Zhang Yeshen, Yu Shijie, Chen Ziying, Liu Haobin, Li Huixian, Long Xinyang, Ye Fei, Luo Wenzhi, Dai Yining, Tu Shan, Chen Weikun, Kong Siyu, He Yu, Xue Ling, Tan Ning, Liang Huiying, Zhang Zhihui, He Pengcheng, Duan Chongyang, Liu Yuanhui
Department of Cardiology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou 510080, China.
Department of Guangdong Provincial Key Laboratory of Coronary Heart Disease Prevention, Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou 510080, China.
Eur Heart J. 2024 Dec 23;45(48):5156-5167. doi: 10.1093/eurheartj/ehae706.
Observational studies have highlighted that gestational diabetes mellitus is associated with a higher risk of cardiovascular diseases, but the causality remains unclear. Herein, the causality between genetic predisposition to gestational diabetes mellitus and the risk of cardiovascular diseases was investigated using sex-specific Mendelian randomization analysis.
Linkage disequilibrium score regression analysis and two-sample Mendelian randomization analysis were applied to infer the genetic correlation and causality, respectively. Mediation analysis was conducted using a two-step Mendelian randomization approach. Sensitivity analyses were performed to differentiate causality from pleiotropy. The genome-wide association study summary statistics for gestational diabetes mellitus were obtained from FinnGen consortium, while for cardiovascular diseases were generated based on individual-level genetic data from the UK Biobank.
Linkage disequilibrium score regression analyses revealed that gestational diabetes mellitus had a significant genetic correlation with coronary artery disease and myocardial infarction after Benjamini-Hochberg correction in ever-pregnant women. In Mendelian randomization analyses, odds ratios (95% confidence interval) for coronary artery disease and myocardial infarction were 1.09 (1.01-1.17) and 1.12 (.96-1.31) per unit increase in the log-odds of genetic predisposition to gestational diabetes mellitus in ever-pregnant women, respectively. Further, Type 2 diabetes and hypertension were identified as mediators for the causality of genetic predisposition to gestational diabetes mellitus on coronary artery disease. In sensitivity analyses, the direction of odds ratio for the association between instrumental variables with gestational diabetes mellitus-predominant effects and the risk of coronary artery disease was consistent with the primary results in ever-pregnant women, although not statistically significant.
This study demonstrated a suggestive causal relationship between genetic predisposition to gestational diabetes mellitus and the risk of coronary artery disease, which was mainly mediated by Type 2 diabetes and hypertension. These findings highlight targeting modifiable cardiometabolic risk factors may reduce the risk of coronary artery disease in women with a history of gestational diabetes mellitus.
观察性研究强调妊娠期糖尿病与心血管疾病风险较高相关，但因果关系仍不明确。在此，使用性别特异性孟德尔随机化分析研究妊娠期糖尿病遗传易感性与心血管疾病风险之间的因果关系。
分别应用连锁不平衡评分回归分析和两样本孟德尔随机化分析来推断遗传相关性和因果关系。采用两步孟德尔随机化方法进行中介分析。进行敏感性分析以区分因果关系和多效性。妊娠期糖尿病的全基因组关联研究汇总统计数据来自芬兰基因组联盟，而心血管疾病的汇总统计数据则基于英国生物银行的个体水平遗传数据生成。
连锁不平衡评分回归分析显示，在曾怀孕的女性中，经本雅明尼 - 霍赫贝格校正后，妊娠期糖尿病与冠状动脉疾病和心肌梗死存在显著遗传相关性。在孟德尔随机化分析中，曾怀孕女性中，妊娠期糖尿病遗传易感性对数优势每增加一个单位，冠状动脉疾病和心肌梗死的优势比（95%置信区间）分别为1.09（1.01 - 1.17）和1.12（0.96 - 1.31）。此外，2型糖尿病和高血压被确定为妊娠期糖尿病遗传易感性与冠状动脉疾病因果关系的中介因素。在敏感性分析中，具有妊娠期糖尿病主要效应的工具变量与冠状动脉疾病风险之间关联的优势比方向与曾怀孕女性的主要结果一致，尽管无统计学意义。
本研究表明妊娠期糖尿病遗传易感性与冠状动脉疾病风险之间存在提示性因果关系，主要由2型糖尿病和高血压介导。这些发现突出了针对可改变的心脏代谢危险因素可能降低有妊娠期糖尿病史女性的冠状动脉疾病风险。
