ABSTRACT
Aims The causal role of high-density lipoproteins (HDL) in coronary artery disease (CAD) has been questioned. We aimed to analyse whether genetically determined quantitative and qualitative HDL characteristics were independently associated with CAD.
Methods and Results We designed a two-sample multivariate Mendelian randomization study with available genome-wide association summary data. We identified genetic variants associated with HDL cholesterol and apolipoprotein A-I quantity, HDL size, particle levels, and cholesterol content to define our genetic instrumental variables in one sample (Kettunen et al study), and analysed their association with CAD risk in a second sample (CARDIoGRAMplusC4D). We validated these results in two other datasets (METSIM and UK-Biobank). Results showed that genetically determined HDL cholesterol and apolipoprotein A-I levels were not associated with CAD risk. HDL mean diameter (β=0.27 [95%CI=0.19; 0.35]) and the levels of cholesterol transported in very large HDL particles (β=0.29 [95%CI=0.17; 0.40] were directly associated with CAD risk, whereas the concentrations of cholesterol transported in medium-sized HDLs (β=-0.076 [95%CI=−0.10; −0.052]) were inversely related to this risk. These results were validated in the METSIM and UK-Biobank data. Genetic variants linked to high cholesterol content in medium-sized HDLs (located within LIPC and PLTP) were associated with a greater cholesterol efflux capacity (β=0.094 [95%CI=0.013; 0.18]).
Conclusion Some HDL characteristics, such as particle size and cholesterol content, are related to CAD risk. This relationship could be mediated by a greater cholesterol efflux capacity and is related to LIPC and PLTP, novel potential therapeutic targets.