Distinct metabolic features of genetic liability to type 2 diabetes and coronary artery disease: a reverse Mendelian randomization study

Abstract

ABSTRACTType 2 diabetes (T2D) and coronary artery disease (CAD) both have known genetic determinants, but the mechanisms through which their associated genetic variants lead to disease onset remain poorly understood. Here, we used large-scale metabolomics data to directly compare the metabolic features of genetic liability to T2D and to CAD. We performed two-sample reverse Mendelian randomization (MR) to estimate effects of genetic liability to T2D and CAD on 249 circulating metabolites from targeted nuclear magnetic resonance spectroscopy in the UK Biobank (N=118,466). We examined the potential for medication use to distort effect estimates by examining effects of disease liability on metformin and statin use and by conducting age-stratified metabolite analyses. Using inverse variance weighted (IVW) models, higher genetic liability to T2D was estimated to decrease high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C) (e.g., HDL-C: -0.05 SD; 95% CI -0.07, -0.03, per doubling of liability), whilst increasing all triglyceride groups and branched chain amino acids (BCAAs). Estimates for CAD liability suggested an effect on reducing HDL-C as well as raising very-low density lipoprotein cholesterol (VLDL-C) and LDL-C, and LDL triglycerides. Liability to each disease was estimated to decrease apolipoprotein-A1, whilst only CAD liability was estimated with IVW to increase apolipoprotein-B (0.10 SD; 95% CI 0.03, 0.17). In pleiotropy-robust sensitivity models, T2D liability was still estimated to increase BCAAs, but several effect estimates for higher CAD liability reversed and supported decreased LDL-C and apolipoprotein-B. Estimated effects of CAD liability differed uniquely and substantially by age for non-HDL-C traits in particular, with, e.g., pleiotropy-robust models suggesting that higher CAD liability lowers LDL-C only at older ages when use of statins is common. Our results from pleiotropy-robust models support largely distinct metabolic features of genetic liability to T2D and to CAD, particularly higher BCAAs in T2D and lower LDL-C and apolipoprotein-B in CAD. Such apparently favourable effects of CAD liability differ substantially by age and likely reflect mediation by statin use in adulthood.