Roles of Cardiometabolic Factors in Mediating the Causal Effect of Type 2 Diabetes on Cardiovascular Diseases: A Two-Step, Two-Sample Multivariable Mendelian Randomization Study

Ken Chen; Zhenhuang Zhuang; Chunli Shao; Jilin Zheng; Qing Zhou; Erdan Dong; Tao Huang; Yi-Da Tang

doi:10.3389/fcvm.2022.813208

Roles of Cardiometabolic Factors in Mediating the Causal Effect of Type 2 Diabetes on Cardiovascular Diseases: A Two-Step, Two-Sample Multivariable Mendelian Randomization Study

Front Cardiovasc Med. 2022 Feb 24:9:813208. doi: 10.3389/fcvm.2022.813208. eCollection 2022.

Authors

Ken Chen^{1

2}, Zhenhuang Zhuang³, Chunli Shao^{1

2

4

5}, Jilin Zheng^{1

2}, Qing Zhou^{1

2}, Erdan Dong^{6

7}, Tao Huang^{3

8

9

10}, Yi-Da Tang^{1

2

4

5}

Affiliations

¹ 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.
² Department of Cardiology, Graduate School of Peking Union Medical College, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
³ Department of Epidemiology & Biostatistics, School of Public Health, Peking University, Beijing, China.
⁴ Department of Cardiology and Institute of Vascular Medicine, Peking University Third Hospital, Beijing, China.
⁵ Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, China.
⁶ Department of Cardiology and Institute of Vascular Medicine, NHC Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Beijing Key Laboratory of Cardiovascular Receptors Research, Peking University Third Hospital, Beijing, China.
⁷ Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, The Institute of Cardiovascular Sciences, Peking University, Beijing, China.
⁸ Department of Global Health, School of Public Health, Peking University, Beijing, China.
⁹ Key Laboratory of Molecular Cardiovascular Sciences (Peking University), Ministry of Education, Beijing, China.
¹⁰ Center for Intelligent Public Health, Institute for Artificial Intelligence, Peking University, Beijing, China.

Abstract

Objective: 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.

Design: Two-step, two-sample multivariable Mendelian randomization (MVMR) study.

Setting: International genome-wide association study (GWAS) consortia data.

Exposure: 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.

Main outcomes: Cardiovascular disease includes coronary heart disease (CHD), myocardial infarction (MI), and stroke.

Methods: 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.

Results: 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.

Conclusion: 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.

Keywords: Mendelian randomization study; blood pressure; cardiovascular disease; triglycerides (TG); type-2 diabetes (T2DM).