Genetics of Lipid Traits and Relationship to Coronary Artery Disease

Despite the critical importance of plasma lipoproteins in the development of atherosclerosis, varying degrees of evidence surround the causal associations of lipoproteins with coronary artery disease (CAD). These causal contributions can be assessed by employing genetic variants as unbiased proxies for lipid levels. A relatively large number of low-density lipoprotein cholesterol (LDL-C) variants strongly associate with CAD, confirming the causal impact of this lipoprotein on atherosclerosis. Although not as firmly established, genetic evidence supporting a causal role of triglycerides (TG) in CAD is growing. Conversely, high-density lipoprotein cholesterol (HDL-C) variants not associated with LDL-C or TG have not yet been shown to be convincingly associated with CAD, raising questions about the causality of HDL-C in atherosclerosis. Finally, genetic variants at the LPA locus associated with lipoprotein(a) [Lp(a)] are decisively linked to CAD, indicating a causal role for Lp(a). Translational investigation of CAD-associated lipid variants may identify novel regulatory pathways with therapeutic potential to alter CAD risk.