title: Genotypic effect of the -565C>T polymorphism in the ABCA1 gene promoter on ABCA1 expression and severity of atherosclerosis.
abstract: OBJECTIVE
  Loss-of-function mutations of the ATP-binding cassette transporter A1 (ABCA1) gene cause Tangier disease, a rare genetic disorder with accumulation of lipid-laden macrophages and increased risk of atherosclerosis. Common variants of this gene may be a genetic factor for atherosclerosis in the general population. This study was performed to test the reported association between the -565C>T polymorphism and atherosclerosis severity and to investigate whether this variant per se had an effect on promoter activity of the ABCA1 gene.
  
  
  RESULTS
  A cohort of patients with coronary atherosclerosis were genotyped for the -565C>T polymorphism. Logistic regression analyses showed that homozygotes of the -565T allele had greatest mean number of diseased coronary arteries, particular in nonsmokers. Real-time reverse-transcriptase polymerase chain reaction showed that in atherosclerotic plaques removed from patients undergoing endarteretomy, ABCA1 expression levels were lowest in those who had the T/T genotype and highest in those of the C/C genotype. Transfection and reporter assays demonstrated that in cultured macrophages, the -565T allelic promoter had a lower activity in driving gene expression than the -565C allelic promoter. Electrophoretic mobility shift assays displayed differential binding of nuclear proteins to the 2 alleles.
  
  
  CONCLUSIONS
  These results indicate that the -565C>T polymorphism has an allele-specific effect on ABCA1 gene expression and provide further evidence of a genotypic effect on coronary atherosclerosis severity. The study showed that the ABCA1 gene -565C>T polymorphism was associated with severity of coronary atherosclerosis in a cohort of patients from Southern England and that this sequence variant per se had an effect on promoter activity of the ABCA1 gene. The data support the notion that common ABCA1 gene variants can contribute to interindividual variability in atherosclerosis susceptibility and severity.
authors.affiliation: Human Genetics Division, School of Medicine, University of Southampton, Southampton, UK.
authors.forename: Theodosios
authors.initials: T
authors.lastname: Kyriakou
authors.forename: Conrad
authors.initials: C
authors.lastname: Hodgkinson
authors.forename: David E
authors.initials: DE
authors.lastname: Pontefract
authors.forename: Srikanth
authors.initials: S
authors.lastname: Iyengar
authors.forename: W Martin
authors.initials: WM
authors.lastname: Howell
authors.forename: Yuk-ki
authors.initials: YK
authors.lastname: Wong
authors.forename: Per
authors.initials: P
authors.lastname: Eriksson
authors.forename: Shu
authors.initials: S
authors.lastname: Ye
mesh_terms: D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000096:biosynthesis / Q000235:genetics*; D000368:Aged; D000483:Alleles; D002478:Cells, Cultured / Q000378:metabolism; D015331:Cohort Studies; D015897:Comorbidity; D003324:Coronary Artery Disease / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000601:surgery; D003924:Diabetes Mellitus, Type 2 / Q000453:epidemiology; D004691:Endarterectomy; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics; D017930:Genes, Reporter; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing; D005838:Genotype; D006801:Humans; D006949:Hyperlipidemias / Q000453:epidemiology; D008264:Macrophages / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009687:Nuclear Proteins / Q000378:metabolism; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic / Q000235:genetics*; D011485:Protein Binding; D011993:Recombinant Fusion Proteins / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012307:Risk Factors; D012907:Smoking / Q000453:epidemiology; D014162:Transfection
chemical_list: C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D009687:Nuclear Proteins; D011993:Recombinant Fusion Proteins