The Role of a Common Variant of the Cholesteryl Ester Transfer Protein Gene in the Progression of Coronary Atherosclerosis

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Abstract
The high-density lipoprotein (HDL) cholesterol concentration is inversely related to the risk of coronary artery disease. The cholesteryl ester transfer protein (CETP) has a central role in the metabolism of this lipoprotein and may therefore alter the susceptibility to atherosclerosis. The DNA of 807 men with angiographically documented coronary atherosclerosis was analyzed for the presence of a polymorphism in the gene coding for CETP. The presence of this DNA variation was referred to as B1, and its absence as B2. All patients participated in a cholesterol-lowering trial designed to induce the regression of coronary atherosclerosis and were randomly assigned to treatment with either pravastatin or placebo for two years. The B1 variant of the CETP gene was associated with both higher plasma CETP concentrations (mean [±SD], 2.29±0.62 μg per milliliter for the B1B1 genotype vs. 1.76±0.51 μg per milliliter for the B2B2 genotype) and lower HDL cholesterol concentrations (34±8 vs. 39±10 mg per deciliter). In addition, we observed a significant dose-dependent association between this marker and the progression of coronary atherosclerosis in the placebo group (decrease in mean luminal diameter: 0.14±0.21 mm for the B1B1 genotype, 0.10±0.20 mm for the B1B2 genotype, and 0.05±0.22 mm for the B2B2 genotype). This association was abolished by pravastatin. Pravastatin therapy slowed the progression of coronary atherosclerosis in B1B1 carriers but not in B2B2 carriers (representing 16 percent of the patients taking pravastatin). There is a significant relation between variation at the CETP gene locus and the progression of coronary atherosclerosis that is independent of plasma HDL cholesterol levels and the activities of lipolytic plasma enzymes. This common DNA variant appears to predict whether men with coronary artery disease will benefit from treatment with pravastatin to delay the progression of coronary atherosclerosis.

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