title: Functional polymorphism in ABCA1 influences age of symptom onset in coronary artery disease patients.
abstract: ATP-binding-cassette-transporter-A1 (ABCA1) plays a pivotal role in intracellular cholesterol removal, exerting a protective effect against atherosclerosis. ABCA1 gene severe mutations underlie Tangier disease, a rare Mendelian disorder that can lead to premature coronary artery disease (CAD), with age of CAD onset being two decades earlier in mutant homozygotes and one decade earlier in heterozygotes than in mutation non-carriers. It is unknown whether common polymorphisms in ABCA1 could influence age of symptom onset of CAD in the general population. We examined common promoter and non-synonymous coding polymorphisms in relation to age of symptom onset in a group of CAD patients (n = 1164), and also carried out in vitro assays to test effects of the promoter variations on ABCA1 promoter transcriptional activity and effects of the coding variations on ABCA1 function in mediating cellular cholesterol efflux. Age of symptom onset was found to be associated with the promoter - 407G > C polymorphism, being 2.82 years higher in C allele homozygotes than in G allele homozygotes and intermediate in heterozygotes (61.54, 59.79 and 58.72 years, respectively; P = 0.002). In agreement, patients carrying ABCA1 haplotypes containing the -407C allele had higher age of symptom onset. Patients of the G/G or G/C genotype of the -407G > C polymorphism had significant coronary artery stenosis (>75%) at a younger age than those of the C/C genotype (P = 0.003). Reporter gene assays showed that ABCA1 haplotypes bearing the -407C allele had higher promoter activity than haplotypes with the -407G allele. Functional analyses of the coding polymorphisms showed an effect of the V825I substitution on ABCA1 function, with the 825I variant having higher activity in mediating cholesterol efflux than the wild-type (825V). A trend towards higher symptom onset age in 825I allele carriers was observed. The data indicate an influence of common ABCA1 functional polymorphisms on age of symptom onset in CAD patients.
authors.affiliation: Human Genetics Division, School of Medicine, University of Southampton, UK.
authors.forename: Theodosios
authors.initials: T
authors.lastname: Kyriakou
authors.forename: David E
authors.initials: DE
authors.lastname: Pontefract
authors.forename: Enrique
authors.initials: E
authors.lastname: Viturro
authors.forename: Conrad P
authors.initials: CP
authors.lastname: Hodgkinson
authors.forename: Ross C
authors.initials: RC
authors.lastname: Laxton
authors.forename: Neda
authors.initials: N
authors.lastname: Bogari
authors.forename: George
authors.initials: G
authors.lastname: Cooper
authors.forename: Michael
authors.initials: M
authors.lastname: Davies
authors.forename: Joel
authors.initials: J
authors.lastname: Giblett
authors.forename: Ian N M
authors.initials: IN
authors.lastname: Day
authors.forename: Iain A
authors.initials: IA
authors.lastname: Simpson
authors.forename: Christiane
authors.initials: C
authors.lastname: Albrecht
authors.forename: Shu
authors.initials: S
authors.lastname: Ye
mesh_terms: D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics* / Q000378:metabolism; D017668:Age of Onset; D000368:Aged; D001483:Base Sequence; D003324:Coronary Artery Disease / Q000453:epidemiology* / Q000235:genetics* / Q000378:metabolism; D004198:Disease Susceptibility; D005260:Female; D006239:Haplotypes; D006801:Humans; D008075:Lipoproteins, HDL / Q000097:blood / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic
chemical_list: C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D008075:Lipoproteins, HDL