Genetic etiology of isolated low HDL syndrome: incidence and heterogeneity of efflux defects.
OBJECTIVE
We have used a multitiered approach to identify genetic and cellular contributors to high-density lipoprotein (HDL) deficiency in 124 human subjects.


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.
Kiss
Robert S
RS
University of Ottawa Heart Institute, 40 Ruskin St, Ottawa, Ontario, K1Y 4W7, Canada.
Kavaslar
Nihan
N
Okuhira
Kei-ichiro
K
Freeman
Mason W
MW
Walter
Stephanie
S
Milne
Ross W
RW
McPherson
Ruth
R
Marcel
Yves L
YL
D016632:Apolipoprotein A-I / Q000235:genetics* / Q000378:metabolism; D015415:Biomarkers / Q000097:blood; D015153:Blotting, Western; D008076:Cholesterol, HDL / Q000097:blood*; D008078:Cholesterol, LDL / Q000097:blood; D004587:Electrophoresis, Agar Gel; D020022:Genetic Predisposition to Disease; D006801:Humans; D006937:Hypercholesterolemia / Q000097:blood / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation; D010641:Phenotype; D049294:Phospholipid Transfer Proteins / Q000097:blood / Q000235:genetics; D012313:RNA / Q000235:genetics*; D002785:Sterol O-Acyltransferase / Q000097:blood / Q000235:genetics; D013577:Syndrome
C505693:APOA1 protein, human; D016632:Apolipoprotein A-I; D015415:Biomarkers; D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; C493430:PLTP protein, human; D049294:Phospholipid Transfer Proteins; D012313:RNA; D002785:Sterol O-Acyltransferase