Lipid and metabolic syndrome traits in coronary artery disease: a Mendelian randomization study

Mendelian randomization (MR) of lipid traits in CAD has provided evidence for causal associations of LDL-C and TGs in CAD, but many lipid trait genetic variants have pleiotropic effects on other cardiovascular risk factors that may bias MR associations. The goal of this study was to evaluate pleiotropic effects of lipid trait genetic variants and to account for these effects in MR of lipid traits in CAD. We performed multivariable MR using inverse variance-weighted and MR-Egger methods in large (n ≥ 300,000) GWAS datasets. We found that 30% of lipid trait genetic variants have effects on metabolic syndrome traits, including BMI, T2D, and systolic blood pressure (SBP). Nonetheless, in multivariable MR analysis, LDL-C, HDL-C, TGs, BMI, T2D, and SBP are independently associated with CAD, and each of these associations is robust to adjustment for directional pleiotropy. MR at loci linked to direct effects on HDL-C and TGs suggests locus- and mechanism-specific causal effects of these factors on CAD.