Influence Of Cytochrome P450 Enzyme (CYP2C19 And CYP3A5) Polymorphisms On Clopidogrel Responsiveness In Coronary Atherosclerotic Heart Disease Patients

Objective: To investigate the influence of Cytochrome P450 enzyme(CYP2C19 and CYP3A5 )polymorphisms on clopidogrel responsiveness in Chinese Coronary Atherosclerotic Heart Disease(CAHD) patients of Han nationality.Methods: PCR-RFLP technology was used to genotype the CYP2C19 681G/A and CYP3A5 6986A/G polymorphisms in 548 patients with CAHD {369 male patients, 179 female patients ,mean age 66.77±11.33, included 260 clopidogrel-treated patients and 103 patients undergoing elective Percutaneous coronary intervention(PCI)} and 222 control group (healthy subjects from Jianyang Region Fujian Province for epidemiologic survey, 131 male, 91 female, mean age 59.45±10.50). We assessed the association between CYP genetypes and clopidogrel lab resistance {CLR: Inhibition of adenosine-diphosphate-induced maximal platelet aggregation (MPA) after 10 days'clopidogrel-treatment≤10%} in the 260 CAHD patiernts who were treated with clopidogrel. We then contrasted MPA, CLR and cardiovascular outcomes {include acute coronary syndrome (ACS) and/or inpatient care, cardiogenic sudden death} after a follow-up for median 7(3～12)months between different genetype groups (according to different CYP2C19 681 and CYP3A5 6986 genotypes) in the 103 patients undergoing PCI.Results:1.The frequencies of different genotypes of CYP2C19 681 and CYP3A5 6986 were in agreement with Hardy-Weinberg equilibrium in our study(P>0.05).2. The 260 CAHD patients who were treated with clopidogrel: The patients carrying CYP2C19 681GG genetype(135/260) have a higher reduction of MPA after10 days'clopidogrel-treatment than the CYP2C19 681GA carriers, CYP2C19 681AA carriers are the lowest (15.88±11.67%,11.50±10.76%和8.15±6.38%,P<0.01). The rate of CLR is 35.77%(93/260), the patients carrying CYP2C19 681GG genetype occupy 38.71%(36/93), the patients carrying CYP2C19 681A allele(GA+AA) occupy 61.29%{(52+5)/93,P<0.01}. Otherwise, there were no significant differences mong the CYP3A5 6986 genotypes.3.103 patients undergoing PCI: Compared with the patients carrying CYP2C19 681GG genetype(52/103), the patients carrying CYP2C19 681A allele (GA+AA)(51/103) had a lower reduction of MPA(P<0.01), a higher rate of CLR(23/51 vs 9/52 , P<0.01) after 10 days'clopidogrel-treatment, and a higher rate of cardiovascular events(24/51 vs 6/52,P<0.001) after a follow-up for median 7(3～12)months. Otherwise, there were no significant differences mong the CYP3A5 6986 genotypes.Conclusion: CYP2C19 681G>A mutation weakens the antiplatelet effect of clopidogrel, which is a major influential factor of the effect and prognosis to CAHD patients who were treated with clopidogrel. Otherwise CYP3A5 6986 polymorphisms is not the major influential factor.