Effect of genetic variation in P2Y12 on TRAP-stimulated platelet response in healthy subjects

In platelets, thrombin receptor signaling depends upon the release of adenosine diphosphate and subsequent activation at purinergic subtype Y (P2Y) receptors. The purpose of this study is to evaluate the influence of specific P2Y 12 polymorphisms on platelet reactivity in healthy subjects mediated by thrombin receptor activating peptide (TRAP). We recruited a total of 29 healthy volunteers who had been previously genotyped for two polymorphisms of the P2Y 12 receptor: the H2 haplotype (rs2046934) and 34C>T (rs6785930). Flow cytometry and the VerifyNow assay were used to assess platelet activation and aggregation stimulated by TRAP in the presence and absence of specific receptor antagonists for the P2Y 1 , P2Y 12 , and thromboxane A2 receptors. We identified a significant recessive effect of the P2Y 12 -receptor H2 haplotype on TRAP-induced flow cytometry. Specifically, H2/H2 carriers ( n = 5) demonstrated a significant reduction in both glycoprotein IIb/IIIa receptor activation ( p < 0.001) and CD62P expression ( p = 0.035). While the VerifyNow assay did not reveal any effect of haplotype on TRAP-mediated platelet aggregation ( p = 0.72), the H2/H2 subjects demonstrated greater platelet inhibition in the presence of cangrelor, a specific receptor antagonist for the P2Y 12 receptor ( p = 0.023). No consistent effects of the separate 34C>T genotype (rs6785930) were demonstrated under the conditions evaluated. The findings of this study suggest a potential association between P2Y 12 -receptor H2/H2 carriers and reduced platelet function mediated by TRAP in healthy volunteers.