Platelet reactivity and clopidogrel resistance are associated with the H2 haplotype of the P2Y12-ADP receptor gene

Background: Platelet hyperreactivity was reported in clopidogrel-naive 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 mu mol/L) platelet aggregation was determined by impedance (Omega) aggregometry in 43 clopidogrel-nave 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- nave 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. (c) 2008 Elsevier Ireland Ltd. All rights reserved.