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An Increased Coronary Risk Is Paradoxically Associated with Common Cholesteryl Ester Transfer Protein Gene Variations That Relate to Higher High-Density Lipoprotein Cholesterol: A Population-Based Study

Departments of Endocrinology (S.E.B., B.H.R.W., A.v.T., R.P.F.D.), Cardiology (H.L.H.), and Nephrology (P.E.d.J., M.W.Z.) and Genotyping Facility (G.v.d.S.), Medical Biology, University of Groningen and 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: R. P. F. Dullaart, Department of Endocrinology, University Medical Center Groningen and University of Groningen, Hanzeplein 1, P.O. Box 30-001, 9700 RB Groningen, The Netherlands. E-mail: r.p.f.dullaart{at}int.umcg.nl.

Background: Several cholesteryl ester transfer protein (CETP) polymorphisms affect high-density lipoprotein (HDL) cholesterol, but the impact of CETP gene variants on incident coronary disease in the general population is uncertain after correction for their effect on HDL cholesterol.

Design: We determined relationships between the CETP –629CA promoter (n = 8141), the TaqIB (n = 8289), and the I405V (n = 8265) polymorphisms, serum lipids, C-reactive protein, and clinical factors with incident coronary heart disease (defined as death from or hospitalization for myocardial infarction, ischemic heart disease, or coronary intervention) during a median of 4.94 yr follow-up.

Subjects: A predominantly Caucasian general population was studied.

Results: HDL cholesterol was 0.08 mmol/liter higher in –629A carriers than in –629CC homozygotes (P < 0.001). The unadjusted coronary hazard was 1.26 [95% confidence interval (CI), 0.95–1.68; P = 0.11] in A carriers compared with CC homozygotes and increased to 1.46 (95% CI, 1.10–1.95; P = 0.01) after adjustment for HDL cholesterol. This effect remained after additional adjustment for apolipoprotein A-I, triglycerides, C-reactive protein, age, and gender. Likewise, the HDL-cholesterol-adjusted hazard ratio was also higher in AA than in CC homozygotes (hazard ratio, 1.72; 95% CI, 1.22–2.42; P < 0.01). Similar findings were obtained with the TaqIB polymorphism. The 405V allele was weakly associated with incident coronary heart disease after HDL cholesterol adjustment (P = 0.09).

Conclusions: A common CETP promoter polymorphism, which beneficially contributes to higher HDL cholesterol, is paradoxically associated with increased incidence of coronary disease in the general population. Thus, CETP gene variation may affect coronary risk apart from the level of HDL cholesterol.