Differential Effects of Genetically Determined Cholesterol Efflux Capacity on Coronary Artery Disease and Ischemic Stroke

BACKGROUND: Observational studies indicated that cholesterol efflux capacity (CEC) of high-density lipoprotein (HDL) is inversely associated with cardiovascular events, independently of the HDL cholesterol concentration. The aim of the study is to examine the casual relevance of CEC for coronary artery disease (CAD) and myocardial infarction (MI), and compare it with that for ischemic stroke and its subtypes using a Mendelian randomization approach. METHODS: We performed a 2-sample Mendelian randomization to estimate the casual relationship of CEC with the risk of CAD, MI, and ischemic stroke. A CEC-related genetic variant (rs141622900) and other five genetic variants were used as the instrumental variables. Association of genetic variants with CAD were estimated in a GWAS involving 60,801 CAD cases and 123,504 controls. They were then compared with the associations of these variants with ischemic stroke and its subtypes (large vessel, small vessel, and cardioembolic) involving 40,585 ischemic stroke cases and 406,111 controls. RESULTS: Using the SNP of rs141622900 as the instrument, a 1-SD increase in CEC was associated with 45% lower risk for CAD (odds ratio [OR] 0.55, 95% confidence interval [CI] 0.44–0.69, p < 0.001) and 33% lower risk for MI (odds ratio [OR] 0.67, 95% CI 0.52–0.87, p = 0.002). By contrast, the causal effect of CEC was much weaker for ischemic stroke (odds ratio [OR] 0.79, 95% CI 0.64–0.97, p = 0.02; p for heterogeneity = 0.03) and, in particular, for cardioembolic stroke (p for heterogeneity = 0.006) when compared with that for CAD. Results using five genetic variants as the instrument also indicated consistently weaker effects on ischemic stroke than on CAD. CONCLUSION: Genetic predicted higher CEC may be associated with decreased risk of CAD. However, the casual association of CEC with ischemic stroke and specific subtypes would need to be validated in further Mendelian randomization studies.