title: Genetic etiology of isolated low HDL syndrome: incidence and heterogeneity of efflux defects.
abstract: 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.
authors.affiliation: University of Ottawa Heart Institute, 40 Ruskin St, Ottawa, Ontario, K1Y 4W7, Canada.
authors.forename: Robert S
authors.initials: RS
authors.lastname: Kiss
authors.forename: Nihan
authors.initials: N
authors.lastname: Kavaslar
authors.forename: Kei-ichiro
authors.initials: K
authors.lastname: Okuhira
authors.forename: Mason W
authors.initials: MW
authors.lastname: Freeman
authors.forename: Stephanie
authors.initials: S
authors.lastname: Walter
authors.forename: Ross W
authors.initials: RW
authors.lastname: Milne
authors.forename: Ruth
authors.initials: R
authors.lastname: McPherson
authors.forename: Yves L
authors.initials: YL
authors.lastname: Marcel
mesh_terms: 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
chemical_list: 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