title: 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.
abstract: OBJECTIVE
  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.
authors.affiliation: Department of Medical and Surgical Critical Care, University of Florence, Florence, Italy. betti.giusti@unifi.it
authors.forename: Betti
authors.initials: B
authors.lastname: Giusti
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Gori
authors.forename: Rossella
authors.initials: R
authors.lastname: Marcucci
authors.forename: Claudia
authors.initials: C
authors.lastname: Saracini
authors.forename: Ilaria
authors.initials: I
authors.lastname: Sestini
authors.forename: Rita
authors.initials: R
authors.lastname: Paniccia
authors.forename: Serafina
authors.initials: S
authors.lastname: Valente
authors.forename: Davide
authors.initials: D
authors.lastname: Antoniucci
authors.forename: Rosanna
authors.initials: R
authors.lastname: Abbate
authors.forename: Gian Franco
authors.initials: GF
authors.lastname: Gensini
mesh_terms: D054058:Acute Coronary Syndrome / Q000097:blood / Q000188:drug therapy* / Q000235:genetics*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics* / Q000378:metabolism; D001241:Aspirin / Q000627:therapeutic use; D000077144:Clopidogrel; D065731:Cytochrome P-450 CYP2C19; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics* / Q000378:metabolism; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000235:genetics* / Q000378:metabolism; D010597:Pharmacogenetics; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000378:metabolism / Q000627:therapeutic use*; D011110:Polymorphism, Genetic; D018048:Receptors, Purinergic P2 / Q000235:genetics* / Q000378:metabolism; D058925:Receptors, Purinergic P2Y12; D013988:Ticlopidine / Q000031:analogs & derivatives / Q000378:metabolism / Q000627:therapeutic use
chemical_list: C548576:P2RY12 protein, human; D010975:Platelet Aggregation Inhibitors; D018048:Receptors, Purinergic P2; D058925:Receptors, Purinergic P2Y12; D003577:Cytochrome P-450 Enzyme System; D000077144:Clopidogrel; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D013988:Ticlopidine; D001241:Aspirin