[Effects of genetic variations of cholesteryl ester transfer protein on atorvastatin treatment efficacy and clinical outcomes in patients with coronary artery disease].

OBJECTIVE:To explore the polymorphism of cholesteryl ester transfer protein (CETP) gene -629C/A among the coronary heart disease (CHD) Han population of Tianjin area and evaluate the influences of genetic factors on atorvastatin therapeutic effects and clinical outcomes in pharmacogenomics and provide theoretical rationales for individualized treatment. METHODS:A total of 332 angiographically confirmed CHD patients at Tianjin Chest Hospital were recruited from October 2010 to July 2011. The CETP gene promoter polymorphism at position -629 was determined by polymerase chain reaction-restricted fragment length polymorphism (PCR-RFLP). The serum level of CETP was determined by enzyme-linked immunosorbent assay (ELISA).Lipid levels were determined at baseline and 12 months post-treatment with 20 mg/d atorvastatin in all patients. Clinical follow-up were performed for more than 1 year (range, 12-23 months). And major adverse cardiac events (MACE, including death, non-fatal infarction, revascularization and stroke) were analyzed. The Kaplan-Meier Log-rank test was used to compare MACE-free survival between different genotypes. RESULTS:(1) The frequencies of variant -692A allele was 0.476, AA genotype showed reduced CETP levels and higher HDL-C levels compared with CC and CA genotypes. But it did not reach statistical significance (F = 0.893, P = 0.411 and F = 1.279, P = 0.282 respectively). Although a negative trend correlation existed between serum levels of HDL-C and CETP, it did not reach statistical significance (r = -0.151, P = 0.081) . (2) After 12-month therapy of atorvastatin, CC genotype was shown to be associated with higher LDL-C, LP(a) reduction and HDL-C elevation in response to atorvastatin compared with CA and AA genotype.LDL-C levels decreased 43.5% in CC homozygotes, 25.5% in CA heterozygotes and 11.7% in AA homozygotes (P = 0.001).HDL-C levels increased 9.2% in CC homozygotes, 6.8% in CA heterozygotes and 5.5% in AA homozygotes.However the changes of HDL-C levels in three genotypes showed no significant difference (P = 0.412). (3) There was a 7.83% incidence of MACE after a mean follow-up of (18.66 ± 5.99) months. The outcomes were death (n = 3, 0.90%), non-fatal infarction (n = 7, 2.11%), revascularization (n = 13, 3.92%) and stroke (n = 3, 0.90%). The cumulative MACE free survival rates were 96.2% , 92.1% and 87.3% in CC, CA and AA genotypes respectively (Log-rank P = 0.444). CONCLUSION:Variant AA genotype shows a higher level of HDL-C s and a lowered level of CETP.However CC genotype offers a better benefit of statin therapy associated with lowered levels of LDL-C and LP(a). And the long-term clinical prognosis is not affected among three genotypes.