The Association Between The Cytochrome 3a4 Gene 894C>T And 12G>A Single Nucleotide Polymorphism With The Clopidogrel Resistance

Background and objectives: Clopidogrel, as one of the most important antiplatelet agents, is widely used in preventing thrombotic events in patients with acute coronary syndromes or undergoing percutaneous coronary intervention. Clopidogrel in addition to aspirin is the standard antiplatelet regimen after PCI. However, ischemic events still occur in population under routine dosage of clopidogrel treatment, which may due to the variabilities of platelet response to clopidogrel. This phenomenon is defined as clopidogrel resistance. The mechanism of clopidogrel resistance(CR) has not been clearly elucidated yet, however, gene polymorphism is considered as one of the most important reasons. Clopidogrel in fact is an inactive pro-drug that requires oxidation by the hepatic cytochrome P450 3A4 (CYP3A4). The present study was aimed to explore the relation between the gene polymorphism of CYP3A4 and the clopidogrel resistance by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis. In this way, we hope we can calculate clopidrogel resistance in clinical and to guide the clinical optimal antiplatelet therapy.Methods: The present study is a case-control study. A total of 300 hospitalized patients were enrolled. All patients received loading doses of 600mg clopidogrel and 300 mg aspirin. 5μmol/L ADP -induced platelet aggregation were assessed before and 24h after clopidogrel administration. An absolute reduction of platelet aggregation <10% compared with baseline was defined as CR. Genomic DNA was extracted from whole blood samples according to standard protocols, the single nucleotide polymorphism of the CYP 3a4894C>T and CYP 3a412G>A was genotyed by polymerase chain reaction-restriction fragment length polymorphism in all the patients.Results: (1) The occurrence of CR in this population is 23.3%. (2) There is CYP3a4 894C/T polymorphism in Northern Chinese Han population. The frequencies of the three kinds of genotypes in CR and Non-CR (NCR) patients were 45.7%, 50.0%, 4.3% and 63.5%, 31.7%, 4.8%. The frequency of TT genotype is significantly higher in NCR group than that in CR group(OR = 2.06, 95 % CI:1.201～3.547,P = 0.020). C allele carriers were more likely to develop clopidogrel resistant (OR = 1.59, 95 % CI: 1.037～2.442, P = 0.023). (3) There is CYP3a4 12G/A polymorphism in Northern Chinese Han population. The frequencies of the two kinds of genotypes inclunding GG and GA in CR group and NCR group were 83.9%, 17.1% and 77%, 23%, respectively. There was no obvious differents between the two group (P > 0.05).Conclusion: CYP3a4 894C/T polymorphism may have correlation with the CR in the Northern Chinese Han population.