Scholarlink

Background <p>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.</p> Methods <p>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.</p> Result <p>LDSC analysis identified MetS and CAVS (rg = 0.264, <i>p</i> = 4.61 × 10<sup>–26</sup>). In the two-sample MR study, Mets (<i>p</i> = 1.39 × 10<sup>–20</sup>, OR = 1.82, 95%CI = 1.60–2.07), waist circumference (WC, <i>p</i> = 5.50 × 10<sup>–10</sup>, OR = 1.51, 95%CI = 1.33–1.72), triglycerides (TG, <i>p</i> = 2.24 × 10<sup>− 9</sup>, OR = 1.42, 95%CI = 1.22–1.65), and systolic blood pressure (SBP, <i>p</i> = 1.83 × 10<sup>− 6</sup>, OR = 1.04, 95%CI = 1.02–1.06) were positively correlated with CAVS. In contrast, high-density lipoprotein (HDL-C, <i>p</i> = 0.002, OR = 0.9, 95%CI = 0.82–0.99), and diastolic blood pressure (DBP, <i>p</i> = 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.</p> Conclusion <p>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.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

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

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年3月19日

查看全文
  • Shu Yang,
  • Zhiqiang Bai,
  • Xiangqing Ye,
  • Sike Mo,
  • Jianeng Chen,
  • Minghuang Zhang,
  • Dingyi Zhu,
  • Minghua Zhu

摘要

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.