CLINICAL RESEARCH: GENETIC POLYMORPHISMS AND ISCHEMIC HEART DISEASE
Common genetic variation of the cholesteryl ester transfer protein gene strongly predicts future cardiovascular death in patients with coronary artery disease
Stefan Blankenberg, MD* ,*,
Hans J. Rupprecht, MD*,
Christoph Bickel, MD*,
Xian-Cheng Jiang, PhD ,
Odette Poirier, PhD,
Karl J. Lackner, MD ,
J.ürgen Meyer, MD, FACC*,
François Cambien, MD,
Laurence Tiret, PhD AtheroGene Investigators
* 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.
|
Abbreviations and Acronyms
| | CAD | | coronary artery disease | | CETP | | cholesteryl ester transfer protein | | CI | | confidence interval | | HDL | | high-density lipoprotein | | HRR | | hazard risk ratio | | LDL | | low-density lipoprotein | | MI | | myocardial infarction | | RCT | | reverse cholesterol transport | | VLDL | | very-low-density lipoprotein |
|
This article has been cited by other articles:
|
|
|
|
 
J. J. Regieli, J. W. Jukema, D. E. Grobbee, J. J.P. Kastelein, J. A. Kuivenhoven, A. H. Zwinderman, Y. van der Graaf, M. L. Bots, and P. A. Doevendans
CETP genotype predicts increased mortality in statin-treated men with proven cardiovascular disease: an adverse pharmacogenetic interaction
Eur. Heart J.,
November 2, 2008;
29(22):
2792 - 2799.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
I. Porchay-Balderelli, F. Pean, N. Bellili, R. Jaziri, M. Marre, F. Fumeron, and for the DIABHYCAR Study Group
The CETP TaqIB Polymorphism Is Associated With the Risk of Sudden Death in Type 2 Diabetic Patients
Diabetes Care,
November 1, 2007;
30(11):
2863 - 2867.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. E. Borggreve, H. L. Hillege, B. H. R. Wolffenbuttel, P. E. de Jong, M. W. Zuurman, G. van der Steege, A. van Tol, R. P. F. Dullaart, and on behalf of the PREVEND Study Group
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
J. Clin. Endocrinol. Metab.,
September 1, 2006;
91(9):
3382 - 3388.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. Minoretti, C. Falcone, M. Calcagnino, E. Emanuele, M. P. Buzzi, E. Coen, and D. Geroldi
Prognostic significance of plasma osteopontin levels in patients with chronic stable angina
Eur. Heart J.,
April 1, 2006;
27(7):
802 - 807.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. S. Forrester, R. Makkar, and P.K. Shah
Increasing High-Density Lipoprotein Cholesterol in Dyslipidemia by Cholesteryl Ester Transfer Protein Inhibition: An Update for Clinicians
Circulation,
April 12, 2005;
111(14):
1847 - 1854.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. Anderson
Candidate-based proteomics in the search for biomarkers of cardiovascular disease
J. Physiol.,
February 15, 2005;
563(1):
23 - 60.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S.M. Boekholdt, F.M. Sacks, J.W. Jukema, J. Shepherd, D.J. Freeman, A.D. McMahon, F. Cambien, V. Nicaud, G.J. de Grooth, P.J. Talmud, et al.
Cholesteryl Ester Transfer Protein TaqIB Variant, High-Density Lipoprotein Cholesterol Levels, Cardiovascular Risk, and Efficacy of Pravastatin Treatment: Individual Patient Meta-Analysis of 13 677 Subjects
Circulation,
January 25, 2005;
111(3):
278 - 287.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
G. J. de Grooth, A. H. E. M. Klerkx, E. S. G. Stroes, A. F. H. Stalenhoef, J. J. P. Kastelein, and J. A. Kuivenhoven
A review of CETP and its relation to atherosclerosis
J. Lipid Res.,
November 1, 2004;
45(11):
1967 - 1974.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. L. Wolfe and D. J. Rader
Cholesteryl Ester Transfer Protein and Coronary Artery Disease: An Observation With Therapeutic Implications
Circulation,
September 14, 2004;
110(11):
1338 - 1340.
[Full Text]
[PDF]
|
|
|
|
|
|
|
C.C. Shoulders, E.L. Jones, and R.P. Naoumova
Genetics of familial combined hyperlipidemia and risk of coronary heart disease
Hum. Mol. Genet.,
April 1, 2004;
13(90001):
R149 - 160.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. L. Anderson and J. F. Carlquist
Genetic polymorphisms of hepatic lipase and cholesteryl ester transfer protein, intermediate phenotypes, and coronary risk: Do they add up yet?
J. Am. Coll. Cardiol.,
June 4, 2003;
41(11):
1990 - 1993.
[Full Text]
[PDF]
|
|
|
|
