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

AIMS/HYPOTHESIS: The extent to which effects of BMI on CHD are mediated by glycaemic and lipid risk factors is unclear. In this study we examined the effects of these traits using genetic evidence. METHODS: We used two-sample Mendelian randomisation to determine: (1) the causal effect of BMI on CHD (60,801 case vs 123,504 control participants), type 2 diabetes (34,840 case vs 114,981 control participants), fasting glucose (n = 46,186), insulin (n = 38,238), HbA(1c) (n = 46,368) and LDL-cholesterol, HDL-cholesterol and triacylglycerols (n = 188,577); (2) the causal effects of glycaemic and lipids traits on CHD; and (3) the extent to which these traits mediate any effect of BMI on CHD. RESULTS: One SD higher BMI (~ 4.5 kg/m(2)) was associated with higher risk of CHD (OR 1.45 [95% CI 1.27, 1.66]) and type 2 diabetes (1.96 [95% CI 1.35, 2.83]), higher levels of fasting glucose (0.07 mmol/l [95% CI 0.03, 0.11]), HbA(1c) (0.05% [95% CI 0.01, 0.08]), fasting insulin (0.18 log pmol/l [95% CI 0.14, 0.22]) and triacylglycerols (0.20 SD [95% CI 0.14, 0.26]) and lower levels of HDL-cholesterol (−0.23 SD [95% CI −0.32, −0.15]). There was no evidence for a causal relation between BMI and LDL-cholesterol. The causal associations of higher triacylglycerols, HbA(1c) and diabetes risk with CHD risk remained after performing sensitivity analyses that considered different models of horizontal pleiotropy. 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 triacylglycerols or HbA(1c), respectively, and to 1.09 (95% CI 0.94, 1.27) with adjustment for both. CONCLUSIONS/INTERPRETATION: Increased triacylglycerol levels and poor glycaemic control appear to mediate much of the effect of BMI on CHD. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00125-017-4396-y) contains peer-reviewed but unedited supplementary material, which is available to authorised users.