Objective-We have previously reported that genetic variation at the cholesteryl ester transfer protein (CETP) TaqIB locus is correlated with plasma lipid levels and coronary heart disease (CHD) risk in the Framingham Offspring Study (FOS). In FOS, the B2 allele was associated with increased levels of high density lipoprotein (HDL) cholesterol (HDL-C), decreased CETP activity, and reduced CHD risk for men having the B2B2 genotype. The present study was undertaken to further define the relationship between this polymorphism and CHD risk at the population level. Methods and Results-We tested for associations between the CETP TaqIB genotype and plasma lipoprotein levels, response to gemfibrozil therapy, and CHD end points in 852 men participating in the Veterans Affairs HDL-C Intervention Trial (VA-HIT), a study designed to explore the potential benefits of raising HDL levels in men having established CHD with low HDL-C (Յ40 mg/dL) as their primary lipid abnormality. In VA-HIT, 13.9% of the men had the B2B2 genotype relative to 19.1% of the men in FOS (Ϫ27%, PϽ0.03), whereas more men in VA-HIT had the B1B1 genotype (15%, PϽ0.05). Similar to our finding in FOS, B2B2 men in VA-HIT had the highest mean level of HDL-C (32.6Ϯ4.8 mg/dL), followed by B1B2 men (32.0Ϯ5.3 mg/dL), and, last, by B1B1 men (30.9Ϯ4.9 mg/dL). Interestingly, B1B1 men, who had the least favorable plasma lipid profile at baseline, had the greatest triglyceride-lowering response to gemfibrozil (Ϫ34%, Pϭ0.006). CETP TaqIB genotype was also associated with the risk of CHD end points in VA-HIT, with an adjusted risk ratio of 0.52 for B2B2 men (Pϭ0.08). Conclusions-Our data demonstrate that in men with CHD and HDL deficiency, the CETP TaqI B2B2 genotype is (1) significantly reduced and (2) associated with higher levels of plasma HDL-C and lower CHD risk. Together with our earlier report, these results support the concept that increased HDL-C levels, resulting from reduced CETP activity, are associated with decreased CHD risk. Key Words: cholesteryl ester transfer protein Ⅲ coronary heart disease Ⅲ high density lipoproteins Ⅲ polymorphism Ⅲ Veterans Affairs HDL-C Intervention Trial N umerous population studies have shown that a strong inverse relationship exists between plasma HDL cholesterol (HDL-C) levels and coronary heart disease (CHD) risk. [1][2][3][4] It has long been theorized that the atheroprotective effect of HDL is primarily due to its role in reverse cholesterol transport (RCT), the process by which HDL mediates the transport of excess cholesterol from peripheral cells back to the liver for excretion into the bile. 5 RCT is a complex pathway, involving transport proteins, modifying enzymes, and cell surface receptors. One of the enzymes with a key role in RCT is cholesteryl ester transfer protein (CETP), which promotes the exchange of cholesteryl esters from HDL to the apoB-containing lipoproteins, thus, providing an avenue for the uptake of cholesteryl esters by hepatic receptors. 6
See page 1055The CETP gene, located on chromosome 16q21, cons...
