Human Molecular Genetics Advance Access originally published online on April 5, 2007
Human Molecular Genetics 2007 16(12):1412-1422; doi:10.1093/hmg/ddm091
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Functional polymorphism in ABCA1 influences age of symptom onset in coronary artery disease patients
1 Human Genetics Division, School of Medicine, University of Southampton, UK, 2 Lehrstuhl für Physiologie, Technische Universität München, Germany, 3 Cardiothoracic Unit, Southampton General Hospital, UK, 4 Institute of Biochemistry and Molecular Medicine, University of Berne, Switzerland and 5 William Harvey Research Institute, Barts and the London School of Medicine, UK
* To whom correspondence should be addressed at: Clinical Pharmacology, William Harvey Research Institute, John Vane Science Centre, Charterhouse Square, London EC1M 6BQ, UK. Tel: +44 2078823425; Fax: +44 2078823408; Email: s.ye{at}qmul.ac.uk
Received January 11, 2007; Revised March 9, 2007; Accepted April 1, 2007
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.
The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.