HDL and atherosclerotic cardiovascular disease: genetic insights into complex biology

Key Points High HDL-cholesterol (HDL-C) level in plasma is a robust marker of reduced risk of cardiovascular disease; but the cholesterol content of HDL is not a causative factor of atherosclerotic cardiovascular disease HDLs are heterogeneous subpopulations of discrete particles that differ quantitatively and qualitatively in apolipoprotein and lipid composition Advances in understanding the molecular mechanisms involved in cholesterol efflux and the pathophysiology of monogenic dyslipoproteinaemia have expanded our knowledge of the role of HDL in reverse cholesterol transport and atherogenesis Critical links between common variation in genetic determinants of HDL-C concentration and a more detailed knowledge of HDL pathways, such as biogenesis, remodelling, structure, molecular composition, function, and catabolism, are lacking An integrated systems biology approach that includes the essential elements of metabolomics, transcriptomics, lipidomics, and proteomics is required to understand the complex metabolism of HDL and its potential atheroprotective properties Genetic analysis of patients receiving therapeutic interventions targeting HDL offers the opportunity to gain insights into the complexities of HDL and the potential benefits of such treatments on atherosclerotic cardiovascular disease