Common genetic variation of the cholesteryl ester transfer protein gene strongly predicts future cardiovascular death in patients with coronary artery disease.
OBJECTIVE
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.
Blankenberg
Stefan
S
Department of Medicine II, Johannes Gutenberg-University Mainz, Mainz, Germany. stefan.blankenberg@chups.jussieu.fr
Rupprecht
Hans J
HJ
Bickel
Christoph
C
Jiang
Xian-Cheng
XC
Poirier
Odette
O
Lackner
Karl J
KJ
Meyer
Jürgen
J
Cambien
François
F
Tiret
Laurence
L
D000368:Aged; D000483:Alleles; D002352:Carrier Proteins / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D053480:Cholesterol Ester Transfer Proteins; D008076:Cholesterol, HDL / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D015331:Cohort Studies; D003324:Coronary Artery Disease / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality*; D023381:Endpoint Determination; D005260:Female; D005500:Follow-Up Studies; D005819:Genetic Markers / Q000187:drug effects / Q000235:genetics; D014644:Genetic Variation / Q000187:drug effects / Q000235:genetics*; D005838:Genotype; D005858:Germany / Q000453:epidemiology; D006023:Glycoproteins; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use; D015810:Linkage Disequilibrium / Q000235:genetics; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D011237:Predictive Value of Tests; D016019:Survival Analysis; D013997:Time Factors; D016896:Treatment Outcome
C506642:CETP protein, human; D002352:Carrier Proteins; D053480:Cholesterol Ester Transfer Proteins; D008076:Cholesterol, HDL; D005819:Genetic Markers; D006023:Glycoproteins; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors