血浆代谢物与冠心病的因果关系:双向两样本孟德尔随机化分析  

Causal Relationship between Plasma Metabolites and Coronary Heart Disease:a Bidirectional Two-Sample Mendelian Randomization Analysis

作　　者：张兴 迪拉热·太外库力 宋洁 张小雪 简易 王晓燕[1] 梁俊卿 王倩辉 周贤惠[1] ZHANG Xing;DILARE·Taiwaikuli;SONG Jie;ZHANG Xiaoxue;JIAN Yi;WANG Xiaoyan;LIANG Junqing;WANG Qianhui;ZHOU Xianhui(Department of Cardiac Pacing and Electrophysiology,First Affiliated Hospital of Xinjiang Medical University,Urumqi 830054,China)

机构地区：[1]新疆医科大学第一附属医院心脏起搏电生理科,新疆维吾尔自治区乌鲁木齐市830054

出　　处：《实用心脑肺血管病杂志》2024年第9期38-45,共8页Practical Journal of Cardiac Cerebral Pneumal and Vascular Disease

基　　金：国家自然科学基金资助项目(82060069)。

摘　　要：目的通过双向两样本孟德尔随机化(MR)分析探索血浆代谢物与冠心病(CHD)的因果关系。方法采用双向两样本MR分析方法,正向MR分析时将血浆代谢物作为暴露因素,CHD作为研究结局;反向MR分析时则将CHD作为暴露因素,血浆代谢物作为研究结局。从GWAS Catalog数据库获取1400种血浆代谢物,其均为欧洲人群样本,样本量为8299例,单核苷酸多态性(SNP)数量约1540万个。从IEU OpenGWAS project网站获取CHD数据集,其为欧洲人群样本,样本量为86995例,SNP数量为2420361个。使用R 4.3.3软件、采用Two Sample MR包(版本号:0.4.22)在Windows 11系统上进行MR分析,以逆方差加权法(IVW)分析结果为主,以MR-Egger回归、加权中位数法(WME)、简单模型、加权模型分析结果为补充。采用Cochran'sQ检验判断SNP间是否存在统计学异质性,采用MR-Egger回归的截距项、MR-PRESSO Outlier检验、MR-PRESSO Global检验分析SNP的水平多效性,采用留一法分析单个SNP对IVW分析结果的影响,绘制漏斗图以评估SNP的潜在偏倚。结果共筛选出62个与血浆代谢物强相关的SNP,15个与CHD强相关的SNP。最终共纳入6种血浆代谢物。正向IVW分析结果显示:1-棕榈酰-GPG(16∶0)升高是CHD的保护因素[OR=0.842,95%CI(0.766~0.926)],N-乙酰腐胺[OR=1.125,95%CI(1.067~1.186)]、N-乙酰天冬氨酸[OR=1.068,95%CI(1.029~1.109)]、5-乙酰氨基-6-甲酰氨基-3-甲基尿嘧啶[OR=1.095,95%CI(1.048~1.144)]、N-乙酰瓜氨酸[OR=1.079,95%CI(1.034~1.126)]、花生四烯酸(20∶4n6)至油酸至反式十八碳一烯酸的比率[OR=1.316,95%CI(1.136~1.524)]升高是CHD的危险因素(P<0.05);反向IVW分析结果显示:CHD是1-棕榈酰-GPG(16∶0)[OR=1.089,95%CI(1.014~1.169)]、花生四烯酸(20∶4n6)至油酸至反式十八碳一烯酸的比率[OR=1.094,95%CI(1.013~1.182)]升高的危险因素(P<0.05),CHD与N-乙酰腐胺、N-乙酰天冬氨酸、5-乙酰氨基-6-甲酰氨基-3-甲基尿嘧啶、N-乙酰瓜氨酸无因果关系(P>0.05)。MObjective To explore the causal relationship between plasma metabolites and coronary heart disease(CHD)through bidirectional two-sample Mendelian randomization(MR)analysis.Methods A bidirectional two-sample MR analysis was conducted.In the forward MR analysis,plasma metabolites were considered as the exposure factors and CHD was considered as the outcome.Conversely,in the reverse MR analysis,CHD was considered as the exposure factor and plasma metabolites were considered as the outcome.A total of 1400 plasma metabolites were obtained from the GWAS Catalog database,which were all European population samples with a sample size of 8299 cases and the number of single nucleotide polymorphism(SNP)was about 15.4 million.The CHD dataset was obtained from the IEU OpenGWAS project website.It was a European population sample with a sample size of 86995 cases and the number of SNP was 2420361.The MR analysis was performed using R 4.3.3 software and the Two Sample MR package(version 0.4.22)on a Windows 11 system.The analysis results were mainly based on the inverse variance weighting(IVW),supplemented by MR-Egger regression,weighted median estimator(WME),simple model,and weighted model analysis results.Cochran'sQtest was used to determine whether there was statistical heterogeneity between SNPs.The intercept term of MR-Egger regression,MR-PRESSO Outlier test,and MR-PRESSO Global test were used to analyze the horizontal pleiotropy of SNPs.The leave-one-out method was used to analyze the impact of a single SNP on the IVW analysis results,and the funnel plot was drawn to evaluate the potential bias of SNPs.Results A total of 62 SNPs strongly associated with plasma metabolites and 15 SNPs strongly associated with CHD were screened out.Six plasma metabolites were ultimately included.The positive IVW analysis results showed that the increased 1-palmitoyl-GPG(16∶0)was a protective factor for CHD[OR=0.842,95%CI(0.766-0.926)],the increased N-acetylputrescine[OR=1.125,95%CI(1.067-1.186)],N-acetylasparagine[OR=1.068,95%CI(1.029-1.109)

关 键 词：冠心病 血浆代谢物 因果关系 孟德尔随机化分析 

分 类 号：R541.4[医药卫生—心血管疾病]