Role of the C1236T (rs1128503) polymorphism of the MDR-1 gene on clopidogrel responsiveness

Abstract: Background: Clopidogrel intestinal absorption and active metabolite formation are influenced by P- glycoprotein-mediated efflux. The functional activity of P-glycoprotein is under genetic control by the Multi Drug Resistance-1 (MDR-1) gene. If genetic variations of MDR-1 contribute to variability in clopidogrel response in patients with coronary artery disease remains poorly explored. Methods: The C1236T (rs1128503) polymorphism of the MDR- 1 gene was assessed in 62 patients. Patients were divided into 2 groups: carriers and non-carriers of the T allele. Platelet aggregation was performed before and 24 hours after clopidogrel administration. Standard (300mg; n=45) and high (600mg: n=17) loading dose regimens were used. All patients were on treatment with aspirin (100mg/day). Peak platelet aggregation was assessed by LTA using 6 μmol/L ADP stimuli. Post-treatment platelet reactivity and percentage inhibition of platelet aggregation (IPA) were determined. Results: 71% and 29% of the study population were T and non-T allele carriers, respectively. At baseline, there were no differences in platelet aggregation between the two groups. At 24 hours there were no differences in post-treatment platelet reactivity between groups following a 300mg loading dose administration. However, following a 600mg loading dose administration, post-treatment platelet reactivity was significantly higher in T allele carriers (35±11% vs 16±3%; p=0.006). Accordingly, there were no differences in IPA following a 300mg dose and IPA was significantly lower in T allele carriers following a 600mg dose (44±18% vs 73±5%, p=0.001). Conclusions: The C1236T polymorphism of the MDR-1 gene modulates clopidogrel responsiveness in the acute phase of treatment when using high loading dose regimens.