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

Pharmacogenet Genomics. 2007 Dec;17(12):1057-64. doi: 10.1097/FPC.0b013e3282f1b2be.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Coronary Syndrome / blood
  • Acute Coronary Syndrome / drug therapy*
  • Acute Coronary Syndrome / genetics*
  • Adult
  • Aged
  • Aged, 80 and over
  • Alleles
  • Aryl Hydrocarbon Hydroxylases / genetics*
  • Aryl Hydrocarbon Hydroxylases / metabolism
  • Aspirin / therapeutic use
  • Clopidogrel
  • Cytochrome P-450 CYP2C19
  • Cytochrome P-450 CYP3A
  • Cytochrome P-450 Enzyme System / genetics*
  • Cytochrome P-450 Enzyme System / metabolism
  • Female
  • Humans
  • Male
  • Middle Aged
  • Mixed Function Oxygenases / genetics*
  • Mixed Function Oxygenases / metabolism
  • Pharmacogenetics
  • Platelet Aggregation / drug effects
  • Platelet Aggregation Inhibitors / metabolism
  • Platelet Aggregation Inhibitors / therapeutic use*
  • Polymorphism, Genetic*
  • Receptors, Purinergic P2 / genetics*
  • Receptors, Purinergic P2 / metabolism
  • Receptors, Purinergic P2Y12
  • Ticlopidine / analogs & derivatives
  • Ticlopidine / metabolism
  • Ticlopidine / therapeutic use


  • P2RY12 protein, human
  • Platelet Aggregation Inhibitors
  • Receptors, Purinergic P2
  • Receptors, Purinergic P2Y12
  • Cytochrome P-450 Enzyme System
  • Clopidogrel
  • Mixed Function Oxygenases
  • Aryl Hydrocarbon Hydroxylases
  • CYP2C19 protein, human
  • Cytochrome P-450 CYP2C19
  • Cytochrome P-450 CYP3A
  • CYP3A4 protein, human
  • Ticlopidine
  • Aspirin