Exploring the Causal Pathway From Body Mass Index to Coronary Heart Disease: A Network Mendelian Randomization Study

Abstract

Introduction: The causality of the association between body mass index (BMI) and coronary heart disease (CHD) had been proved previously, yet the underlying mechanisms remain to be elucidated. We applied a network Mendelian randomization (MR) framework to determine the causal association between BMI and CHD and explored whether glycometabolism (HbA1c) and cholesterol metabolism (Total cholesterol, TC; Low-density lipoprotein cholesterol, LDL; High-density lipoprotein cholesterol, HDL; Triglycerides, TG) serve as causal mediators from BMI to CHD by integrating summary-level genome wide association study (GWAS) data. Methods: Summary statistics from several GWAS studies were used in a 2-sample MR study design. The conventional MR approach (Inverse variance weighted, IVW) method, MR Egger method and Weighted median method were used. Network MR analysis-an approach using genetic variants as the instrumental variables for both the exposure and mediator to infer causality was performed to examine the causal association between BMI and CHD, with specific emphasis on glycometabolism and cholesterol metabolism as mediators from BMI to CHD. Summary statistics from the GIANT consortium were used (n=152893) for BMI, CARDIoGRAMplusC4D consortium data were used (n=184305) for CHD, GLGC consortia data were used (n=108363) for TC, LDL, HDL and TG, and MAGIC consortia data were used (n=108363) for HbA1c. Results: The IVW method estimate indicated that the odds ratio (OR) (95% confidence interval [CI]) for CHD was 1.562 (1.391-1.753) per 1 SD (kg/m2) increase in BMI. Results were consistent in MR Egger method (OR, 1.653; 95% CI, 1.246-2.192; P=0.001) and weighted median methods (OR, 1.473; 95% CI, 1.267-1.711; P=0.000). MR estimate indicated that BMI was positively associated with HbA1c, TG and negetively associated with HDL, but was not associated with TC or LDL. Moreover, HbA1c, TC, LDL and TG were positively associated with CHD, yet there was no causal association between HDL and CHD. HbA1c was positively associated with TC, LDL and HDL, but was not associated with TG. There were no causal associations between cholesterol metabolism (TC, LDL, HDL or TG) and HbA1c. Conclusions: Higher BMI confered an increased risk of CHD, which were partially mediated by glycometabolism and cholesterol metabolism. HbA1c, TG might be the main mediators in the link from BMI to CHD. Besides, poor glycometabolism likely caused poor cholesterol metabolism, yet the reversed causal association was not established. Funding Statement: The authors state: Not applicable. Declaration of Interests: The authors state: Not applicable. Ethics Approval Statement: The authors state: Not applicable.