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J Am Coll Cardiol, 2003; 41:1983-1989, doi:10.1016/S0735-1097(03)00408-X © 2003 by the American College of Cardiology Foundation |
,*
* Department of Medicine II, Johannes Gutenberg-University Mainz, Mainz, Germany
Department of Clinical Chemistry, Johannes Gutenberg-University Mainz, Mainz, Germany
Institut National de la Santé et de la Recherche Médicale (INSERM) U525, Faculté de Médecine Pitié-Salpêtrière, Paris, France
Department of Anatomy and Cell Biology, State University of New York, Downstate Medical Center, Brooklyn, New York, USA
Manuscript received August 27, 2002; revised manuscript received December 3, 2002, accepted December 26, 2002.
* Reprint requests and correspondence: Dr. Stefan Blankenberg, INSERM U 525, Faculté de Médecine Pitié-Salpêtrière, 91 bld de l’Hôpital, 75634 Paris cedex 13, France.
stefan.blankenberg{at}chups.jussieu.fr
OBJECTIVES: We sought to evaluate the association between cholesteryl ester transfer protein (CETP) genotypes and the risk of future cardiovascular mortality in patients with coronary artery disease (CAD).
BACKGROUND: Polymorphisms of the CETP gene influence CETP activity and high-density lipoprotein (HDL) cholesterol concentration and might affect the long-term prognosis and response to statin therapy in patients with CAD.
METHODS: We used serum samples and deoxyribonucleic acid collected at baseline from a prospective cohort of 1,211 patients with CAD prospectively followed up (median follow-up of 4.1 years), 82 of whom experienced a fatal cardiovascular event. The CETP/C-629A and I405V polymorphisms, CETP activity, and HDL cholesterol were determined.
RESULTS: Patients carrying the –629A allele had significantly lower CETP activity and higher HDL cholesterol levels. There was a significant association between this polymorphism and the risk of future cardiovascular death. Mortality decreased from 10.8% in CC homozygotes to 4.6% in CA heterozygotes and 4.0% in AA homozygotes (p < 0.0001). This association was independent of potential confounders, particularly HDL cholesterol and CETP activity levels. The clinical benefit of statin therapy was restricted to CC homozygotes, in whom cardiovascular mortality was divided by half (p = 0.01 for treatment x genotype interaction). Similar trends were observed with the CETP/I405V polymorphism, but these effects seemed to be mainly the consequence of linkage disequilibrium with the CETP/C-629A polymorphism.
CONCLUSIONS: In patients with CAD, the CETP/–629A allele had a strong protective effect on future mortality from cardiovascular causes, independent of its role on HDL cholesterol and CETP activity levels. Additionally, this common polymorphism appeared to predict which patients with CAD will experience a survival benefit from statin therapy.
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