Genetic determinants of low high-density lipoprotein cholesterol

Purpose of review High-density lipoprotein cholesterol (HDL-C) has been well established as an inverse predictor of coronary heart disease (CHD) and in recent years, investigations have focused on the genetic regulation of high-density lipoprotein. Although numerous candidate genes contribute to the low HDL-C phenotype, their impact on CHD is heterogeneous, reflecting diverse gene-gene interactions and gene-envi ron mental relationships. This review summarizes recent data involving HDL regulatory genes and their role in atherothrombosis. Recent findings The primary genetic determinants associated with relative HDL-C deficiency states are the ATP binding cassette protein, ABCA1; apolipoprotein (APO) A1; and lecithin cholesteryl acyl transferase. Other potentially important candidates invoked in low HDL-C syndromes in humans include APOC3, lipoprotein lipase, sphingomyelin phosphodiesterase 1, and glucocerebrosiclase. Molecular variation in ABCAl and APOAl and, in selected cases, lecithin cholesteryl acyl transferase deficiency have been associated with increased CHD, whereas two notable variants, APOAl(milano) and APOAl(Paris), are associated with reduced risk. Summary Low HDL-C syndromes have generally been correlated with an increased risk of CHD. However, single-gene abnormalities responsible for HDL-C deficiency states may have variable effects on atherothrombotic risk.