title: Platelet reactivity and clopidogrel resistance are associated with the H2 haplotype of the P2Y12-ADP receptor gene.
abstract: BACKGROUND
  Platelet hyperreactivity was reported in clopidogrel-naiotave carriers of the H2 haplotype of the P2Y(12) platelet ADP receptor. Here, we studied the influence of this genetic variant on clopidogrel responsiveness.
  
  
  METHODS
  ADP-mediated (5 micromol/L) platelet aggregation was determined by impedance (Omega) aggregometry in 43 clopidogrel-naïve blood donors and 557 patients treated with aspirin and clopidogrel after percutaneous coronary stent implantation. A cut-off of 5 Omega was used to classify the aggregation response. Haplotype tagging single nucleotide polymorphism G52T was genotyped using a TaqMan assay.
  
  
  RESULTS
  The number of H2 alleles correlated with aggregation in clopidogrel-naïve subjects in healthy subjects (p=0.041): impedance results were 8.4+/-3.6, 10.5+/-1.6 and 12.5+/-2.1 Omega in carriers of the H1/H1 (n=30), H1/H2 (n=11) and H2/H2 (n=2) haplotypes, respectively. 87.1% (n=485) and 12.9% (n=72) of clopidogrel treated patients were responders and nonresponders, respectively. Women were more likely to be nonresponders (O.R. 3.90 [95% CI 2.34-6.50]). Carriers of a H2/H2 haplotype (n=14) exhibited stronger aggregation than patients with at least one H1 allele (6.3+/-7.5 vs. 1.8+/-3.3 Omega, p=0.0212) and were more frequently nonresponders (p=0.004). Consequently, the H2/H2 haplotype was associated with clopidogrel resistance (O.R. 5.42 [95% CI 1.82-16.11]). This risk factor was independent of the gender effect.
  
  
  CONCLUSIONS
  This is the first large study in clopidogrel treated patients suggesting that a homozygote H2 genotype contributes to clopidogrel resistance. The clinical significance of this finding remains to be demonstrated.
authors.affiliation: Department of Medicine III, University of Heidelberg, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Staritz
authors.forename: Kerstin
authors.initials: K
authors.lastname: Kurz
authors.forename: Monika
authors.initials: M
authors.lastname: Stoll
authors.forename: Evangelos
authors.initials: E
authors.lastname: Giannitsis
authors.forename: Hugo A
authors.initials: HA
authors.lastname: Katus
authors.forename: Boris T
authors.initials: BT
authors.lastname: Ivandic
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D000077144:Clopidogrel; D004351:Drug Resistance / Q000235:genetics*; D005260:Female; D006239:Haplotypes / Q000235:genetics*; D006801:Humans; D008297:Male; D010974:Platelet Aggregation / Q000187:drug effects* / Q000235:genetics*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D011237:Predictive Value of Tests; D018048:Receptors, Purinergic P2 / Q000235:genetics*; D058925:Receptors, Purinergic P2Y12; D012307:Risk Factors; D013988:Ticlopidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D055815:Young Adult
chemical_list: C548576:P2RY12 protein, human; D010975:Platelet Aggregation Inhibitors; D018048:Receptors, Purinergic P2; D058925:Receptors, Purinergic P2Y12; D000077144:Clopidogrel; D013988:Ticlopidine