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

Julie H. Oestreich, Steven R. Steinhubl, Suellen P. Ferraris, Charles D. Loftin, Wendell S. Akers

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

Abstract

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 P2Y12 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 P2Y12 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 P2Y1, P2Y12, and thromboxane A2 receptors. We identified a significant recessive effect of the P2Y12-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 P2Y12 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 P2Y12-receptor H2/H2 carriers and reduced platelet function mediated by TRAP in healthy volunteers.

Original languageEnglish
Pages (from-to)372-379
Number of pages8
JournalJournal of Thrombosis and Thrombolysis
Volume38
Issue number3
DOIs
StatePublished - Oct 2014

Bibliographical note

Funding Information:
Conflict of interest This research was supported in part by Grants from Sigma Xi National Research Society and the University of Kentucky General Clinical Research Center M01 RR02602 and awards from the American Heart Association and the Pharmaceutical Research and Manufacturers of America Foundation (J.H.O.). C.D.L. was supported by the National Institutes of Health [HL083122]. Dr. Oestreich has served as a consultant for The Medicines Company®. For the remaining authors, no potential conflicts of interest were declared.

Funding Information:
Acknowledgments The authors acknowledge the support of the Flow Cytometry and Cell Sorting Core Facility and the Center for Clinical and Translational Science at the University of Kentucky. The authors also thank Ms. Melody Montgomery for help in editing this manuscript.

Keywords

  • ADP receptors
  • Genetic test
  • P2Y12 receptor haplotype
  • Platelet function test
  • Thrombin receptor activating peptide

ASJC Scopus subject areas

  • Hematology
  • Cardiology and Cardiovascular Medicine

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