Effects of CYP2C19 and ABCB1 gene polymorphisms on anti-platelet function of clopidogrel and recurrent vascular events in patients with acute ischemic stroke

Abstract

Objective To evaluate the effects of the polymorphisms of CYP2C19, ABCB1 genes on the clopidogrel response and clinical vascular events in patients with acute ischemic stroke. Methods We recruited 209 acute ischemic stroke patients treated with clopidogrel from February 2012 to February 2014. The platelet inhibitive rate with clopidogrel treatment for 5 days was measured using thrombelastography. The CYP2C19*2/*3 and ABCB1 C3435T/T (-620) C genotypes were screened by the ligase detection reaction. The relationships between the gene polymorphisms and platelet inhibitive rate were analyzed with one-way analysis of variance and multivariate linear regression. The primary endpoint was the composite of vascular death, stroke recurrence and acute myocardial infarction. The associations between the genotype and primary endpoint were evaluated by the Kaplan-Meier method. The risk factors of the primary endpoint were analyzed by the Cox proportional hazards model. Results The platelet inhibitive rate in patients with homozygous (TT) of ABCB1 C3435T (42.9%±14.2%) was significantly lower than that in patients with heterozygous (TC; 53.2%±21.3%) and wild-type genotypes (CC; 58.1%±21.2%; F=5.517, P=0.005). The platelet inhibitive rate in patients with CYP2C19 loss of function (LOF) alleles showed that the intermediate metabolized type (51.8%±25.4%) and chronic metabolized type (44.5%±22.6%) were lower than extensive metabolized type (59.3%±23.2%; F=4.278, P=0.015). However, there was no statistically significant difference among the subtypes of ABCB1 T (-620) C. Multivariable linear regression model demonstrated that the CYP2C19*2/*3 and ABCB1 C3435T polymorphisms were independently associated with the platelet inhibitive rate. In addition, the higher body mass index (>26 kg/m2) was significantly associated with lower platelet inhibitive rate. Kaplan-Meier analysis showed that the risks of primary endpoint increased in CYP2C19 LOF allele carrier during (9.5±5.2) months follow-up (χ2=4.842, P=0.028). The CYP2C19 gene polymorphisms and age were independent risk factors for primary endpoint in the final multivariate Cox regression model. There was no significant relationship between the polymorphisms of ABCB1 gene and the primary endpoint. Conclusion For patients with acute ischemic stroke who carried CYP2C19 LOF alleles, the pestcide effect of clopidogrel was decreased and the risk of ischemic events was increased. Key words: Stroke; Genetic polymorphisms; Clopidogrel; Thrombelastography; CYP2C19 gene; ABCB1 gene