Platelet reactivity and clopidogrel resistance are associated with the H2 haplotype of the P2Y sub(12)-ADP receptor gene

• Published in: International journal of cardiology 2009-04, Vol.133 (3), p.341-345
• Main Authors: Staritz, Peter, Kurz, Kerstin, Stoll, Monika, Giannitsis, Evangelos, Katus, Hugo A, Ivandic, Boris T
• Format: Article
• Language: English
• ISSN: 0167-5273; 1874-1754
• DOI: 10.1016/j.ijcard.2007.12.118

Platelet hyperreactivity was reported in clopidogrel-naive carriers of the H2 haplotype of the P2Y sub(12) platelet ADP receptor. Here, we studied the influence of this genetic variant on clopidogrel responsiveness. Methods - ADP-mediated (5 kmol/L) platelet aggregation was determined by impedance ([Omega]) aggregometry in 43 clopidogrel-naive 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-naive 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.