Cytochrome P450 2C19 loss-of-function polymorphism, but not CYP3A4 IVS10+12G/A and P2Y12 T744C polymorphisms, is associated with response variability to dual antiplatelet treatment in high-risk vascular patients

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Abstract
Objectives The aim of this study was to evaluate the effect of polymorphisms affecting the clopidogrel metabolism (CYP3A4 IVS10+12G/A and CYP2C19*2) and the P2Y12 receptor (P2Y12 T744C) on modulating platelet function in acute coronary syndrome patients on dual antiplatelet treatment. Background Residual platelet reactivity (RPR) phenomenon on antiplatelet therapy requires clarification. P2Y12 T744C, CYP3A4 IVS10+12G/A and, in healthy individuals only, CYP2C19*2 polymorphisms have been investigated; however, the influence on platelet reactivity in a large population of high-risk vascular patients on dual antiplatelet treatment has not yet been elucidated. Methods A total of 1419 acute coronary syndrome patients on dual antiplatelet treatment were studied. Platelet function was evaluated by platelet-rich plasma aggregation. Electronic nanochips and restriction-fragment length polymorphism were used for analysis of polymorphisms. Results Only CYP2C19*2, out of the three investigated polymorphisms, is associated with higher platelet reactivity. Carriers of the *2 allele had significantly higher platelet aggregation values after arachidonic acid (AA; P=0.043), 2 μmol/l adenosine 5′ diphosphate (ADP; PP=0.001) stimuli. The genotype distribution of CYP2C19*2 polymorphism significantly differed between patients with and without RPR, as evaluated by 10-μmol/l ADP-induced platelet aggregation (P=0.002) and by AA-induced platelet aggregation (P=0.045). At the multivariate linear regression analysis, the CYP2C19*2 polymorphism remained a significant and independent risk factor for dual antiplatelet treatment variability. Conclusions This study demonstrates, for the first time, that the *2 CYP2C19 allele is associated with higher platelet aggregability and RPR in high-risk vascular patients on dual antiplatelet treatment. These findings can have a significant impact on the future design of pharmacogenetic antiaggregant strategies for high-risk vascular patients on dual antiplatelet treatment.