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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2007;27:1139.)
© 2007 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Genetic Etiology of Isolated Low HDL Syndrome

Incidence and Heterogeneity of Efflux Defects

Robert S. Kiss; Nihan Kavaslar; Kei-ichiro Okuhira; Mason W. Freeman; Stephanie Walter; Ross W. Milne; Ruth McPherson; Yves L. Marcel

From the Lipoprotein and Atherosclerosis Research Group (R.S.K., N.K., S.W., R.W.M., R.M., Y.L.M.), University of Ottawa Heart Institute; Department of Medicine (R.M.), Division of Cardiology; Department of Pathology and Laboratory Medicine (Y.L.M.), University of Ottawa, Ontario, Canada; and Department of Medicine (K.-i.O., M.W.F.), Massachusetts General Hospital, Harvard Medical School, Boston.

Correspondence to Y.L. Marcel or R. McPherson, University of Ottawa Heart Institute, 40 Ruskin St, Ottawa, Ontario, K1Y 4W7, Canada. E-mail ylmarcel{at}ottawaheart.ca or rmcpherson@ottawaheart.org

Objective— We have used a multitiered approach to identify genetic and cellular contributors to high-density lipoprotein (HDL) deficiency in 124 human subjects.

Methods and Results— We resequenced 4 candidate genes for HDL regulation and identified several functional nonsynonymous mutations including 2 in apolipoprotein A-I (APOA1), 4 in lecithin:cholesterol acyltransferase (LCAT), 1 in phospholipid transfer protein (PLTP), and 7 in the ATP-binding cassette transporter ABCA1, leaving 88% (110/124) of HDL deficient subjects without a genetic diagnosis. Cholesterol efflux assays performed using cholesterol-loaded monocyte-derived macrophages from the 124 low HDL subjects and 48 control subjects revealed that 33% (41/124) of low HDL subjects had low efflux, despite the fact that the majority of these subjects (34/41) were not carriers of dysfunctional ABCA1 alleles. In contrast, only 2% of control subjects presented with low efflux (1/48). In 3 families without ABCA1 mutations, efflux defects were found to cosegregate with low HDL.

Conclusions— Efflux defects are frequent in low HDL syndromes, but the majority of HDL deficient subjects with cellular cholesterol efflux defects do not harbor ABCA1 mutations, suggesting that novel pathways contribute to this phenotype.

Cholesterol efflux defects are a common feature in subjects with low HDL, in the absence of coding sequence variants in ABCA1, suggesting that the majority of low HDL syndromes have novel genetic causes. Furthermore, we provide preliminary evidence that this is a heritable cellular phenotype, which cosegregates with low HDL.

Key Words: lipoproteins • cholesterol • genes • HDL • monocyte • macrophage

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