Search Results (79)

This study aims to identify genetically influenced metabolites (GIMs) associated with SSBP and elucidate their regulatory pathways through metabolome genome-wide association studies (mGWASs). Untargeted metabolomics and genome-wide genotyping were performed on 54 participants from the Systematic Epidemiological Study of Salt Sensitivity (EpiSS). The mGWAS was conducted on 970 plasma metabolites, and their potential biological mechanisms were explored. The multivariable logistic regression model and mendelian randomization (MR) were employed to investigate the association and causal relationship between GIMs and SSBP. Metabolomic analysis was performed on 100 subjects in the replication analysis to validate the GIMs identified in the discovery set and their causal association with SSBP. The mGWAS revealed associations between 1485 loci and 18 metabolites. After performing linkage disequilibrium analysis, 368 independent mQTLs were identified and annotated to 141 genes. These functional genes were primarily implicated in the signal transduction of sinoatrial node and atrial cardiac muscle cells. Five key genes were identified using CytoHubba, including CAMK2A, TIAM1, RYR2, RBFOX1, and NRXN3. One-sample MR analysis revealed 14 GIMs with causal associations to SSBP, with LysoPC (0:0/22:5n-3) positively associated with SSBP (p < 0.05). The causal relationship between Phe-lle and SSBP was validated in the replication analysis. This study elucidates the genetic regulatory mechanisms underlying metabolites and identifies GIMs that are causally associated with SSBP. These findings provide insights into identifying metabolic biomarkers of SSBP and characterizing its genetic and metabolic regulation mechanisms. Full article

Background and Objectives: Pre-eclampsia (PE) is a serious pregnancy complication defined by the onset of hypertension and multi-organ dysfunction occurring after 20 weeks of gestation. Studies have indicated the correlation between diabetes mellitus (DM) and PE, but the causal relationship remains unclear. Materials and Methods: The two-sample Mendelian randomization (MR) approach, including the inverse variance weighted random effects (IVW-RE) model and the traditional sensitivity model, was employed to assess the causal effects of pre-pregnancy type 1 diabetes (T1D) and type 2 diabetes (T2D) on PE using summary-level data obtained from genome-wide association studies. Additionally, diabetes-related factors, such as glycated hemoglobin (HbA1c) levels, fasting insulin levels, and body mass index (BMI), were evaluated for their potential causal effects on the risk of PE. Pleiotropy-robust and multivariable Mendelian randomization (MVMR) methods were further used because of the intricate associations among the traits. Insulin and metformin use was also assessed for their causal role in PE risk. Results: Our findings show that genetically predicted T1D (OR = 1.06, 95% CI: 1.03–1.09, p < 0.001), T2D (OR = 1.09, 95% CI: 1.04–1.14, p < 0.001), and BMI (OR = 1.64, 95% CI 1.49 to 1.80, p < 0.001) had causal effects on the incidence of PE, while the effects of HbA1c (OR = 0.77, 95% CI 0.59 to 1.02, p = 0.064) and fasting insulin levels (OR = 1.35, 95% CI 0.89 to 2.05, p = 0.153) on the occurrence of PE were not significant. The results were verified by MVMR analysis. Additionally, insulin use increased the risk of pre-eclampsia (OR = 1.11, 95% CI 1.05–1.17, p < 0.001). Conclusions: Our findings demonstrate a causal relationship between pre-pregnancy diabetes (DM) and obesity and the risk of PE from a genetic epidemiological perspective. Adverse maternal factors, including DM and obesity prior to pregnancy, should be considered in mechanistic studies of PE. In addition, comprehensive interventions for risk factors such as pre-pregnancy DM and obesity should be emphasized in clinical practice. Full article

Background: Cholelithiasis is the most common disorder affecting the biliary system. Choline is an essential nutrient in the human diet and is crucial for the synthesis of neurotransmitters. Previous studies have suggested an association between choline metabolites and cholelithiasis. However, the underlying mechanisms remain unclear. This research aims to fill the knowledge gap regarding the role of choline metabolites in cholelithiasis. Methods: Genetic data related to choline metabolites and other covariates were retrieved from the U.K. Biobank and IEU OpenGWAS database. Two-sample (TSMR) and multivariate Mendelian randomization (MVMR) analyses, mediation analysis, linkage disequilibrium score regression (LDSC), colocalization analysis, and enrichment analysis were performed. Results: A significant causal relationship was identified between serum level of sphingomyelin and cholelithiasis (p-value = 0.0002). A protective causal effect was identified in MVMR analysis. The following mediated MR analysis indicated that only LDL mediated a large part of the causal relationship (59.18%). Seven genes, including GCKR, SNX17, ABCG8, MARCH8, FUT2, APOH, and HNF1A, were revealed to be colocalized with the causal signal between sphingomyelin and cholelithiasis. Conclusion: The present study has identified a protective effect between sphingomyelin and cholelithiasis. This effect is largely mediated by LDL. The findings of this study offer valuable information for further exploration of the molecular mechanisms of cholelithiasis. Full article

Background: As urbanization progresses, the resulting air pollution has become an increasingly severe public health issue, known to exacerbate respiratory and cardiovascular diseases. Recent studies suggest that it may also affect blood coagulation mechanisms. In this study, Mendelian randomization (MR) analysis was used to explore the causal relationship between air pollution and pulmonary embolism (PE). Methods: This study employs MR techniques, using genetic variants associated with air pollution exposure to assess their impact on VTE. Data from large-scale genomic studies, including the UK Biobank and OpenGWAS, were analyzed to explore the relationship between genetic susceptibility to air pollution and the risk of pulmonary embolism. The study also conducted multivariable MR analysis, adjusting for potential confounders such as smoking and BMI. Results: The study finds that long-term exposure to PM2.5 and PM10 significantly increases the risk of pulmonary embolism, with the association for PM2.5 being the most significant. The study also indicates that pollutants like PM2.5–10, NO₂, and NO_x have a smaller but still notable impact on PE risk. Multivariable MR analysis confirmed the robustness of these results, further highlighting the role of air pollution in thrombosis. Conclusions: In conclusion, this study emphasizes the significant causal relationship between air pollution and PE, providing evidence that pollutants like PM2.5, PM10, and NO_x contribute to thrombotic events. Full article

Background/Objectives: Individuals with metabolic syndrome (MetS) present reduced 25(OH)D levels. We performed a two-sample Mendelian randomization (MR) study to investigate whether causal relationships exist between 25(OH)D levels and MetS/MetS risk traits, including waist circumference, body mass index (BMI), hypertension (systolic/diastolic blood pressure), triglyceride, high-density lipoprotein cholesterol, and glucose levels. Methods: We employed genetic variants related to 25(OH)D levels from the SUNLIGHT Consortium and a European genome-wide association study meta-analysis, including UK Biobank (UKB) data, as well as variants for MetS and MetS risk traits from UKB and multiple European consortia. Several MR methods were used, i.e., inverse-variance weighted, weighted median, and MR–Egger regression. Heterogeneity and horizontal pleiotropy analyses were performed to ensure the stability of candidate single-nucleotide polymorphisms (SNPs) as the instrumental variable. We first conducted univariable MR to investigate the relationship between 25(OH)D levels and MetS, including its related risk traits, and subsequently performed multivariable MR to adjust for potential confounders. Results: This study did not provide evidence of a causal relationship between 25(OH)D levels and MetS/MetS risk traits. However, we found that several risk traits of MetS, such as waist circumference, BMI, and TG, had an inverse–causal relationship with 25(OH)D levels, suggesting that 25(OH)D levels could be secondary consequences of metabolic illnesses. Conclusions: We identified no causal relationship between 25(OH)D levels and MetS/MetS risk factors. However, 25(OH)D levels may result from MetS traits. Full article

Background: Genetic evidence from Mendelian randomization (MR) analyses suggests that higher lean mass causally protects against Alzheimer’s disease (AD) and enhances cognitive function. However, the potential confounding role of height, which shares genetic etiology with lean mass, has not been fully examined. Methods: Genetic predictors of whole-body lean mass were obtained from a genome-wide association study (GWAS) performed in the UK Biobank cohort (UKB; n = 448,322). Genetic predictors of height were also obtained from UKB (height_0.5M = 455,332) and from a GWAS meta-analysis (height_1.5Mn = 1,578,425). The study outcomes included clinically diagnosed AD (21,982 cases and 41,944 controls) and cognitive performance (n = 269,867). All study participants were of European ancestry. We conducted univariable and multivariable MR analyses to examine the total and independent effects of lean mass and height on the specified outcomes under different statistical adjustment strategies. Results: In univariable MR analyses, genetically proxied lean mass (odds ratio [OR] per 1-standard deviation [SD] increase 0.81, 95% confidence interval [CI] 0.72–0.91, p = 3.8 × 10⁻⁴) and height (OR 0.90, 95% CI 0.84–0.96, p = 0.001) were associated with reduced risk of AD. Genetically proxied lean mass (β 0.10, 95% CI 0.08–0.12, p = 6.24 × 10⁻⁶) and height (β 0.07, 95% CI 0.05–0.08, p = 1.16 × 10⁻¹⁵) were further associated with improved cognitive performance. In multivariable MR analyses, adjustment for height_1.5M partially attenuated the lean mass association with AD (OR 0.91, 95% CI 0.74–1.12, p = 0.40), whereas the height_1.5M-AD association remained similar after adjusting for lean mass (OR 0.89, 95% CI 0.79–1.00, p = 0.04). Adjustment for height also attenuated the association of lean mass with cognitive performance (β 0.00, 95% CI −0.07–0.06, p = 0.94), whereas height maintained a similar association with improved cognitive performance after adjustment for lean mass (β 0.07, 95% CI 0.03–0.10, p = 0.001). Conclusions: Height may confound the genetic associations between lean mass and both cognitive performance and AD risk. Residual direct effects of lean mass on AD risk cannot be excluded due to limitations in statistical power and genetic instrument strength in MVMR. These findings emphasize the necessity of adjusting for height when using MR to investigate the clinical effects of lean mass. Full article

Aims: This study aimed to investigate the causal effects of physical activity, sedentary behaviour, and diet on atrial fibrillation (AF) and heart failure (HF) using multivariate Mendelian randomization (MR) analysis and genetic variants as instrumental variables. Methods: The study employed multivariate MR analysis with physical activity, sedentary behaviour, and diet as exposures and AF and HF as outcomes. Data were obtained from the UK Biobank (over 500,000 participants) and the FinnGen project (218,792 participants of European ancestry). Genetic variants associated with physical activity, diet, and sedentary behaviour were used as instrumental variables. The main analysis methods included the inverse variance weighted (IVW) method, MR-Egger, and weighted median methods. Heterogeneity was assessed using Cochran’s Q test. Results: The analyses generally did not demonstrate significant causal relationships between physical activity or sedentary behaviour and AF. Diet showed a potential protective effect on AF in some analyses but was not consistently significant across methods. For HF, physical activity and sedentary behaviour did not show significant causal relationships. Diet showed a significant protective effect against HF in the IVW method but was not consistent across all methods. Conclusions: This study suggests that while there may be some protective effects of these lifestyle factors on cardiovascular disease, most analyses did not show significant causality, and results were inconsistent. Further research is needed to validate these findings. Full article

Air pollutants have both acute and chronic impacts on human health, affecting multiple systems and organs. While PM2.5 exposure is commonly assumed to be strongly associated with all respiratory diseases, this relationship has not been systematically analyzed. This study employed a two-sample Mendelian randomization approach to investigate the effects of PM2.5 on eight common lung diseases, using data from GWAS. Additionally, multivariable Mendelian randomization was applied to assess the direct effects of various air pollutants and the mediating roles of common factors such as BMI and smoking. At a significance threshold of 5×10⁻⁸, PM2.5 showed a significant causal relationship with both asthma and COPD. When the screening threshold was relaxed to 5× 10⁻⁶, this exposure continued to demonstrate significant associations not only with asthma and COPD, but also with other respiratory diseases, including pneumonia, emphysema/chronic bronchitis, and lung cancer. In the multivariable Mendelian randomization analysis, which controlled for smoking and bacterial infections, the association with pneumonia became non-significant, while the relationships with the other four diseases persisted. This study provides a systematic exploration of the relationship between PM2.5 and eight pulmonary diseases from a new perspective, deepening our understanding of the impact of air pollution on health and laying the foundation for future efforts to mitigate these effects. Full article

Purpose: To investigate the causal relationship between type 1 diabetes (T1D) and cataracts and to explore the mediating role of serum metabolites. Methods: This study employed bidirectional Mendelian randomization (MR) using genetic variants as instrumental variables to infer causality in both directions: from T1D to cataracts and cataracts to T1D. Genetic data for T1D, its complications, and cataracts were sourced from independent genome-wide association study (GWAS) datasets. A two-step multivariable MR combined with mediation analysis was conducted to evaluate the indirect effects of serum metabolites in the causal pathway from T1D to cataracts. Results: The MR analysis demonstrated a significant causal association between T1D and an increased risk of cataracts (OR = 1.01–1.05; p < 0.05). Further analysis showed that patients with T1D complications such as coma, ketoacidosis, nephropathy, and retinopathy exhibited a significantly higher risk of developing cataracts compared to those without complications. Sensitivity analyses upheld the robustness of these findings, with no evidence of heterogeneity or pleiotropy. Additionally, 102 serum metabolites were found to exhibit statistically significant mediation effects on cataract risk, with four (13-HODE + 9-HODE, 2-naphthol sulfate, docosadienoate (22:2n6), and X-12906) showing significant mediation effects. Specifically, 13-HODE + 9-HODE had a protective effect, while the other three metabolites were linked to an increased cataract risk. Conclusions: This study provides strong evidence of a causal link between T1D and cataracts, highlighting the mediating role of specific serum metabolites. These findings underscore the importance of early detection and management of cataracts in patients with T1D and suggest potential therapeutic targets for mitigating cataract risk. Further research should focus on replicating these findings in diverse populations and exploring the underlying metabolic pathways in greater detail. Full article

Objectives: Observational research shows associations of the gut microbiota and its metabolites with autoimmune thyroid disease (AITD), but the causality is undetermined. Methods: Two-sample Mendelian randomization (MR) was employed to analyze the association of the gut microbiota and its metabolites with AITD. A total of 119 gut microbiotas and nine fecal/circulating metabolites were the exposures. AITD, Graves’ disease (GD), and Hashimoto’s thyroiditis (HT) were the outcomes. Inverse-variance weighting (IVW) was primarily used to assess causality; Cochran’s Q was used to assess heterogeneity. Sensitivity analyses (weighted median, MRPRESSO regression, MRPRESSO intercept, MRPRESSO global, Steiger filtering, leave-one-out) were conducted to assess causal estimate robustness. Multivariable MR (MVMR) was used to estimate the effects of body mass index (BMI) and alcohol consumption frequency on causality. Results: The outcomes were potentially causally associated with 22 gut microbiotas and three metabolites. After multiple-test correction, 3-indoleglyoxylic acid retained significant causality with AITD (IVW: odds ratio [OR] = 1.09, 95% confidence interval [CI] = 1.05–1.14, p = 2.43 × 10⁻⁵, FDR = 0.009). The sensitivity analyses were confirmatory (weighted median: OR = 1.06, 95% CI = 1.01–1.12, p = 0.025; MRPRESSO: OR = 1.09, 95% CI = 1.15–1.14, p = 0.001). MVMR revealed no confounding effects on this association (BMI: OR = 1.21, 95% CI =1.08–1.35, p = 0.001; drinks/week: OR = 1.22, 95% CI = 1.04–1.43, p = 0.014). Conclusions: MR revealed no significant causal effects of the gut microbiota on the outcomes. However, MR revealed the causal effects of 3-indoleglyoxylic acid on the risk of AITD. Full article

Background: Cardiovascular diseases (CVDs) are a major public health concern. The impact of dietary components on CVD risk has been recognized, but their interactions require further investigation. This study aimed to examine the associations between major nutrient intake and CVD risk and to assess potential causal relationships via Mendelian randomization. Methods: We conducted a cross-sectional analysis using data from the National Health and Nutrition Examination Survey (NHANES) 2017–2020, with a sample size of 5464 adult participants. Nutrient intake was derived from two 24 h dietary recalls. Associations between four principal nutrients and CVD risk were evaluated via Mendelian randomization analysis. Additionally, weighted multivariable logistic regression analyses were performed to adjust for potential confounders, including age, sex, BMI, and other lifestyle factors. Results: An observational analysis revealed that increased log-transformed dietary fat intake was associated with reduced heart failure risk (OR = 0.722, 95% CI: 0.549–0.954). Log-transformed protein intake was protective against heart failure (OR = 0.645, 95% CI: 0.471–0.889), coronary artery disease (OR = 0.684, 95% CI: 0.504–0.931), and stroke (OR = 0.747, 95% CI: 0.568–0.988). IVW-MR analyses confirmed causal relationships between relative fat intake and heart failure risk (OR = 0.766, 95% CI: 0.598–0.982, p = 0.035) and between protein intake and stroke risk (OR = 0.993, 95% CI: 0.988–0.998, p = 0.010). MR analysis also revealed causal relationships between relative fat intake and coronary artery disease risk and between relative protein intake and hypertension risk. Conclusions: Both the observational and Mendelian randomization studies indicated that dietary fat is inversely associated with heart failure risk and that protein intake is correlated with reduced stroke risk. Future studies should investigate the optimal balance of macronutrients for CVD prevention, explore potential mechanisms underlying these associations, and consider long-term dietary interventions to validate these findings. Full article

Background/Objectives: Nutritional deficiencies have been proposed as possible etiological causes for autoimmune diseases, among which type 1 diabetes (T1D). Vitamin K (VK) has potentially positive effects on type 2 diabetes, but its role on T1D in humans remains largely unknown. We aimed to examine the presence of a causal association between VK and T1D using a Mendelian randomization (MR) approach. Methods: Genetic variants from a genome-wide association study (GWAS) for VK (N = 2138 Europeans) were used as instruments in our two-sample MR study to investigate whether circulating VK levels are causally associated with the risk of T1D in a large European T1D GWAS cohort (18,942 cases/520,580 controls). Through a multivariable MR (MVMR), the effects of both VK and specific gut microbiota on T1D were investigated given that the gut microbiome synthesizes VK. Results: We found that changes in levels of circulating VK did not affect T1D risk in our univariate two-sample MR, but this study had limited power to detect small effects of VK (OR for T1D of less than 0.8). However, our MVMR indicated a suggestive association of VK with the risk of T1D adjusting for two different gut microbiome populations. Conclusions: In conclusion, VK levels are unlikely to significantly affect the risk of T1D, but small effects cannot be excluded, and the role of gut microbiome in this association should be further investigated. Full article

Background: The association between coffee and pancreatic cancer risk has reported inconsistent results. Therefore, a Mendelian randomization (MR) study was undertaken to investigate the association between coffee and pancreatic cancer from a genetic perspective. Methods: In East Asian and European populations, independent genetic variants strongly associated with coffee were chosen as instrumental variables (IVs) from relevant genome-wide association studies (GWASs). GWAS data for pancreatic cancer were obtained from the JENGER (Japanese Encyclopedia of Genetic Associations by Riken) project and GWAS catalog database. Two-sample (TSMR) and multivariable Mendelian randomization (MVMR) analyses were conducted to investigate the genetically predicted causal relationship between coffee consumption and pancreatic cancer. A fixed-effect meta-analysis was employed to aggregate estimates from the two populations to reveal the overall association. Results: Both in East Asian and European populations, an increase in coffee intake of a cup per day was not associated with pancreatic cancer risk, regardless of coffee type (including caffeine drinks, instant coffee, decaffeinated coffee, ground coffee, etc.). The results aligned with the findings of the meta-analysis (OR = 1.100, 95%CI = 0.862–1.403, p = 0.450). Also, for coffee intake with positive results in the TSMR analysis (OR = 1.739, 95%CI 1.104–2.739, p = 0.017), consistent negative results were observed after adjusting for potential confounders (smoking traits, drinking, type 2 diabetes, body mass index) in the MVMR analyses. Conclusions: This study found no genetically predicted causal relationship between coffee consumption and pancreatic cancer risk. Full article

Background: Acute acalculous cholecystitis (AAC) is a type of cholecystitis with high mortality rate while its pathogenesis remains complex. Choline is one of the essential nutrients and is related to several diseases. This study aimed to explore the causal relationship between choline metabolites and AAC and its potential mechanisms. Methods: This research utilized the two-sample Mendelian randomization method to investigate the causal relationship between choline metabolites and AAC. Additionally, multivariable Mendelian randomization and mediated Mendelian randomization were used to explore potential confounding effects from low-density lipoprotein (LDL), high-density lipoprotein (HDL), triglycerides (TGs), and coronary artery disease (CAD). Linkage disequilibrium score regression (LDSC), co-localization analysis, and enrichment analysis were used to investigate relevant molecular mechanisms. Results: There is a negative causal relationship between total choline (OR [95%CI] = 0.9982 [0.9974, 0.9990], p = 0.0023), phosphatidylcholine (OR [95%CI] = 0.9983 [0.9976–0.9991], p = 0.0040), sphingomyelin (OR [95%CI] = 0.9980 [0.9971–0.9988], p = 0.0001), and AAC. The mediating effects of LDL were −0.0006 for total choline, −0.0006 for phosphatidylcholine, and −0.0008 for sphingomyelin, indicating a protective effect of total choline, phosphatidylcholine, and sphingomyelin on AAC. Colocalized SNP rs75331444, which is mapped to gene ABCG8, was identified for total choline (PPH4 = 0.8778) and sphingomyelin (PPH4 = 0.9344). Conclusions: There is a causal relationship between choline metabolites and cholecystitis, mediated through the protective action of LDL. Our results suggest that ABCG8 may play a role in the development of non-calculous cholecystitis. Full article

Background: Understanding the causal relations between dietary habits and stroke is crucial for prioritizing public health interventions and developing effective health strategies. This study utilized Mendelian randomization (MR) analysis to examine the causal associations between 20 dietary habits and various stroke subtypes, aiming to identify potential mediators and evaluate the proportions of mediation. Methods: A two-sample MR analysis was conducted to examine the causal relationships between dietary habits and stroke incidence. Mediation analysis, two-step MR (TSMR), and multivariable MR (MVMR) were employed to identify potential mediators. Genetic data pertaining to dietary habits and stroke were obtained from extensive genome-wide association study (GWAS) consortia. The inverse variance-weighted (IVW) method served as the primary analytical approach, with the additional scrutiny of significant correlations conducted through the Egger regression, MR-Pleiotropy Residual Sum and Outlier (MR-PRESSO), and weighted median techniques. Results: Our analyses indicated that genetically predicted intakes of dried fruits, cheese, cereal, oily fish, and hot drink temperatures were protective against stroke, whereas higher intakes of lamb/mutton, poultry, and added salt significantly elevated stroke risk. Specifically, dried fruit consumption demonstrated a protective effect against total stroke (β = −0.009, p = 0.013), ischemic stroke (β = −0.475, p = 0.003), and small-vessel ischemic stroke (β = −0.682, p = 0.033) through reductions in BMI levels, accounting for mediated proportions of 3.2%, 17.1%, and 8.5%, respectively. Furthermore, cheese intake provided a protective effect against ischemic stroke (β = −0.275, p = 0.003) by decreasing BMI and increasing HDL-C levels, with mediated proportions of 30.5% and 6.5%. Together, BMI and HDL-C accounted for 34.9% of the beneficial effect of cheese intake on reducing the risk of ischemic stroke. In contrast, an increased salt intake exhibited a positive association with large-artery ischemic stroke (β = 0.432, p = 0.033) through BMI elevation, with a mediated proportion of 10.9%. Conclusions: Our findings provide compelling evidence supporting causal relationships between dietary habits and stroke subtypes, while identifying mediators and evaluating the proportions of mediation. Adhering to a low-calorie, nutrient-dense diet enriched with dried fruits, cheese, and cereal, along with reduced salt and poultry consumption, could potentially mitigate stroke risk. Full article