HDL cholesterol (HDL-C) deficiency is the most common lipid abnormality observed in patients with premature coronary heart disease (CHD). Recently, our laboratory and others demonstrated that mutations in the ATP-binding cassette transporter 1 (ABCA1) gene are responsible for Tangier disease, a rare genetic disorder characterized by severely diminished plasma HDL-C concentrations and a predisposition for CHD. To address the question of whether common variants within the coding sequence of ABCA1 may affect plasma HDL-C levels and CHD risk in the general population, we determined the frequencies of three common ABCA1 variants (G596A, A2589G and G3456C) in men participating in the Veterans Affairs Cooperative HDL Cholesterol Intervention Trial (VA-HIT), a study designed to examine the benefits of HDL raising in men having low HDL-C (< or =40 mg/dl) and established CHD, as well as in CHD-free men from the Framingham Offspring Study (FOS). Allele frequencies (%) 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 the variants were significantly associated with plasma HDL-C concentrations in either population; however, in VA-HIT, the G3456C variant was associated with a significantly increased risk for CHD end points, suggesting a role for this variant in the premature CHD observed in this population.