The effect of cholesteryl ester transfer protein-629C→A promoter polymorphism on high-density lipoprotein cholesterol is dependent on serum triglycerides

Context: The -629C -> A cholesteryl ester transfer protein (CETP) promoter polymorphism is a determinant of HDL cholesterol (HDL-C). The effect of the closely linked CETP TaqIB polymorphism on HDL-C has been suggested to be modified by obesity and hyperinsulinemia. Objective: Because the CETP-mediated cholesteryl ester transfer out of HDL is stimulated by high triglycerides, we hypothesized that triglycerides modify the effect of the CETP-629C -> A promoter polymorphism on HDL-C. Design: In 7083 nondiabetic subjects of the PREVEND population, the -629C -> A promoter polymorphism, HDL-C, serum triglycerides, waist circumference, and insulin resistance (HOMA(ir)) were determined. Serum apolipoprotein A-I was available in 6948 subjects. The TaqIB polymorphism was also assessed. Setting: The study is set in the general community. Results: HDL-C and serum apolipoprotein A-I were on average 0.14 mmol/liter and 0.05 g/liter higher in -629AA ( 22.9%) compared to -629CC (26.8%) homozygotes ( P < 0.001 for both). This genotype effect on HDL-C was on average 0.15 mmol/liter in the lowest triglyceride tertile but only 0.08 mmol/liter in the highest tertile ( P < 0.01). Multiple regression analysis showed that HDL-C was determined by the CETP promoter variant ( P < 0.001), gender ( P < 0.001), triglycerides ( P < 0.001), and interactions between triglycerides and genotype ( P < 0.05), between triglycerides and gender ( P < 0.05), and between genotype and gender ( P < 0.05), independently from waist, HOMAir, alcohol use, age, and use of lipid-lowering drugs. The TaqIB polymorphism also interacted with triglycerides on HDL-C. The -629C -> A promoter polymorphism did not interact with obesity and HOMAir on HDL-C. Conclusions: The HDL-C-raising effect of the CETP-629A allele is diminished with higher triglycerides, which may be explained by a predominant effect of triglyceride-rich lipoproteins over circulating CETP itself on cholesteryl ester transfer out of HDL with rising triglycerides.