Genetic determinants of low high-density lipoprotein cholesterol.
OBJECTIVE
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-environmental relationships. This review summarizes recent data involving HDL regulatory genes and their role in atherothrombosis.


RESULTS
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 glucocerebrosidase. Molecular variation in ABCAI and APOAI and, in selected cases, lecithin cholesteryl acyl transferase deficiency have been associated with increased CHD, whereas two notable variants, APOAIMilano and APOAIParis, are associated with reduced risk.


CONCLUSIONS
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.
Miller
Michael
M
Department of Medicine, University of Maryland Hospital and Veterans Affairs Medical Center, Baltimore, Maryland, USA. mmiller@heart.umaryland.edu
Zhan
Min
M
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism; D016632:Apolipoprotein A-I / Q000235:genetics / Q000378:metabolism; D053305:Apolipoprotein C-III; D001056:Apolipoproteins C / Q000235:genetics / Q000378:metabolism; D003327:Coronary Disease / Q000235:genetics*; D005962:Glucosylceramidase / Q000172:deficiency / Q000235:genetics; D006801:Humans; D008071:Lipoprotein Lipase / Q000235:genetics / Q000378:metabolism; D008075:Lipoproteins, HDL / Q000235:genetics* / Q000378:metabolism*; D010641:Phenotype; D007862:Phosphatidylcholine-Sterol O-Acyltransferase / Q000235:genetics / Q000378:metabolism; D013108:Sphingomyelin Phosphodiesterase / Q000235:genetics / Q000378:metabolism; D013631:Tangier Disease / Q000235:genetics
C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D016632:Apolipoprotein A-I; D053305:Apolipoprotein C-III; D001056:Apolipoproteins C; D008075:Lipoproteins, HDL; D007862:Phosphatidylcholine-Sterol O-Acyltransferase; D008071:Lipoprotein Lipase; D013108:Sphingomyelin Phosphodiesterase; D005962:Glucosylceramidase