Genetics of increased HDL cholesterol levels: insights into the relationship between HDL metabolism and atherosclerosis.

Abstract

Astrong inverse association exists between plasma HDL cholesterol (HDL-C) levels and incidence of coronary artery disease.1 Although environmental factors play a role, variation in HDL-C levels are at least 50% genetically determined.2 The genetics of syndromes of very low HDL-C have been extensively studied. Mutations in apoA-I (the major HDL structural protein), ABCA1 (which promotes efflux of cellular lipids to apoA-I forming nascent HDL particles), and LCAT (which converts unesterified cholesterol to cholesteryl ester [CE] to form the lipid core of mature HDL particles) have all been demonstrated to cause very low levels of HDL-C and apoA-I due to rapid catabolism of apoA-I.3 However, their relationship to premature atherosclerosis is often uncertain, leading to the concept that the HDL-mediated “flux” of cholesterol from the periphery to the liver, where cholesterol is delivered for excretion into the bile (a process known as reverse cholesterol transport [RCT]), may be more important than the actual plasma concentrations of HDL-C in protecting against atherosclerosis. See page 1869 Syndromes of inherited high HDL-C also exist, but have been much less studied. The only known monogenic cause of inherited high HDL-C in humans is deficiency of the cholesteryl ester transfer protein (CETP), which transfers HDL CE out of HDL to apoB-containing lipoproteins. CETP deficiency results in markedly reduced rates of turnover of apoA-I.4 CETP deficiency occurs primarily in Japan, where its relationship to cardiovascular risk is still under debate: some investigators believe it is associated with protection from cardiovascular disease,5 whereas others contend that it increases cardiovascular risk.6,7 This topic is not merely academic, as inhibitors of CETP are under development as novel HDL-raising therapies.8 Studies with CETP inhibitors will definitively answer whether raising HDL-C through CETP inhibition in humans reduces atherosclerotic vascular disease. The evolution of the CETP …