二甲双胍和勃起功能障碍的双向孟德尔随机化研究

Two-sample Mendelian Randomization Study of Metformin and Erectile Dysfunction

目的利用双样本孟德尔随机化研究方法探索二甲双胍与勃起功能障碍之间潜在的因果关系,从遗传学的角度对潜在的机制提供思路。方法从全基因组关联研究(Genome-wide association studies,GWAS)公开数据库中筛选出与欧洲人群相关的二甲双胍、勃起功能障碍单核苷酸多态性(Single nucleotide polymorphism,SNP)数据集。在第一步分析中,以二甲双胍为暴露,以勃起功能障碍为结果,筛选出123个独立SNPs(P<1e-05)与二甲双胍相关的数据被提取为有效的工具变量。此外,在第二步分析中进行MR分析,以消除与勃起功能障碍密切相关的SNP的干扰。采用逆方差加权法(Inverse variance weighted,IVW),通过异质性检验、多效性检验、散点图、森林图和漏斗图对MR结果进行敏感性分析和可视化。以比值比(Odds ratio,OR)及95%置信区间(Confidence interval,CI)作为效应指标探讨二甲双胍与勃起功能障碍的因果关系。结果IVW结果表明使用二甲双胍可增加勃起功能障碍的患病风险(OR=19.52,95%CI=1.13~355.2)。工具变量的F值均大于10,不存在弱工具变量。Cochran Q检验、MR-PRESSO检验表明工具变量间不存在异质性或水平多效性。结论使用二甲双胍与勃起功能障碍发病风险呈正相关的因果关联。

OBJECTIVE The potential causal relationship between metformin and erectile dysfunction was explored using the two-sample Mendelian randomization method,and the potential mechanism was explored from the perspective of genetics.METHODS From genome-wide association studies(GWAS)public selected in the database associated with metformin,erectile dysfunction of single nucleotide polymorphisms(SNP).In the first step analysis,123 independent SNPs(P<1e-05)related to metformin were selected as effective instrumental variables,taking metformin as exposure and erectile dysfunction as results.In addition,MR Analysis was performed in the second step analysis to eliminate interference from SNPs closely associated with erectile dysfunction.Inverse variance weighted(IVW)method was used to analyze the sensitivity of MR Results through heterogeneity test,pleiotropy test,scatter plot,forest plot and funnel plot.oddsratio(OR)and 95%confidenceinterval(CI)were used as effect indicators to investigate the causal relationship between metformin and erectile dysfunction.RESULTS The IVW methodology indicated that the use of metformin is linked to an increased risk of developing erectile dysfunction(OR=19.52,95%CI=1.13-355.2).The instrumental variables demonstrated robustness with an F-value greater than 10 and showed no evidence of being weak instruments.Both the Cochran′s Q test and MR-PRESSO test indicated no significant heterogeneity or horizontal pleiotropy among the instrumental variables.CONCLUSION There is a significant positive association between the use of metformin and the risk of erectile dysfunction.This finding challenges prior assumptions about metformin′s role in ED and underscores the need for further research on its implications.