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 micromol/l adenosine 5' diphosphate (ADP; P<0.0001) and 10 
micromol/l ADP (P=0.001) stimuli. The genotype distribution of CYP2C19*2 
polymorphism significantly differed between patients with and without RPR, as 
evaluated by 10-micromol/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.