Platelet reactivity and clopidogrel resistance are associated with the H2 haplotype of the P2Y12 -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
• Subjects: Adult; Aged; Aged, 80 and over; Alleles; Biological and medical sciences; Cardiology. Vascular system; Cardiovascular; Drug Resistance - genetics; Female; Haplotypes - genetics; Humans; Male; Medical sciences; Platelet Aggregation - drug effects; Platelet Aggregation - genetics; Platelet Aggregation Inhibitors - pharmacology; Predictive Value of Tests; Receptors, Purinergic P2 - genetics; Receptors, Purinergic P2Y12; Risk Factors; Ticlopidine - analogs & derivatives; Ticlopidine - pharmacology; Young Adult
• ISSN: 0167-5273; 1874-1754
• DOI: 10.1016/j.ijcard.2007.12.118

Abstract Background Platelet hyperreactivity was reported in clopidogrel-naϊve carriers of the H2 haplotype of the P2Y12 platelet ADP receptor. Here, we studied the influence of this genetic variant on clopidogrel responsiveness. Methods ADP-mediated (5 μmol/L) platelet aggregation was determined by impedance (Ω) 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 Ω 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 Ω 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 Ω, 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.