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The Effect of Cholesteryl Ester Transfer Protein –629CA Promoter Polymorphism on High-Density Lipoprotein Cholesterol Is Dependent on Serum Triglycerides

Departments of Endocrinology (S.E.B., B.H.R.W., A.v.T., R.P.F.D.), Cardiology (H.L.H.), Nephrology (P.E.d.J.), Clinical Pharmacology (S.J.L.B.), Internal Medicine (S.J.L.B.), and Genotyping Facility (G.v.d.S.), Medical Biology, University Medical Center Groningen, 9700 RB Groningen, The Netherlands; and Department of Cell Biology and Genetics (A.v.T.), Erasmus University Medical Center, 3000 CA Rotterdam, The Netherlands

Address all correspondence and requests for reprints to: S. E. Borggreve, M.D., Department of Endocrinology, University Medical Centre Groningen, P.O. Box 30.001, 9700 RB Groningen, The Netherlands. E-mail: s.e.borggreve{at}int.umcg.nl.

Context: The –629CA 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 –629CA promoter polymorphism on HDL-C.

Design: In 7083 nondiabetic subjects of the PREVEND population, the –629CA 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, HOMA_ir, alcohol use, age, and use of lipid-lowering drugs. The TaqIB polymorphism also interacted with triglycerides on HDL-C. The –629CA promoter polymorphism did not interact with obesity and HOMA_ir 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.

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