization analysis was also performed. The results showed that Ubiquitin-conjugating enzyme E2 variant 1 (UBE2V1) was causally associated with PV (OR = 0.909, 95% CI: 0.830-0.996, P = 0.040), Ubiquitin-conjugating enzyme E2 L3 (UBE2L3) was causally associated with AD (OR = 0.799, 95% CI: 0.709-0.990, P < 0.001). Both UBE2V1 and UBE2L3 may play protective roles in patients with PV or AD, respectively. No other significant result has been investigated. No heterogeneity or pleiotropy was observed. This study provided new evidence of the relationship between UBE2V1 and PV, UBE2L3 and AD. Our MR suggested that UBE2V1 plays an inhibitory role in PV progression, UBE2L3 plays an inhibitory role in AD. These could be novel and effective ways to treat PV and AD.
10.1007/s00403-024-02976-4
Causal effects of lipid-lowering drugs on skin diseases: a two-sample Mendelian randomization study.
Frontiers in medicine
Background:Although previous studies have indicated an association between low-density lipoprotein (LDL) and skin diseases, their causal effects remain inconclusive. This study aimed to assess the causal relationship between genetically proxied lipid-lowering drugs and skin cancers and psoriasis. Methods:Two-sample Mendelian randomization (MR) analysis was performed using single-nucleotide polymorphisms (SNPs) from genome-wide association studies (GWAS). The inverse-variance weighted (IVW) method was used to determine causal relationships. The "leave-one-out" sensitivity test, Cochran's Q-statistic and MR-Egger intercept were used to assess heterogeneity and horizontal pleiotropy. Results:We identified 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) and proprotein convertase subtilisin-kexin type 9 (PCSK9) as genetically proxied lipid-lowering drugs. Genetically proxied inhibition of HMGCR (stains) was causally associated with reduced risk of nonmelanoma skin cancer (OR 0.982, 95% CI 0.967-0.997, = 0.016 by weighted median; OR 0.977, 95% CI 0.966-0.989, < 0.001 by IVW) and psoriasis (OR 0.585, 95% CI 0.378-0.905, = 0.016 by IVW), while PCSK9 inhibition (alirocumab) was causally associated with reduced risk of psoriasis (OR 0.560, 95% CI 0.413-0.761 by weighted median; OR 0.564, 95% CI 0.447-0.712 by IVW; < 0.001) in the ieu-b-5089 dataset. Similar results were observed in the ieu-b-110 dataset for HMGCR and PCSK9. Sensitivity analysis revealed no evidence of heterogeneity or horizontal pleiotropy. Conclusion:This study revealed the existing HMGCR inhibitors (stains) might be protective for reducing nonmelanoma skin cancer risk, and HMGCR inhibitors (stains) and PCSK9 inhibitor (alirocumab) might be promising for reducing psoriasis risk in the European population.
10.3389/fmed.2024.1396036
Beverage consumption and facial skin aging: Evidence from Mendelian randomization analysis.
Journal of cosmetic dermatology
BACKGROUND:Observational studies have linked coffee, alcohol, tea, and sugar-sweetened beverage (SSB) consumption to facial skin aging. However, confounding factors may influence these studies. The present two-sample Mendelian randomization (MR) investigated the potential causal association between beverage consumption and facial skin aging. METHODS:The single-nucleotide polymorphisms (SNPs) associated with coffee, alcohol, and tea intake were derived from the IEU project. The SSB-associated SNPs were selected from a genome-wide association study (GWAS). Data on facial skin aging were derived from the largest GWAS involving 16 677 European individuals. The inverse variance-weighted (IVW) was the main MR analysis method, supplemented by other methods (MR-Egger, weighted median, simple mode, and weighted mode). The MR-Egger intercept analysis was used for sensitivity analysis. Moreover, we conducted a replication analysis using data from another GWAS dataset on coffee consumption to validate our findings. RESULTS:Four instrumental variables (IVs) sets were used to examine the causal association between beverage consumption (coffee, alcohol, tea, SSB) and facial skin aging. Our results revealed that genetically predicted higher coffee consumption reduced the risk of facial skin aging (OR: 0.852; 95% CI: 0.753-0.964; p = 0.011, IVW method). The sensitivity analysis confirmed the robustness of the findings, with no evidence of pleiotropy or heterogeneity. The results of replicated MR analysis on coffee consumption were consistent with the initial analysis (OR = 0.997; 95% CI = 0.996-0.999; p = 0.003, IVW method). CONCLUSIONS:This study manifests that higher coffee consumption is significantly associated with a reduced risk of facial skin aging. These findings can offer novel strategies for identifying the underlying etiology of facial skin aging.
10.1111/jocd.16153
Inflammatory Bowel Disease and Skin Cancer: A Two-Sample Mendelian Randomization Analysis.
Genetic testing and molecular biomarkers
At present, numerous clinical studies suggest a correlation between inflammatory bowel disease (IBD) and skin cancer. However, some articles present differing views that IBD does not increase the risk of skin cancer. The presence of potential reverse causality and residual confounding is inherent in conventional observational studies. Thus, this study used a two-sample Mendelian randomization (MR) study design to estimate the causal effect of IBD on the risk of skin cancer, including cutaneous malignant melanoma (CMM, also named melanoma skin cancer) and nonmelanoma skin cancer (NMSC). In this study, a two-sample MR analysis was used to estimate the causal effect of IBD on skin cancer outcomes. The inverse-variance weighted (IVW) method was used as the main MR analysis, with multiple sensitivity analyses conducted to assess the robustness of findings. In examining the association between IBD and NMSC, all -values of the IVW methods were found to be <0.05, providing evidence for a causal effect of IBD on an increased risk of NMSC. However, IVW for IBD on CMM yielded -values >0.05, indicating no causal relationship between IBD and CMM. These findings were consistent across other MR methods, with no evidence of pleiotropy or heterogeneity. Sensitivity analyses confirmed the robustness of our results. Using MR analysis, we found evidence for a causal effect of genetic liability for IBD on an increased risk of NMSC. However, our study did not find sufficient evidence to support a significant impact of IBD on CMM outcomes.
10.1089/gtmb.2023.0480
Associations between type 1 diabetes and autoimmune skin diseases: Mendelian randomization analysis.
Heliyon
Background:Type 1 diabetes mellitus (T1DM) may be associated with various autoimmune diseases, but the causal relationship between T1DM and autoimmune skin diseases is not yet clear. Methods:The summary statistical data on T1DM and nine autoimmune skin diseases in European populations were extracted for mendelian randomization (MR) analysis. Subsequently, the analysis was replicated in East Asian populations. In the MR estimation, inverse variance-weighted (IVW), MR-Egger, weighted median, simple mode, and weighted mode methods were utilized. Outliers were excluded using MR-PRESSO, and horizontal pleiotropy was assessed with MR-Egger. Additionally, a multivariable MR analysis was conducted to investigate whether T1DM has an independent effect on autoimmune skin diseases after adjusting for potential confounders. Results:In Europe, the MR estimated based on IVW method indicated a causal association between genetically determined T1DM and systemic lupus erythematosus (SLE) (OR = 1.38, 95%CI: 1.26-1.50, p<0.01), rheumatoid arthritis (RA) (OR = 1.15, 95%CI: 1.05-1.25, p<0.01), as well as multiple sclerosis (MS) (OR = 1.17, 95%CI: 1.01-1.36, p = 0.04), but there is no association between T1DM and atopic dermatitis (AD), vitiligo, lichen planus (LP), hidradenitis suppurativa (HS), alopecia areata (AA) and systemic sclerosis (SS). After adjusting for time spent watching television, body mass index, type 2 diabetes mellitus, and body fat percentage, we found a causal relationship between T1DM and SLE (OR = 1.29, 95%CI: 1.16-1.44, p < 0.01), RA (OR = 1.28, 95%CI: 1.20-1.38 p < 0.01) and MS (OR = 1.11, 95%CI: 1.04-1.18, p < 0.01). Then, no genetic causal association was found between TIDM and SLE, and AD in East Asia. These results didn't exhibit horizontal pleiotropy, and "leave-one-out" analysis demonstrated result stability. Conclusion:Our MR research indicates a causal relationship between T1DM and SLE, RA, and MS in Europe. However, no causal relationship between T1DM and SLE has been observed in East Asia. Therefore, it is important to regularly monitor relevant immunological markers of SLE, RA, and MS in T1DM patients and take preventive measures.
10.1016/j.heliyon.2024.e32781
Causal relationship between inflammatory skin diseases and breast cancer: A bidirectional Mendelian randomization study.
Skin research and technology : official journal of International Society for Bioengineering and the Skin (ISBS) [and] International Society for Digital Imaging of Skin (ISDIS) [and] International Society for Skin Imaging (ISSI)
INTRODUCTION:Prior research has explored the relationship between inflammatory skin disorders and breast cancer (BC), yet the causality of this association remains uncertain. METHODS:Utilizing a bidirectional two-sample Mendelian randomization (MR) approach, this study aimed to elucidate the causal dynamics between various inflammatory skin conditions-namely acne, atopic dermatitis, psoriasis vulgaris, urticaria, and rosacea-and BC. Genetic variants implicated in these disorders were sourced from comprehensive genome-wide association studies representative of European ancestry. In the forward MR, BC was posited as the exposure, while the reverse MR treated each inflammatory skin disease as the exposure. A suite of analytical methodologies, including random effects inverse variance weighted (IVW), weighted median (WME), and MR-Egger, were employed to probe the causative links between inflammatory skin diseases and BC. Sensitivity analyses, alongside evaluations for heterogeneity and pleiotropy, were conducted to substantiate the findings. RESULTS:The MR analysis revealed an increased risk of acne associated with BC (IVW: OR = 1.063, 95% CI = 1.011-1.117, p = 0.016), while noting a decreased risk of atopic dermatitis (AD) in BC patients (IVW: OR = 0.941, 95% CI = 0.886-0.999, p = 0.047). No significant associations were observed between BC and psoriasis vulgaris, urticaria, or rosacea. Conversely, reverse MR analyses detected no effect of BC on the incidence of inflammatory skin diseases. The absence of pleiotropy and the consistency of these outcomes strengthen the study's conclusions. CONCLUSION:Findings indicate an elevated incidence of acne and a reduced incidence of AD in individuals with BC within the European population.
10.1111/srt.13782
The Causal Relationship Between Skin Microbiota and Facial Aging: A Mendelian Randomization Study.
Aesthetic plastic surgery
BACKGROUND:Facial aging is a complex process influenced by environmental factors, genetics, and lifestyle. The contribution of the skin microbiota to this process remains poorly understood. METHODS:This two-sample Mendelian randomization (MR) study was performed using genome-wide genotype data from the UK Biobank and previously published studies on skin microbiota. The primary approach for MR analyses included inverse-variance weighting (IVW), MR-Egger regression, simple mode, weighted median, and weighted mode methods. Sensitivity analyses were performed to assess heterogeneity and pleiotropy, and reverse-direction MR analyses were performed to evaluate potential reverse causation. RESULTS:The MR analysis identified ten skin microbiotas with potential causal relationships with facial aging. Protective skin microbiotas included Genus Finegoldia, ASV011 [Staphylococcus (unc.)], ASV008 [Staphylococcus (unc.)], phylum Firmicutes, Family Rhodobacteraceae, and ASV021 [Micrococcus (unc.)], which were negatively associated with facial aging. Conversely, Order Pseudomonadales, Family Moraxellaceae, ASV039 [Acinetobacter (unc.)], and phylum Bacteroidetes were positively associated with facial aging, indicating a risk factor for accelerated aging. Sensitivity analyses confirmed the robustness of these findings, and reverse-direction MR analyses did not suggest any reverse causation. CONCLUSION:This study identified specific skin microbial that may influence facial aging and offered new insights into the rejuvenation strategies. NO LEVEL ASSIGNED:This journal requires that authors assign a level of evidence to each submission to which Evidence-Based Medicine rankings are applicable. This excludes Review Articles, Book Reviews, and manuscripts that concern Basic Science, Animal Studies, Cadaver Studies, and Experimental Studies. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .
10.1007/s00266-024-04217-5
Can alterations in cathepsin levels restrain the development of skin cancer?: A bidirectional multivariate Mendelian-randomization study.
Medicine
Malignant skin tumors mainly include basal cell carcinoma, squamous cell carcinoma, and malignant melanoma. There is currently observational research suggesting that changes in cathepsin (CTS) may be a factor in the development of malignant skin tumors, but no studies have yet demonstrated a causal relationship between tissue protease changes and the occurrence of malignant skin tumors. Current studies have shown that cathepsin is involved in tumor cell invasion and metastasis by regulating growth factors and cellular immune function in tumor microenvironment, decomposing extracellular matrix and basement membrane, and promoting angiogenesis. In this study, we conducted a bidirectional Mendelian-randomization study using publicly available genome-wide association study (GWAS; GWAS Catalog) data. This study applies a bidirectional multivariate Mendelian randomization (MR) approach to investigate the causal relationship between cathepsin, basal cell carcinoma, squamous cell carcinoma, and malignant melanoma. In cases where multiple cathepsins are implicated as etiological factors in certain diseases, a multivariable analysis is conducted to assess the direct and indirect causal effects of the exposure factors. In this study, we present a comprehensive MR analysis to investigate the relationship between 9 cathepsin and basal cell carcinoma, squamous cell carcinoma, and malignant melanoma. Based on our MR analysis using the largest GWAS Catalog dataset available, we are able to draw relatively reliable conclusions. In the MR study, we found that tissue protease L2 can promote skin cancer, Cathepsin O, and Cathepsin F are associated with an increased risk of basal cell carcinoma. Cathepsin H can inhibit basal cell carcinoma and malignant melanoma. In the reverse MR study, it was found that squamous cell carcinoma may cause an increase in Cathepsin O expression. In the multivariate analysis, it was found that Cathepsin H is a direct factor in reducing the occurrence of skin cancer and melanoma, with no apparent causal relationship to non-melanoma skin cancer. Cathepsin has a dual impact on skin cancer cells, and the expression of different cathepsins at the edge of skin tumors may indicate different developmental tendencies of skin cancer. Cathepsin may serve as effective biomarkers for predicting tumors.
10.1097/MD.0000000000039628
Exploring the association between skin microbiota and inflammatory skin diseases: a two-sample Mendelian randomization analysis.
Archives of dermatological research
Dysbiosis in the skin microbiome is closely associated with various inflammatory skin diseases. However, current research on the causal relationship between the skin microbiome and inflammatory skin diseases lacks comprehensive and detailed investigation. We used a two-sample Mendelian randomization (MR) approach to explore associations between the skin microbiome and seven inflammatory skin diseases, including acne, atopic dermatitis, erysipelas, vitiligo, psoriasis, rosacea, and urticaria. The GWAS summary data for the skin microbiome was derived from 647 participants in two German population-based cohorts, and for the inflammatory skin diseases, they were sourced from the FinnGen consortium. Our primary MR analysis method was the inverse variance weighted (IVW) method, complemented by alternatives like MR-Egger regression, weighted median estimation, and constrained maximum likelihood. Sensitivity analyses, including Cochran's Q test, MR-Egger intercept test, and MR-PRESSO outlier detection, were conducted to validate and stabilize our findings. We identified significant causal relationships between the skin microbiome and seven inflammatory skin diseases: acne, atopic dermatitis, erysipelas, vitiligo, psoriasis, rosacea, and urticaria, with 7, 6, 9, 1, 7, 4, and 7 respective causal relationships for each disease. These relationships comprise 20 protective and 14 risk causal relationships. We applied the false discovery rate correction to these results. Sensitivity analysis revealed no significant pleiotropy or heterogeneity. Our study revealed both beneficial and detrimental causal relationships between diverse skin microbiota and inflammatory skin diseases. Additionally, the ecological niche of the skin microbiome was crucial to its functional impact. This research provided new insights into how skin microbiota impacted skin diseases and the development of therapeutic strategies.
10.1007/s00403-024-03433-y
Causal relationship between 150 skin microbiomes and prostate cancer: insights from bidirectional mendelian randomization and meta-analysis.
Frontiers in immunology
Background:Despite relevant research, the relationship between skin microbiomes and prostate cancer remains controversial. This study utilizes bidirectional Mendelian randomization (MR) analysis combined with meta-analysis to explore the potential link between the two. Objective:This study aims to identify the causal relationship between 150 skin microbiomes and prostate cancer (PCa) using bidirectional Mendelian randomization (MR) and meta-analysis. Methods:This study employed a comprehensive Bidirectional Two-sample MR analysis using publicly available genetic data to ascertain the relationship between 150 skin microbiomes and PCa. We conducted extensive sensitivity analyses, tests for heterogeneity, and assessments of horizontal pleiotropy to ensure the accuracy of our results. Subsequently, we conducted a meta-analysis to strengthen our conclusions' robustness further. Finally, we performed reverse causal verification on the positive skin microbiomes and PCa. Results:After conducting a meta-analysis and multiple corrections of the MR analysis results, our findings reveal a correlation between Neisseria in dry skin and PCa risk, identifying it as a risk factor. The IVW result shows an of 1.009 (95% : 1.004-1.014, = 0.027). Furthermore, the reverse MR analysis indicates the absence of an inverse causal relationship between the two. Apart from the identified skin microbiome, no significant associations were found between the other microbiomes and PCa. Conclusions:The study identified a correlation between Neisseria in dry skin, one of the 150 skin microbiomes, and the risk of developing PCa, establishing it as a risk factor for increased susceptibility to PCa.
10.3389/fimmu.2024.1463309
The causal relationship between gut microbiota and immune skin diseases: A bidirectional Mendelian randomization.
PloS one
BACKGROUND:Increasing evidence suggests that alterations in gut microbiota are associated with a variety of skin diseases. However, whether this association reflects a causal relationship remains unknown. We aimed to reveal the causal relationship between gut microbiota and skin diseases, including psoriasis, atopic dermatitis, acne, and lichen planus. METHODS:We obtained full genetic association summary data for gut microbiota, psoriasis, atopic dermatitis, acne, and lichen planus from public databases and used three methods, mainly inverse variance weighting, to analyze the causal relationships between gut microbiota and these skin diseases using bidirectional Mendelian randomization, as well as sensitivity and stability analysis of the results using multiple methods. RESULTS:The results showed that there were five associated genera in the psoriasis group, seven associated genera were obtained in the atopic dermatitis group, a total of ten associated genera in the acne group, and four associated genera in the lichen planus group. The results corrected for false discovery rate showed that Eubacteriumfissicatenagroup (P = 2.20E-04, OR = 1.24, 95%CI:1.11-1.40) and psoriasis still showed a causal relationship. In contrast, in the reverse Mendelian randomization results, there was no evidence of an association between these skin diseases and gut microbiota. CONCLUSION:We demonstrated a causal relationship between gut microbiota and immune skin diseases and provide a new therapeutic perspective for the study of immune diseases: targeted modulation of dysregulation of specific bacterial taxa to prevent and treat psoriasis, atopic dermatitis, acne, and lichen planus.
10.1371/journal.pone.0298443
A Mendelian randomization analysis of inflammatory skin disease risk due to mineral deficiencies.
Frontiers in nutrition
Background:Mineral deficiencies, such as iron (Fe), zinc (Zn), and selenium (Se), play crucial roles in inflammation and immune responses and are linked to chronic inflammatory skin diseases. This study used genome-wide association study (GWAS) data and Mendelian randomization (MR) to investigate the genetic causality among serum levels of five minerals (Fe, Cu, Zn, Se, Ca), three iron metabolism indicators (TSAT, TIBC, ferritin), and three chronic inflammatory skin diseases [psoriasis (PS), atopic dermatitis (AD), acne vulgaris (AV)]. Methods:Two-sample MR analyses using the "TwoSample MR" package in R were conducted with aggregate outcome data from the FinnGen database. The inverse-variance-weighted (IVW) method was applied to assess causal relationships between mineral levels and disease outcomes. Robustness was examined via heterogeneity and pleiotropy tests. Results:IVW analysis showed significant association between blood transferrin saturation (TSAT) and PS ( = 0.004, OR = 1.18). Serum Zn and Se levels showed inverse correlation with AD ( = 0.039, OR = 0.92). However, due to limited SNPs, robustness was reduced. Conclusion:TSAT is genetically linked to PS, highlighting iron homeostasis in disease development. Zn and Se intake may reduce AD risk.
10.3389/fnut.2024.1404117
Neuroticism and inflammatory skin diseases: a bidirectional Mendelian randomization study.
Archives of dermatological research
Previous observational studies have linked inflammatory skin diseases with mental health issues and neuroticism. However, the specific impact of neuroticism and its subclusters (i.e. worry, depressed affect, and sensitivity to environmental stress and adversity) on these conditions remains underexplored. In this work, we explored causal associations between common inflammatory skin diseases and neuroticism. We conducted a two-sample, bidirectional Mendelian randomization (MR) analysis using data from genome-wide association studies in psoriasis, atopic dermatitis, neuroticism and relevant genetic subclusters conducted on participants of European ancestry. Corrections for sample overlap were applied where necessary. We found that psoriasis was causally associated with increased levels of worry (odds ratio, 95% confidence intervals: 1.011, 1.006-1.016, P = 3.84 × 10) while none of the neuroticism subclusters showed significant association with psoriasis. Sensitivity analyses revealed considerable evidence of directional pleiotropy between psoriasis and neuroticism traits. Conversely, genetic liability to atopic dermatitis did not exhibit any significant association with neuroticism traits. Notably, genetically predicted worry was linked to an elevated risk of atopic dermatitis (odds ratio, 95% confidence intervals: 1.227, 1.067-1.41, P = 3.97 × 10). Correction for overlapping samples confirmed the robustness of these results. These findings suggest potential avenues for future interventions aimed at reducing stress and worry among patients with inflammatory skin conditions.
10.1007/s00403-024-03017-w
Causal Relationship of Skin Microbiota on Psoriasis: A Mendelian Randomization Study.
Clinical, cosmetic and investigational dermatology
Objective:Epidemiological investigations have indicated an association between skin microbiota imbalance and psoriasis, however, the causal relationship has not been confirmed through Mendelian randomization (MR). MR employed genetic instrumental variables (IVs) to evaluate the causal relationship between skin microbiota and psoriasis, providing new insights for potential treatments. Methods:Summary statistics for psoriasis and related traits were available from FinnGen R10 and United Kingdom Biobank (UKB) consortium. The genome-wide association studies (GWAS) on skin microbiota in three skin microenvironments came from two population-based German cohorts. Several selection processes were used to determine the optimal instrumental variables. Five MR methods were performed and different sensitivity analyses approaches yield robustness evidence under different assumptions. Results:449 SNPs were employed as IVs for 53 bacterial genera, with F-statistics between 20.18 and 42.44, indicating no evidence of weak instrument bias. was associated with psoriasis from UKB in IVW (OR, 95% CI: 0.914, 0.869-0.961; < 0.001, P = 0.007). The taxon was also associated with psoriasis vulgaris (IVW: OR, 95% CI, 0.918, 0.872-0.967; = 0.001, = 0.054) and psoriasis and related disorders (IVW: OR, 95% CI, 0.915, 0.875-0.957; < 0.001, = 0.008). Consistent causal estimates were identified in terms of both magnitude and direction, indicating a protective effect of . Conclusion:The MR study found that in the antecubital fossa may protect against psoriasis, offering genetic proof that skin microbiota helps prevent the condition.
10.2147/CCID.S484366
Skin Microbiota, Immune Cell, and Skin Fibrosis: A Comprehensive Mendelian Randomization Study.
Biomedicines
BACKGROUND:Microbiota dysbiosis has been reported to lead to leaky epithelia and trigger numerous dermatological conditions. However, potential causal associations between skin microbiota and skin fibrosis and whether immune cells act as mediators remain unclear. METHODS:Summary statistics of skin microbiota, immune cells, and skin fibrosis were identified from large-scale genome-wide association studies summary data. Bidirectional Mendelian randomization was performed to ascertain unidirectional causal effects between skin microbiota, immune cells, and skin fibrosis. We performed a mediation analysis to identify the role of immune cells in the pathway from skin microbiota to skin fibrosis. RESULTS:Three specific skin microbiotas were positively associated with skin fibrosis, while the other three were negative. A total of 15 immune cell traits were associated with increased skin fibrosis risk, while 27 were associated with a decreased risk. Moreover, two immune cell traits were identified as mediating factors. CONCLUSIONS:Causal associations were identified between skin microbiota, immune cells, and skin fibrosis. There is evidence that immune cells exert mediating effects on skin microbiota in skin fibrosis. In addition, some strains exhibit different effects on skin fibrosis in distinct environments.
10.3390/biomedicines12102409
A Mendelian randomization study of genetic liability to cutaneous melanoma and sunburns.
Frontiers in oncology
Background:Some studies have reported that sunburns and cutaneous melanoma (CM) risk is increasing, but a clear causal link has yet to be established. Methods:This current study conducted a two-sample Mendelian randomization (MR) approach to clarify the association and causality between sunburn history and CM using large-scale genome-wide association study data. Results:The inverse-variance weighted method result showed that sunburn might be associated with the risk of CM increasing (p = 2.21 × 10, OR = 1.034, 95% CI= 1.027-1.041), causally. The MR-Egger regression, weighted median method, simple mode method, and weighted mode method results showed similar results. Conclusion:This study offers evidence of sunburn history and increased risk of CM, and it shows that there might be common genetic basics regarding sunburns and CM susceptibility in Caucasian, European, or British ethnic groups.
10.3389/fonc.2024.1393833
Plasma proteins and inflammatory dermatoses: proteome-wide Mendelian randomization and colocalization analyses.
Archives of dermatological research
Current genome-wide association studies (GWAS) of plasma proteomes provide additional possibilities for finding new drug targets for inflammatory dermatoses. We performed proteome-wide Mendelian randomization (MR) and colocalization analyses to identify novel potential drug targets for inflammatory dermatoses. We performed MR and colocalization analysis using genetic variation as instrumental variables to determine the causal relationship between circulating plasma proteins and inflammatory dermatoses. 5 plasma proteins were found to be causally associated with dermatitis eczematosa, SLE, urticaria and psoriasis using cis-pQTLs as instrumental variables, but not found in AD and LP. 19 candidate genes with high colocalization evidence were identified. These potential drug targets still require more research and rigorous validation in future trials.
10.1007/s00403-024-03191-x
Relationship between fatty acid intake and aging: a Mendelian randomization study.
Aging
BACKGROUND:Observational studies have previously shown a possible link between fatty acids and aging-related diseases, raising questions about its health implications. However, the causal relationship between the two remains uncertain. METHODS:Univariable and multivariable Mendelian randomization (MR) was used to analyze the relationship between five types of fatty acids-polyunsaturated fatty acid (PUFA), monounsaturated fatty acid (MUFA), saturated fatty acid (SFA), Omega-6 fatty acid (Omega-6 FA), and Omega-3 fatty acid (Omega-3 FA) and three markers of aging: telomere length (TL), frailty index (FI), and facial aging (FclAg). The primary approach for Mendelian randomization (MR) analysis involved utilizing the inverse variance weighted (IVW) method, with additional supplementary methods employed. RESULTS:Univariate MR analysis revealed that MUFA, PUFA, SFA, and Omega-6 fatty acids were positively associated with TL (MUFA OR: 1.019, 95% CI: 1.006-1.033; PUFA OR: 1.014, 95% CI: 1.002-1.026; SFA OR: 1.016, 95% CI: 1.002-1.031; Omega-6 FAs OR=1.031, 95% CI: 1.006-1.058). PUFA was also associated with a higher FI (OR: 1.033, 95% CI: 1.009-1.057). In multivariate MR analysis, after adjusting for mutual influences among the five fatty acids, MUFA and PUFA were positively independently associated with TL (MUFA OR: 1.1508, 95% CI = 1.0724-1.2350; PUFA OR: 1.1670, 95% CI = 1.0497-1.2973, while SFA was negatively correlated (OR: 0.8005, 95% CI: 0.7045-0.9096). CONCLUSIONS:Our research presents compelling evidence of a causal association between certain fatty acids and indicators of the aging process. In particular, MUFA and PUFA may play a role in slowing down the aging process, while SFAs may contribute to accelerated aging. These findings could have significant implications for dietary recommendations aimed at promoting healthy aging.
10.18632/aging.205674
Alcohol drinking, smoking, and cutaneous melanoma risk: Mendelian randomization analysis.
Gaceta sanitaria
OBJECTIVE:To investigate the causal relationship between poor lifestyle habits, such as smoking and drinking, and cutaneous malignant melanoma. METHOD:In the present study, alcohol consumption and smoking were used as exposure factors, and single nucleotide polymorphisms closely associated with alcohol consumption and smoking were used as instrumental variables, while cutaneous melanoma was set as an outcome variable. Two-sample Mendelian randomization analyses were run between alcohol consumption and melanoma and smoking and melanoma to investigate their causal associations, respectively. RESULTS:We found a positive and statistically significant causal effect of alcohol intake on the risk of cutaneous malignant melanoma (OR: 2.23; 95%CI: 1.11-4.47; p=0.02). The present study showed no significant causal relationship between cigarettes per day and cutaneous melanoma (OR: 0.85; 95%CI: 0.54-1.35; p=0.50) or smoking initiation and cutaneous melanoma (OR: 1.02; 95%CI: 0.74-1.39; p=0.88). CONCLUSIONS:This study provides Mendelian randomization evidence supporting alcohol consumption as a risk factor for cutaneous malignant melanoma. And the causal relationship between smoking and cutaneous malignant melanoma still needs to be further investigated.
10.1016/j.gaceta.2023.102351
Impact of the gut microbiome on skin fibrosis: a Mendelian randomization study.
Frontiers in medicine
Objective:Skin fibrosis is a lesion in the dermis causing to itching, pain, and psychological stress. The gut microbiome plays as an essential role in skin diseases developments. We conducted a Mendelian randomization study to determine the causal association between the gut microbiome and skin fibrosis. Methods:We retrieved valid instrumental variables from the genome-wide association study (GWAS) files of the gut microbiome ( = 18,340) conducted by the MiBioGen consortium. Skin fibrosis-associated data were downloaded from the GWAS Catalog. Subsequently, a two-sample Mendelian randomization (MR) analysis was performed to determine whether the gut microbiome was related to skin fibrosis. A reverse MR analysis was also performed on the bacterial traits which were causally associated with skin fibrosis in the forward MR analysis. In addition, we performed an MR-Pleiotropy Residual Sum and Outlier analysis to remove outliers and a sensitivity analysis to verify our results. Results:According to the inverse variance-weighted estimation, we identified that ten bacterial traits (, , , , , , , and ) were negatively correlated with skin fibrosis while five bacterial traits (, , , ), and ) were positively correlated. No results were obtained from reverse MR analysis. No significant heterogeneity or horizontal pleiotropy was observed in MR analysis. Objective conclusion:There is a causal association between the gut microbiome and skin fibrosis, indicating the existence of a gut-skin axis. This provides a new breakthrough point for mechanistic and clinical studies of skin fibrosis.
10.3389/fmed.2024.1380938
The association between dietary consumption habits and psoriasis: a two-sample Mendelian randomization study.
Frontiers in nutrition
Background:Psoriasis is a chronic inflammatory skin disease characterized primarily by erythema and scales, having a wide-ranging impact globally. Previous studies have suggested that dietary consumption habits may influence psoriasis. The objective of this study was to determine the causal relationship between dietary consumption habits and psoriasis using the Mendelian Randomization (MR) approach. Methods:SNP data for 29 dietary consumption habits and psoriasis were obtained from the GWAS catalog database and the FinnGen database, respectively. The Mendelian Randomization analysis was performed using R software, with the 29 dietary consumption habits as the exposure factors and psoriasis as the outcome. Three MR analysis methods-Inverse Variance Weighted (IVW), Weighted Median Estimator (WME), and MR-Egger regression-were employed to study the causal relationship between dietary consumption habits and psoriasis. Results:The IVW analysis indicated an OR (95%CI) of 0.065 (0.008-0.555), = 0.012, demonstrating a negative correlation between the consumption of dried fruit and psoriasis. Conclusion:Among the 29 dietary consumption habits analyzed, the intake of dried fruits is a protective factor against psoriasis. Therefore, it is clinically advisable to appropriately increase the intake of dried fruits among patients with psoriasis, serving as a nutritional therapy method in conjunction with pharmacological treatment.
10.3389/fnut.2024.1405663
Association between air pollution and bone mineral density: a Mendelian randomization study.
Archives of medical science : AMS
Introduction:The association of air pollution with bone mineral density (BMD) has attracted increasing attention. However, establishing a causal relationship remains uncertain. Methods:We conducted a Mendelian randomization (MR) study employing PM, PM, PM, nitrogen dioxide, and nitrogen oxides as exposures and BMD as the outcome to explore the causality between air pollution and the occurrence of decreased BMD. Results:By employing the IVW method, we identified a negative causality between air pollution (PM, PM, and nitrogen oxides) and BMD. Conclusions:Our findings demonstrate that PM, PM and nitrogen oxides exposure may contribute to decreased BMD.
10.5114/aoms/192628
Gut microbiota and epigenetic age acceleration: a bi-directional Mendelian randomization study.
Aging clinical and experimental research
BACKGROUND:The gut microbiota is closely related to aging, but the genetic relationship between gut microbiota and aging has not been well investigated. The aim of the study was to explore the association of microbiota with epigenetic age acceleration (EAA) using the Mendelian randomization. METHOD:The independent genetic instruments of gut microbiota were obtained from MiBioGen consortium and the Dutch Microbiome Project. EAA data were derived from genome-wide association study. To assess the causal relationship between gut microbiota and EAA, we applied four different methods of Mendelian Randomization (MR) analysis: the inverse variance weighted method (IVW), the MR-Egger regression, the weighted median analysis (WMA), and the weighted mode. Furthermore, sensitivity analyses were conducted to evaluate heterogeneity and horizontal pleiotropy. RESULTS:We identified potential causal associations between 12 bacterial taxa and EAA (P and P < 0.05). Among them, species Holdemania_unclassified (OR: 1.31, 95% CI: 1.13-1.52, P = 0.0004) retained a strong positive association with GrimAge acceleration. Family Acidaminococcaceae (OR: 0.64, 95% CI: 0.44-0.93, P = 0.019) and family Clostridiaceae1 (OR: 0.69, 95% CI: 0.49-0.97 P = 0.031) were negative association with GrimAge acceleration. Reverse MR analyses indicated that EAA was associated with 6 bacterial taxa in IVW and WMA. Among them, a strong inverse association was found between Phenoage acceleration and genus Turicibacter (OR: 0.928, 95%CI: 0.888-0.971, P and P < 0.001). CONCLUSION:Our study implicates the potential causal effects of specific microbiota on EAA, potentially providing novel insights into the prevention aging through specific gut microbiota.
10.1007/s40520-024-02877-6
Circulating immune cells and vitiligo: a bidirectional two-sample Mendelian randomization study.
Frontiers in immunology
Background:The pathogenesis of vitiligo remains elusive. Emerging evidence suggests that vitiligo is an immune-mediated disorder, in which a plethora of immune cells play pivotal roles. However, the association between circulating immune cells and vitiligo continues to be enigmatic. Materials and methods:We extracted single nucleotide polymorphisms (SNPs) associated with immune circulating cells at a genome-wide significance level from the BLOOD CELL CONSORTIUM's genome-wide association study (GWAS) dataset. Summary data for 385,801 cases of vitiligo were obtained from a large-scale Finnish genome-wide association study (ncases=292, ncontrols=385,509). The inverse variance weighted (IVW) method was employed as the primary analytical approach for Mendelian randomization (MR) analysis. Additionally, heterogeneity was assessed using Cochran's Q value, and horizontal pleiotropy was evaluated using MR-Egger Mendelian Randomization Pleiotropy RESidual Sum and Outlier and leave-one-out analyses. Results:The risk of vitiligo was found to increase with the elevation of 4 circulating immune cells, as evidenced by the odds ratios (ORs) and 95% confidence intervals (CIs): basophils (OR=1.81; 95% CI: 1.01-3.24, p=0.0450), monocytes (OR=1.67; 95% CI: 1.23-2.26, p=0.0009), eosinophils (OR=1.78; 95% CI: 1.22-2.59, p=0.0028), and neutrophils (OR=1.65; 95% CI: 1.08-2.54, p=0.0208). After removing outliers, the sensitivity analysis of the above indicators did not show heterogeneity and pleiotropy. Conclusion:Our findings illuminate the association between circulating immune cells and vitiligo, offering insights that could guide clinical practices in the treatment of vitiligo.
10.3389/fimmu.2024.1391186
Adiponectin and Risk of Psoriasis: Observational and Mendelian Randomization Studies in up to 900 000 Individuals.
Clinical chemistry
BACKGROUND:Psoriasis is a chronic inflammatory skin disorder often associated with obesity. Adiponectin, an anti-inflammatory protein-hormone secreted by adipose tissue, may be a link between obesity and psoriasis. We hypothesized that low plasma adiponectin is associated with an increased risk of psoriasis in observational and causal genetic studies. METHODS:In observational analyses, we used information on plasma adiponectin and psoriasis in 30 045 individuals from the Copenhagen General Population Study (CGPS). In one-sample Mendelian randomization analyses, we used genetic information on adiponectin and psoriasis in 107 308 individuals from the CGPS. In two-sample Mendelian randomization analyses, we used genetic information on adiponectin from the ADIPOGen consortium and genetic information on psoriasis in 373 338 and 462 933 individuals from the FinnGen study and UK Biobank (UKB). RESULTS:In observational analyses, a 1-unit log-transformed higher plasma adiponectin was associated with a hazard ratio (HR) for psoriasis of 0.67 (95% confidence interval: 0.48-0.94) in an age- and sex-adjusted model but not in a multivariable adjusted model including obesity measures with a HR of 0.95 (0.66-1.35). In genetic one-sample Mendelian randomization analysis, a 1-unit log-transformed higher plasma adiponectin was not associated with a causal risk ratio for psoriasis of 1.33 (0.77-2.32) in the CGPS. In two-sample Mendelian randomization analyses, a 1-unit log-transformed higher plasma adiponectin was not associated with causal risk ratios for psoriasis of 0.96 (0.81-1.14) in FinnGen and 1.00 (1.00-1.01) in UKB. CONCLUSIONS:Low plasma adiponectin is associated with increased risk of psoriasis in age- and sex-adjusted observational analyses; however, this was not the case after adjustment for obesity measures or in causal genetic analyses.
10.1093/clinchem/hvae160
Association between inflammatory factors and melanoma: a bidirectional Mendelian randomization study.
Cancer causes & control : CCC
PURPOSE:This study performed a bidirectional Mendelian randomization (MR) analysis to elucidate the causal relationships of C-reactive protein and 41 inflammatory regulators with melanoma, including data from UK Biobank, Cardiovascular Risk in Young Finns Study, and Cohorts for Inflammation Work Group. METHODS:We selected the inverse variance weighting (IVW) to merge the estimated causal effects of multiple SNPs into a weighted average. To evaluate the heterogeneities of IVW, the Cochran Q statistic, and I index were used. What's more, several sensitivity analyses were employed, including IVW, MR-Egger, weighted median, and Mendelian Randomization Pleiotropy RESidual Sum and Outlier (MR-PRESSO). RESULTS:With SNPs reaching P < 5 × 10, the analyses findings revealed that IL-16 had a significant positively association with genetically risk of melanoma (OR: 1.05; 95% CI: 1.03-1.07; P < 0.001), and high levels of MCP1 (OR: 1.13; 95% CI: 1.03-1.23; P = 0.01) were suggestively associated with melanoma susceptibility. What's more, TNF-β (OR: 1.07; 95% CI: 1.01-1.13; P = 0.02) and IL-8 (OR: 1.08, 95% CI: 1.01-1.16; P = 0.03) were demonstrated a positive association with the risk of melanoma under a less stringent cut-off (P < 5 × 10). Conversely, we found a facilitative effect of melanoma susceptibility on IP-10 and inhibitory effects on IL-6, IL-1b, and GRO-α. CONCLUSION:The genetic evidence that we have uncovered indicates a potential association between the levels of specific inflammatory markers (IL-16, IL-8, MCP-1, and TNF-β) and the risk of melanoma. Further research is imperative to translate these findings into clinical applications.
10.1007/s10552-024-01890-4
The effects of fatty acids on psoriasis: A two-sample mendelian randomization study.
Journal of cosmetic dermatology
BACKGROUND:Some studies indicated an association between fatty acids (FA) and psoriasis. While definitive correlation between FA and psoriasis is still unclear. Therefore, our objective is to ascertain whether fatty acid levels are causally related to psoriasis using a Mendelian randomization approach. METHOD:We investigated the causal relationship between psoriasis and multiple types of FA by mendelian randomization. All data were acquired from Genome-Wide Association Study. We also performed additional analysis to assess the validity of the causal connection. RESULTS:Our mendelian analysis suggests that n-3 fatty acid levels are associated with a lower risk of psoriasis. [IVW, OR/95% CI: 0.998/(0.997, 0.999), p (2.479 × 10)] Complementary analyses returned similar results, indicating consistency in our findings. No horizontal pleiotropy was found in our analysis. There was no indication of causal effects from other varieties of FA on psoriasis. CONCLUSION:Our studies found that n-3 FA may lower the likelihood of developing psoriasis. We also need well-designed prospective studies and related large-scale, multicenter RCTs to confirm our findings.
10.1111/jocd.16313
The impact of lipidome on five inflammatory skin diseases: a Mendelian randomization study.
Archives of dermatological research
OBJECTIVE:Two-sample Mendelian randomization (TSMR) was employed to examine the association between lipidome and five inflammatory skin diseases. METHOD:To evaluate the association between various molecular subtypes of lipidome and the risk of five inflammatory skin diseases, we analyzed a comprehensive GWAS dataset comprising 179 lipidome. The Two-Sample Mendelian Randomization (TSMR) method was employed to investigate causal relationships. Heterogeneity and pleiotropy were assessed using Cochran's Q test, MR-Egger intercept test, and MR-PRESSO global test. Additionally, a sensitivity analysis was conducted to evaluate the influence of individual single nucleotide polymorphisms on Mendelian Randomization study. RESULTS:Using 179 serum lipidome as exposures and five common inflammatory skin diseases as outcomes, we investigated their associations in this large-scale study. Our findings reveal significant impacts of glycerophospholipids, glycerolipids, and sphingomyelins on inflammatory skin diseases. Glycerophospholipids were protective against pemphigus but predominantly posed risks for other inflammatory skin diseases. Specifically, phosphatidylcholine (16:0_0:0) exhibited the most significant risk association with lichen planus (OR = 1.25, 95% CI 1.11-1.40, P < 0.001). Conversely, glycerolipids showed no effect on lichen planus but were protective against pemphigus while potentially posing risks for other conditions. Triacylglycerol (46:2) showed the most substantial risk association with vitiligo (OR = 1.99, 95% CI 1.35-2.93, P < 0.001). Furthermore, sphingomyelins had no effect on atopic dermatitis but posed potential risks for other inflammatory skin diseases. Sphingomyelin (d40:1) notably emerged as a significant risk factor for pemphigus (OR = 1.91, 95% CI 1.37-2.66, P < 0.001). CONCLUSIONS:This study has elucidated the potential harmful effects of glycerophospholipids, glycerolipids, and sphingomyelins on inflammatory skin diseases, while also providing valuable insights for future research into the pathophysiology, prevention and treatment of these conditions.
10.1007/s00403-024-03294-5
Elevated plasma triglycerides increase the risk of psoriasis: a cohort and Mendelian randomization study.
The British journal of dermatology
BACKGROUND:It is increasingly clear that triglyceride-rich lipoproteins are proinflammatory and cause low-grade systemic inflammation. However, it is currently unknown whether elevated plasma triglycerides are causally related to the development of psoriasis, a skin disorder driven by chronic inflammation. OBJECTIVES:To determine if elevated plasma triglycerides are associated with increased risk of psoriasis in observational and Mendelian randomization analysis. METHODS:Consecutive individuals from the Copenhagen General Population Study were included. We used plasma triglycerides (n = 108 043) and a weighted triglyceride allele score (n = 92 579) on nine known triglyceride-altering genetic variants. Genetic results were replicated in 337 159 individuals from the UK Biobank. Psoriasis was defined using the International Classification of Diseases, version 10 (ICD-10) code for hospital contact in the main analyses, and prescription of topical antipsoriatics for mild psoriasis in the sensitivity analysis. RESULTS:During a follow-up of median (range) 9.3 (0.1-15.1) years from 2003 to 2015 through 2018, 855 (1%) individuals were diagnosed with psoriasis by ICD-10 in the observational analysis and 772 (1%) in the Mendelian randomization analysis. In the observational analysis, the multivariable adjusted hazard ratio for psoriasis by ICD-10 was 1.26 [95% confidence interval (CI) 1.15-1.39] per doubling in plasma triglycerides with a corresponding causal odds ratio of incident psoriasis of 2.10 (95% CI 1.30-3.38). Causality was confirmed from data from the UK Biobank. Results were similar but slightly attenuated when we used topical antipsoriatic prescriptions for mild psoriasis. CONCLUSIONS:Elevated plasma triglycerides are associated with an increased risk of psoriasis in observational and Mendelian randomization analysis.
10.1093/bjd/ljae089
Psoriasis and gut microbiota: A Mendelian randomization study.
Journal of cellular and molecular medicine
In recent years, an increasing number of observational studies have revealed an association between gut microbiota composition and psoriasis patients. However, whether this association reflects a causal relationship remains unclear. This study aimed to identify the causal relationship between gut microbiota and psoriasis through relevant research. In order to determine whether gut microbiota and psoriasis are causally related, we conducted a Mendelian randomization analysis using summary statistics from genome-wide association studies (GWAS). As the exposure factor, we used summary statistics data from a GWAS study conducted by the MiBioGen Consortium, including 18,340 individuals with whole-genome gut microbiota composition, and data from the FinnGen GWAS study on psoriasis, including 9267 patients and 364,071 controls as the disease outcome. Two-sample Mendelian randomization analysis was subsequently performed with inverse variance weighted, MR-Egger and weighted median, while sensitivity analyses were conducted to address heterogeneity and horizontal pleiotropy. The IVW results confirmed the causal relationship between certain gut microbiota groups and psoriasis. Specifically, family Veillonellaceae (OR = 1.162, 95% CI: 1.038-1.301, p = 0.009), genus Candidatus Soleaferrea (OR = 1.123, 95% CI: 1.011-1.247, p = 0.030) and genus Eubacterium fissicatena group (OR = 0.831, 95% CI: 0.755-0.915, p = 0.00016) showed significant associations. Sensitivity analysis did not reveal any abnormalities in SNPs. Currently, we have found some causal relationship between the gut microbiota and psoriasis. However, the study needs further RCTs for further validation.
10.1111/jcmm.18023