作者：崔扬扬，杜林芹，周阳，刘延旭，罗豪，文聪，Ofe Eugene Kwaku，郑健康， 沈秀峰，岳荣川

单位：

637000四川省南充市，川北医学院附属医院心血管内科

单位（英文）：

Department of Cardiology, Affiliated Hospital of North Sichuan Medical College, Nanchong 637000, China

关键词：

冠心病；体质指数；孟德尔随机化分析；因果关系

关键词（英文）：

Coronary disease; Body mass index; Mendelian randomization analysis; Causation

中图分类号：

R 541.4

DOI：

10.12114/j.issn.1008-5971.2023.00.323

基金项目：

国家自然科学基金青年科学基金项目（81600232）；四川省中央引导地方科技发展专项项目（2022ZYD0056）；四 川省科技计划项目（2021YJ0210）；川北医学院2023年度校级科研发展计划项目（CBY23-TD01）

摘要：

目的　采用孟德尔随机化（MR）方法分析体质指数（BMI）与冠心病的因果关系。方法　本研究中 BMI为暴露因素，冠心病为结局。通过IEU OpenGWAS prodect获取样本，纳入样本均来源于欧洲人群，其中BMI数据 集样本量为461 460例，单核苷酸多态性（SNP）数量为9 851 867个；冠心病数据集样本量为361 194例，SNP数量为 13 295 130个。从BMI数据集中选取与BMI高度相关的SNP、从冠心病数据集中选取与BMI有关的SNP，取其交集作为 工具变量。采用MR-Egger回归、加权中位数法（WME）、逆方差加权法（IVW）、简单模型、加权模型共5种回归 模型分析BMI与冠心病的因果关系。结果　本研究筛选出与BMI高度相关的SNP 458个，从冠心病数据集中筛选与BMI 高度相关的SNP 460个，然后删除17个具有中间等位基因的回文SNP和2个重复命名的SNP，最终纳入441个SNP。MR Egger回归、WME、IVW结果显示，BMI升高是冠心病的危险因素（P＜0.01）；而单纯模型和加权模型结果未显示BMI 升高是冠心病的危险因素（P＞0.05），但其β值与MR-Egger回归、WME、IVW的β值方向一致。Cochran Q检验结果 显示，SNP间存在统计学异质性（Q=598.844，P＜0.001），故主要关注IVW结果；MR-Egger截距法结果显示，MR Egger截距项＜0.001（P=0.083），提示该研究不存在水平多效性；留一法分析结果显示，逐一剔除SNP后，剩余SNP仍 位于无效线右边，且其OR值及其95%CI未发生明显改变，提示本研究MR结果较稳健。漏斗图分析结果显示，所有SNP 分布基本对称，提示SNP作为工具变量时，推断出的因果关系受潜在因素的影响相对较小。结论　BMI升高是冠心病 的危险因素，故建议通过控制BMI而预防冠心病。

英文摘要：

Objective To analyze the causal relationship between body mass index (BMI) and coronary heart disease by Mendelian randomization (MR) methods. Methods In this study, BMI was the exposure factor and coronary heart disease was the outcome. The samples were obtained by IEU OpenGWAS prodect, and the included samples were all from the European population. The sample size of BMI data set was 461 460 cases, the number of single nucleotide polymorphism (SNP) was 9 851 867; the sample size of coronary heart disease data set was 361 194 cases, the number of SNP was 13 295 130. SNP highly related to BMI were selected from the BMI data set, and SNP related to BMI were selected from the coronary heart disease data set, and their intersections were taken as instrumental variables. Five regression models including MR-Egger regression, weighted median method (WME) , inverse variance weighting (IVW) , simple model and weighted model were used to analyze the causal relationship between BMI and coronary heart disease. Results In this study, 458 SNP highly related to BMI and 460 SNP highly correlated with BMI were screened from the coronary heart disease dataset, and then 17 palindromic SNP with intermediate alleles and 2 repetitively named SNP were deleted, and 441 SNP were finally included. The results of MR-Egger regression, WME and IVW showed that elevated BMI was a risk factor for coronary heart disease (P < 0.01) . While the results of the simple model and the weighted model showed that the elevated BMI was not a risk factor for coronary heart disease (P > 0.05) , but the results of the simple and weighted models showed that the beta values were in the same direction as those of the MR-Egger regression, WME, and IVW. The results of Cochran Q test showed that there was statistical heterogeneity among SNP (Q=598.844, P < 0.001) , so the IVW results were mainly concerned. The results of MR-Egger intercept method showed that the MR-Egger intercept term was < 0.001 (P=0.083) , suggesting that there was no horizontal pleiotropy in this study. The results of the leave one-out analysis showed that after the SNP were removed one by one, the remaining SNP were still on the right side of the invalid line, and their OR value and 95%CI did not change significantly, suggesting that the MR results of this study were more robust. The results of funnel plot analysis showed that the distribution of all SNP was basically symmetrical, suggesting that when SNP was used as an instrumental variable, the causal relationship inferred was less affected by potential factors. Conclusion Elevated BMI is a risk factor for coronary heart disease, therefore, it is recommended to prevent coronary heart disease by controlling BMI.

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