Chen Ken, Zhuang Zhenhuang, Shao Chunli, Zheng Jilin, Zhou Qing, Dong Erdan, Huang Tao, Tang Yi-Da
Department of Cardiology, State Key Laboratory of Cardiovascular Disease, National Center for Cardiovascular Diseases, Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Department of Cardiology, Graduate School of Peking Union Medical College, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Front Cardiovasc Med. 2022 Feb 24;9:813208. doi: 10.3389/fcvm.2022.813208. eCollection 2022.
The objective of this study is to investigate the roles of cardiometabolic factors (including blood pressure, blood lipids, thyroid function, body mass, and insulin sensitivity) in mediating the causal effect of type 2 diabetes (T2DM) on cardiovascular disease (CVD) outcomes.
Two-step, two-sample multivariable Mendelian randomization (MVMR) study.
International genome-wide association study (GWAS) consortia data.
Type 2 diabetes, blood pressure: systolic blood pressure (SBP), diastolic blood pressure (DBP); blood lipids: low-density lipoprotein (LDL), high-density lipoprotein (HDL), total cholesterol (TC), triglycerides (TG); thyroid function: hyperthyroidism, hypothyroidism; body mass index (BMI), waist-hip-ratio (WHR), and insulin sensitivity.
Cardiovascular disease includes coronary heart disease (CHD), myocardial infarction (MI), and stroke.
Summary-level data for exposures and main outcomes were extracted from GWAS consortia. We used two-sample MR to illustrate the causal effect of T2DM on CVD subtypes and regression-based MVMR to quantify the possible mediation effects of cardiometabolic factors on CVD.
Each additional unit of log odds of T2DM increased 16% risk of CHD [odds ratio (OR): 1.16, 95% CI: 1.12-1.21], 15% risk of myocardial infarction (MI) (OR: 1.15, 95% CI: 1.10-1.20), and 10% risk of stroke (OR: 1.10, 95% CI: 1.06-1.13). In mediation analysis, SBP, DBP, and TG were found as main mediators, while the mediation effects of other cardiometabolic factors were not significant. The proportion of total effect of T2DM on CHD mediated by SBP, DBP, and TG was 16% (95% CI: 8-24%), 7% (95% CI: 1-13%) and 10% (95% CI: 2-18%), respectively. Mediation effect of SBP and DBP on MI and stroke, TG on MI was also prominent, while mediation effect of TG on stroke was not significant. The combined mediation effect of all the three mediators accounted for 29%, 26%, and 13% of the total effect of T2DM on CHD, MI, and stroke, respectively.
Systolic blood pressure, DBP, and TG mediate a substantial proportion of the causal effect of T2DM on CVD and thus interventions on these factors might reduce the considerable excess risk of CVD among patients with T2DM.
本研究旨在探讨心脏代谢因素（包括血压、血脂、甲状腺功能、体重和胰岛素敏感性）在介导2型糖尿病（T2DM）对心血管疾病（CVD）结局的因果效应中的作用。
两步、两样本多变量孟德尔随机化（MVMR）研究。
国际全基因组关联研究（GWAS）联盟数据。
2型糖尿病、血压：收缩压（SBP）、舒张压（DBP）；血脂：低密度脂蛋白（LDL）、高密度脂蛋白（HDL）、总胆固醇（TC）、甘油三酯（TG）；甲状腺功能：甲状腺功能亢进、甲状腺功能减退；体重指数（BMI）、腰臀比（WHR）和胰岛素敏感性。
心血管疾病包括冠心病（CHD）、心肌梗死（MI）和中风。
从GWAS联盟中提取暴露因素和主要结局的汇总水平数据。我们使用两样本MR来说明T2DM对CVD亚型的因果效应，并使用基于回归的MVMR来量化心脏代谢因素对CVD的可能中介效应。
T2DM的对数优势比每增加一个单位，冠心病风险增加16%[优势比（OR）：1.16，95%置信区间（CI）：1.12 - 1.21]，心肌梗死（MI）风险增加15%（OR：1.15，95%CI：1.10 - 1.20），中风风险增加10%（OR：1.10，95%CI：1.06 - 1.13）。在中介分析中，发现SBP、DBP和TG是主要中介因素，而其他心脏代谢因素的中介效应不显著。SBP、DBP和TG介导的T2DM对CHD的总效应比例分别为16%（95%CI：8 - 24%）、7%（95%CI：1 - 13%）和10%（95%CI：2 - 18%）。SBP和DBP对MI和中风的中介效应、TG对MI的中介效应也很显著，而TG对中风的中介效应不显著。这三种中介因素的联合中介效应分别占T2DM对CHD、MI和中风总效应的29%、26%和13%。
收缩压、DBP和TG介导了T2DM对CVD的很大一部分因果效应，因此对这些因素的干预可能会降低T2DM患者中CVD的显著额外风险。
