The role of glycaemic and lipid risk factors in mediating the effect of BMI on coronary heart disease: A two-step, two-sample Mendelian randomization study

Background The extent to which effects of BMI on coronary heart disease (CHD) are mediated by gylcaemic and lipid risk factors is unclear. Methods We used two-sample Mendelian randomization to determine the causal effect of: (i) BMI on CHD (60,801 cases; 123, 504 controls), type 2 diabetes (T2DM; 34,840 cases; 114,981 controls), fasting glucose (n=46,186), insulin (n=38,238), HbA 1c (n=46,368), LDL-cholesterol (LDL-C), HDL-cholesterol (HDL-C) and triglycerides (n=188,577); (ii) glycaemic and lipids traits on CHD; and (iii) extent to which these traits mediated any effect of BMI on CHD. Findings One standard deviation (SD) increase in BMI (~ 4.5kg/m 2 ) increased CHD (odds ratio=1.45 (95% confidence interval (CI): 1.27, 1.66)) and T2DM (1.96 (1.35, 2.83)), and levels of fasting glucose (0.07mmol/l (95%CI 0.03, 0.11)), HbA 1c (0.05% (95%CI 0.01, 0.08)), fasting insulin (0.18log pmol/l (95%CI 0.14, 0.22)) and triglycerides (0.20 SD (95%CI 0.14, 0.26)), and lowered levels of HDL-C (−0.23 SD (95%CI −0.32, −0.15)). BMI was not causally related to LDL-C. After accounting for potential pleiotropy, triglycerides, HbA 1c and T2DM were causally related to CHD. The BMI-CHD effect reduced from 1.45 to 1.16 (95%CI 0.99, 1.36) and to 1.36 (95%CI 1.19, 1.57) with genetic adjustment for triglycerides or HbA 1c respectively, and to 1.09 (95%CI 0.94, 1.27) with adjustment for both. Interpretation Increased triglyceride levels and poor glycaemic control appear to mediate much of the effect of BMI on CHD. Funding European Research Council (669545), European Union (733206), China Medical Board (CMB_2015/16), Conselho Nacional de Desenvolvimento Científico e Tecnológico and UK Medical Research Council (MC_UU_12013/5).