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cSNP analysis of the ABCA1 gene:
Common variant lowers riskfor coronary artery disease
By Bijal P. Trivedi

A common variation in the cholesterol transporter gene ABCA1 (ATP-binding cassette transporter-1), found in 46 percent of Europeans, lowers the risk for coronary artery disease according to a new study.

Michael Hayden, of the University of British Columbia, in Vancouver, Canada, and colleagues found that Europeans carrying the R219K variant of the ABCA1 gene had less severe coronary artery disease. R219K was associated with lower levels of triglycerides and raised levels of high-density lipoprotein cholesterol (HDL-C), the so-called 'good' cholesterol that lowers risk of heart disease. HDL-C was up to 15 percent higher in individuals with two copies of the R219K variant.

Hayden's team measured the blood vessel diameters of individuals carrying R219K and found they were broader with less fat accumulation along the vessel walls, indicating slower progression of arteriosclerosis. Carriers of the variant gene had 29 percent fewer coronary events such as heart attacks, coronary bypass or angioplasty surgeries, strokes or ischemic attacks.

The cholesterol transporter ABCA1 is a serpentine protein that is woven through the cell membrane. Control of cholesterol uptake and release is essential for maintaining the correct levels in the blood and tissue. The locations of the 10 SNPs that cause amino acid changes are shown. View larger

Hayden's investigation of variation within the ABCA1 gene was prompted by the finding that Tangier disease, characterized by almost a complete absence of HDL-C, is caused by a defect in ABCA1. This led Hayden's team to search for other variants of the cholesterol transporter gene that might modify the risk of heart disease.

The researchers identified 16 single nucleotide polymorphisms (SNPs)—a specific type of variation—within the coding region of the ABCA1 gene. Of these, 10 caused amino acid changes in the protein, which have the potential to alter the function of the transporter. In the R219K variant the amino acid arginine is replaced with lysine.

The authors note that the SNPs tend to be concentrated away from the functional regions of the transporter protein. They suggest that this may be why most variations seem to exert such minor effects.

Defective ABC transporters have been implicated in a number of diseases: ABCA1 in Tangier disease, ABCC7, which transports chloride ions, in cystic fibrosis and ABCD1, which transports long fatty acid molecules, in adrenoleukodystropy.

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Clee, S.M. et al. Common genetic variation in ABCA1 is associated with altered lipoprotein levels and a modified risk for coronary artery disease. Circulation 103, 1198-1205 (March 6, 2001).
Read, T-A. et al. Local endostatin treatment of gliomas administered by microencapsulated producer cells. Nat Biotechnol 19, 29-34 (January 2001).

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