Common variants in the gene encoding ATP-binding cassette transporter 1 inmen with low HDL cholesterol levels and coronary heart disease

HDL cholesterol (HDL-C) deficiency is the most common lipid abnormality obs erved in patients with premature coronary heart disease (CHD). Recently, ou r laboratory and others demonstrated that mutations in the ATP-binding cass ette transporter 1 (ABCA1) gene are responsible for Tangier disease, a rare genetic disorder characterized by severely diminished plasma HDL-C concent rations and a predisposition for CHD. To address the question of whether co mmon variants within the coding sequence of ABCA1 may affect plasma HDL-C l evels and CHD risk in the general population, we determined the frequencies of three common ABCA1 variants (G596A, A2589G and G3456C) in men participa ting in the Veterans Affairs Cooperative HDL Cholesterol Intervention Trial (VA-HIT), a study designed to examine the benefits of HDL raising in men h aving low HDL-C (less than or equal to 40 mg/dl) and established CHD, as we ll as in CHD-free men from the Framingham Offspring Study (FOS). Allele fre quencies (%) in VA-HIT were 31, 16, and 4 for the G596A, A2589G, and G3456C variants, respectively, versus 27, 12, and 2 in FOS (P < 0.03). None of th e variants were significantly associated with plasma HDL-C concentrations i n either population: however, in VA-HIT, the G3456C variant was associated with a significantly increased risk for CHD end points, suggesting a role f or this variant in the premature CHD observed in this population. (C) 2001 Elsevier Science Ireland Ltd. All rights reserved.