on November 4, 2004
Published online before print November 4, 2004, doi: 10.1161/01.ATV.0000149379.72018.20
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Submitted on September 22, 2003
Accepted on October 7, 2004
Genotypic Effect of the -565C>T Polymorphism in the ABCA1 Gene Promoter on ABCA1 Expression and Severity of Atherosclerosis
Theodosios Kyriakou ;
From the Human Genetics Division (T.K., C.H., D.E.P., W.M.H., S.Y.), School of Medicine, University of Southampton, Southampton, UK; the Cardiothoracic Unit (D.E.P., S.I., Y.W.), Southampton General Hospital, Southampton, UK; and the Atherosclerosis Research Unit (P.E.), King Gustaf V Research Institute, Karolinska Hospital, Stockholm, Sweden.
* To whom correspondence should be addressed. E-mail: Shu.Ye{at}soton.ac.uk.
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.
Methods and 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.
Key words: ABCA1 • genetics • promoter • polymorphism • atherosclerosis
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