The cholesteryl ester transfer protein Taq1B gene polymorphism predicts clinical benefit of statin therapy in patients with significant coronary artery disease.
BACKGROUND
Cholesteryl ester transfer protein (CETP) regulates plasma lipid distribution. A polymorphism in the CETP gene (Taq1B) is associated with CETP activity, HDL concentration, atherosclerosis progression, and response to statins, and may influence cardiovascular (CV) events. We studied CETP Taq1B genotype, plasma HDL, and clinical events among all patients and patients stratified by statin treatment.


METHODS
Consenting patients (n = 2531) with significant coronary artery disease (> or =1 lesion of > or =70% stenosis) undergoing coronary arteriography were genotyped, grouped by statin prescription at hospital discharge, and prospectively followed-up for the outcomes of all-cause mortality and myocardial infarction.


RESULTS
CETP Taq1B genotype frequencies were: B1B1, 32.9%; B1B2, 50.3%; and B2B2 16.8%. Plasma HDL was reduced for B1B1 patients (33 +/- 12 mg/dL, vs 36 +/- 13 mg/dL and 36 +/- 13 mg/dL for B1B2 and B2B2, respectively, P for trend =.003). Overall, event rates did not differ between genotypes. Event rates were similar among untreated (24.8%) and statin-treated (24.2%) B1 homozygotes (P = NS); statins significantly reduced events for B1B2 subjects (28.0% vs 21.0%, P =.009) and for B2B2 subjects (26.4% vs 17.4%, P =.048). Therapeutic benefit for B2 carriers remained after adjustment for covariates, and regression interaction analysis showed that B2 carriers experienced reduced events (relative risk [RR] 0.62, 95% CI 0.45-0.86), but statins did not benefit those with B1B1 (RR 1.09, 95% CI 0.70-1.7; P for interaction =.02). Findings were similar for the end point of death alone, although a modest benefit was seen in B1B1 patients (RR 0.67, P =.10), in addition to the strong benefit for B1B2 (RR 0.53, P =.001) and B2B2 (RR 0.28, P =.001).


CONCLUSIONS
The CETP Taq1B polymorphism is associated with differential HDL levels but no significant differential in CV risk in the absence of treatment. Importantly, however, CV event reduction by statin therapy is substantially enhanced in the presence of a B2 allele. Our findings suggest, for the first time, the potential of CETP Taq1B genotyping to enable more effective, pharmacogenetically directed therapy.
Carlquist
John F
JF
Cardiovascular Department, LDS Hospital, Salt Lake City, Utah 84143, USA. ldjcarlq@ihc.com
Muhlestein
Joseph B
JB
Horne
Benjamin D
BD
Hart
Noal I
NI
Bair
Tami L
TL
Molhuizen
Henri O F
HO
Anderson
Jeffrey L
JL
D000368:Aged; D000704:Analysis of Variance; D002352:Carrier Proteins / Q000235:genetics* / Q000502:physiology; D002423:Cause of Death; D053480:Cholesterol Ester Transfer Proteins; D008076:Cholesterol, HDL / Q000097:blood*; D003324:Coronary Artery Disease / Q000097:blood / Q000188:drug therapy / Q000235:genetics*; D023921:Coronary Stenosis / Q000097:blood / Q000188:drug therapy / Q000235:genetics; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D006023:Glycoproteins; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use; D008297:Male; D009203:Myocardial Infarction / Q000235:genetics; D011110:Polymorphism, Genetic; D011446:Prospective Studies
C506642:CETP protein, human; D002352:Carrier Proteins; D053480:Cholesterol Ester Transfer Proteins; D008076:Cholesterol, HDL; D006023:Glycoproteins; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors