(Circulation. 2001;103:1198.)
© 2001 American Heart Association, Inc.
Clinical Investigation and Reports |
Common Genetic Variation in ABCA1 Is Associated With Altered Lipoprotein Levels and a Modified Risk for Coronary Artery Disease
From the Centre for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, Canada (S.M.C., K.Y.Z., M.R.H.); the Department of Medical Statistics, Leiden University Medical Center, Leiden, the Netherlands (A.H.Z.); Montreal Genome Centre, McGill University Health Centre, Montreal, Canada (J.C.E., T.J.H.); the Department of Vascular Medicine, Academic Medical Centre, Amsterdam, the Netherlands (H.O.F.M., M.v.W., M.v.D., J.J.P.K.); Xenon Genetics, Inc, Vancouver, Canada (K.R., A.B.-W.); the Department of Cardiology, Leiden University Medical Center and Interuniversity Cardiology Institute, Leiden, the Netherlands (J.W.J.); and the Cardiovascular Genetics Laboratory, McGill University Health Centre, Montreal, Canada (J.G.).
Correspondence to Michael R. Hayden, Centre for Molecular Medicine and Therapeutics, 980 W. 28th Avenue, Vancouver, BC, Canada V5Z 4H4. E-mail mrh{at}cmmt.ubc.ca
Background—Low plasma HDL cholesterol (HDL-C) is associated with an increased risk of coronary artery disease (CAD). We recently identified the ATP-binding cassette transporter 1 (ABCA1) as the major gene underlying the HDL deficiency associated with reduced cholesterol efflux. Mutations within the ABCA1 gene are associated with decreased HDL-C, increased triglycerides, and an increased risk of CAD. However, the extent to which common variation within this gene influences plasma lipid levels and CAD in the general population is unknown.
Methods and Results—We examined the phenotypic effects of single nucleotide polymorphisms in the coding region of ABCA1. The R219K variant has a carrier frequency of 46% in Europeans. Carriers have a reduced severity of CAD, decreased focal (minimum obstruction diameter 1.81±0.35 versus 1.73±0.35 mm in noncarriers, P=0.001) and diffuse atherosclerosis (mean segment diameter 2.77±0.37 versus 2.70±0.37 mm, P=0.005), and fewer coronary events (50% versus 59%, P=0.02). Atherosclerosis progresses more slowly in carriers of R219K than in noncarriers. Carriers have decreased triglyceride levels (1.42±0.49 versus 1.84±0.77 mmol/L, P=0.001) and a trend toward increased HDL-C (0.91±0.22 versus 0.88±0.20 mmol/L, P=0.12). Other single nucleotide polymorphisms in the coding region had milder effects on plasma lipids and atherosclerosis.
Conclusions—These data suggest that common variation in ABCA1 significantly influences plasma lipid levels and the severity of CAD.
Key Words: ABC transporters • coronary disease • lipids • genetics
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|
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|
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|
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|
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|
|
|
|
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|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|