Department of Cardiovascular Surgery, West China Hospital, Sichuan University, Chengdu, P. R. China.
Research Center of Clinical Epidemiology and Evidence-Based Medicine, West China Hospital, Sichuan University, Chengdu, P. R. China.
ESC Heart Fail. 2024 Oct;11(5):3105-3119. doi: 10.1002/ehf2.14877. Epub 2024 Jun 12.
Type 2 diabetes mellitus (T2DM) is associated with increased cardiovascular disease (CVD) risk, but whether T2DM directly causes adverse cardiac remodelling is uncertain. We performed a comprehensive Mendelian randomization (MR) analysis to investigate the causal relevance of T2DM to CVD outcomes and cardiac structure/function.
Bidirectional two-sample MR was conducted using summary-level data from European-ancestry genome-wide association studies. The T2DM GWAS data included 80 154 cases and 853 816 controls from the DIAGRAM consortium. Outcomes included coronary artery disease (CAD), myocardial infarction (MI), stroke, heart failure, atrial fibrillation, and various quantitative cardiac imaging traits assessed by magnetic resonance imaging. MR analysis revealed causal associations between genetic predisposition to T2DM and increased risk of CAD (odds ratio [OR] 1.104, 95% confidence interval [CI] 1.078-1.130, P = 2.59e-16), MI (OR 1.129, 95% CI 1.094-1.166, P = 6.02e-14) and stroke (OR 1.086, 95% CI 1.064-1.109, P = 1.02e-14). These associations were validated in the FinnGen cohort (CAD: OR 1.117, 95% CI 1.075-1.158, P = 1.56e-9; MI: OR 1.132, 95% CI 1.083-1.184, P = 4.27e-8; stroke: OR 1.138, 95% CI 1.107-1.170, P = 3.52e-20). Multivariable MR show consistent findings (CAD: OR 1.063, 95% CI 1.031-1.097, P = 1.11e-4; MI: OR 1.088, 95% CI 1.042-1.135, P = 1.12e-4; stroke: OR 1.066, 95% CI 1.032-1.101, P = 1.18e-4) after adjusting for cardiometabolic traits. T2DM was causally associated with higher left ventricular mass index (β = 0.473, 95% CI 0.193 to 0.752, P = 0.001), lower indexed right atrial minimum (β = -0.048, 95% CI -0.073 to -0.022, P = 2.1e-5), and maximum (β = -0.042, 95% CI -0.065 to -0.019, P = 4.12e-5) areas. The effects on right atrial size remained significant after adjusting for risk factors (minimum area: β = -0.041, 95% CI -0.072 to -0.010, P = 0.009; maximum area: β = -0.039, 95% CI -0.069 to -0.008, P = 0.012). Both apolipoprotein A1 and SBP are important mediators in the causal relationship between T2DM and left ventricular mass index. No reverse causal associations were identified.
Our MR study demonstrates that genetic liability to T2DM plays causal roles in CAD, MI, stroke, and cardiac structure changes including left ventricular hypertrophy and reduced right atrial dimensions. These findings provide genetic evidence supporting glycaemic control in T2DM to mitigate cardiovascular complications and adverse cardiac remodelling.
2 型糖尿病（T2DM）与心血管疾病（CVD）风险增加相关，但 T2DM 是否直接导致不良心脏重塑尚不确定。我们进行了一项全面的孟德尔随机化（MR）分析，以研究 T2DM 与 CVD 结局和心脏结构/功能的因果关系。
使用来自欧洲血统全基因组关联研究的汇总水平数据，进行了双向两样本 MR。T2DM GWAS 数据包括来自 DIAGRAM 联盟的 80154 例病例和 853816 例对照。结局包括冠心病（CAD）、心肌梗死（MI）、中风、心力衰竭、心房颤动以及通过磁共振成像评估的各种定量心脏成像特征。MR 分析显示，遗传易感性与 CAD（优势比[OR]1.104，95%置信区间[CI]1.078-1.130，P=2.59e-16）、MI（OR 1.129，95%CI 1.094-1.166，P=6.02e-14）和中风（OR 1.086，95%CI 1.064-1.109，P=1.02e-14）风险增加之间存在因果关系。这些关联在 FinnGen 队列中得到验证（CAD：OR 1.117，95%CI 1.075-1.158，P=1.56e-9；MI：OR 1.132，95%CI 1.083-1.184，P=4.27e-8；中风：OR 1.138，95%CI 1.107-1.170，P=3.52e-20）。多变量 MR 显示一致的结果（CAD：OR 1.063，95%CI 1.031-1.097，P=1.11e-4；MI：OR 1.088，95%CI 1.042-1.135，P=1.12e-4；中风：OR 1.066，95%CI 1.032-1.101，P=1.18e-4），在调整了心血管代谢特征后。T2DM 与左心室质量指数升高（β=0.473，95%CI 0.193-0.752，P=0.001）、右心房最小（β=-0.048，95%CI -0.073-0.022，P=2.1e-5）和最大（β=-0.042，95%CI -0.065-0.019，P=4.12e-5）面积降低相关。在调整危险因素后，对右心房大小的影响仍然显著（最小面积：β=-0.041，95%CI -0.072-0.010，P=0.009；最大面积：β=-0.039，95%CI -0.069-0.008，P=0.012）。载脂蛋白 A1 和 SBP 是 T2DM 与左心室质量指数之间因果关系的重要介导物。未发现反向因果关系。
我们的 MR 研究表明，T2DM 的遗传易感性在 CAD、MI、中风以及包括左心室肥厚和右心房尺寸减小在内的心脏结构变化中起因果作用。这些发现提供了遗传证据，支持 T2DM 的血糖控制以减轻心血管并发症和不良心脏重塑。
