title: Increased risk of coronary artery disease in Caucasians with extremely low HDL cholesterol due to mutations in ABCA1, APOA1, and LCAT.
abstract: Mutations in ABCA1, APOA1, and LCAT reduce HDL cholesterol (HDLc) in humans. However, the prevalence of these mutations and their relative effects on HDLc reduction and risk of coronary artery disease (CAD) are less clear. Here we searched for ABCA1, APOA1, and LCAT mutations in 178 unrelated probands with HDLc <10th percentile but no other major lipid abnormalities, including 89 with ≥1 first-degree relative with low HDLc (familial probands) and 89 where familial status of low HDLc is uncertain (unknown probands). Mutations were most frequent in LCAT (15.7%), followed by ABCA1 (9.0%) and APOA1 (4.5%), and were found in 42.7% of familial but only 14.6% of unknown probands (p=2.44∗10(-5)). Interestingly, only 16 of 24 (66.7%) mutations assessed in families conferred an average HDLc <10th percentile. Furthermore, only mutation carriers with HDLc <5th percentile had elevated risk of CAD (odds ratio (OR)=2.26 for 34 ABCA1 mutation carriers vs. 149 total first-degree relative controls, p=0.05; OR=2.50 for 26 APOA1 mutation carriers, p=0.04; OR=3.44 for 38 LCAT mutation carriers, p=1.1∗10(-3)). These observations show that mutations in ABCA1, APOA1, and LCAT are sufficient to explain >40% of familial hypoalphalipoproteinemia in this cohort. Moreover, individuals with mutations and large reductions in HDLc have increased risk of CAD. This article is part of a Special Issue entitled Advances in High Density Lipoprotein Formation and Metabolism: A Tribute to John F. Oram (1945-2010).
authors.affiliation: Xenon Pharmaceuticals Inc., Burnaby, BC, Canada.
authors.forename: Ian
authors.initials: I
authors.lastname: Tietjen
authors.forename: G Kees
authors.initials: GK
authors.lastname: Hovingh
authors.forename: Roshni
authors.initials: R
authors.lastname: Singaraja
authors.forename: Chris
authors.initials: C
authors.lastname: Radomski
authors.forename: Jason
authors.initials: J
authors.lastname: McEwen
authors.forename: Elden
authors.initials: E
authors.lastname: Chan
authors.forename: Maryanne
authors.initials: M
authors.lastname: Mattice
authors.forename: Annick
authors.initials: A
authors.lastname: Legendre
authors.forename: John J P
authors.initials: JJ
authors.lastname: Kastelein
authors.forename: Michael R
authors.initials: MR
authors.lastname: Hayden
mesh_terms: D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000328:Adult; D000368:Aged; D016632:Apolipoprotein A-I / Q000235:genetics*; D008076:Cholesterol, HDL / Q000097:blood*; D015331:Cohort Studies; D003324:Coronary Artery Disease / Q000097:blood / Q000453:epidemiology / Q000235:genetics*; D005260:Female; D056726:Genetic Association Studies; D006579:Heterozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D010375:Pedigree; D010641:Phenotype; D007862:Phosphatidylcholine-Sterol O-Acyltransferase / Q000235:genetics*; D015995:Prevalence; D012307:Risk Factors; D017422:Sequence Analysis, DNA; D017384:Sequence Deletion; D044465:White People
chemical_list: C577836:ABCA1 protein, human; C505693:APOA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D016632:Apolipoprotein A-I; D008076:Cholesterol, HDL; D007862:Phosphatidylcholine-Sterol O-Acyltransferase