Causal inference and mediating pathways of metabolic syndrome on calcific aortic valve stenosis: linkage disequilibrium score regression and two-sample, two-step mendelian randomization study

Abstract Background Current evidence regarding the role of Metabolic Syndrome (MetS) and its components in Calcific Aortic Valve Stenosis (CAVS) remains limited and inconsistent. To elucidate the causal relationship and investigate potential mediators, we conducted Linkage Disequilibrium Score Regression (LDSC) and two-sample as well as two-step Mendelian Randomization (MR) analyses. Methods Based on genome-wide association study summary (GWAS) statistics, relevant single nucleotide polymorphisms were screened and utilized as instrumental variables (IVs). Our analytical approach included LDSC, two-sample, and two-step MR. To complement these, we employed Bayesian weighted Mendelian Randomization (BWMR) for validation and performed sensitivity analyses to evaluate the robustness of the results. Result LDSC analysis identified MetS and CAVS (rg = 0.264, p = 4.61 × 10–26). In the two-sample MR study, Mets (p = 1.39 × 10–20, OR = 1.82, 95%CI = 1.60–2.07), waist circumference (WC, p = 5.50 × 10–10, OR = 1.51, 95%CI = 1.33–1.72), triglycerides (TG, p = 2.24 × 10− 9, OR = 1.42, 95%CI = 1.22–1.65), and systolic blood pressure (SBP, p = 1.83 × 10− 6, OR = 1.04, 95%CI = 1.02–1.06) were positively correlated with CAVS. In contrast, high-density lipoprotein (HDL-C, p = 0.002, OR = 0.9, 95%CI = 0.82–0.99), and diastolic blood pressure (DBP, p = 0.002, OR = 0.78, 95%CI = 0.67–0.91) were negatively correlated with CAVS. Two-step MR analysis indicated that among 233 circulating metabolites, 19 risk factors and 3 protective factors mediated the impacts of MetS, WC and TG on CAVS. Conclusion MetS and CAVS share a common genetic architecture, with central adiposity, dyslipidemia, and blood pressure exhibiting distinct causal pathways. Small very-low-density lipoprotein particles, apolipoprotein B, and remnant cholesterol are key mediators linking MetS, WC, TG and CAVS.