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Original Articles

Common Variation in the Platelet Receptor P2RY12 Gene Is Associated With Residual On-Clopidogrel Platelet Reactivity in Patients Undergoing Elective Percutaneous Coronary Interventions

Goran Rude, MSc; Heleen J. Bouman, BSc; Jochem W. van Werkum, MD, PhD; Frank W.G. Leebeek, MD, PhD; Adrian Kruit, PhD; Hendrik J.T. Ruven, PhD; Jurriën M. ten Berg, MD, PhD; Moniek P.M. de Maat, PhD and Christian M. Hackeng, PhD

From the Department of Hematology (G.R., F.W.G.L., M.P.M.M.), Erasmus University Medical Center, Rotterdam, The Netherlands; and Departments of Cardiology (H.J.B., J.W.W., J.M.B.) and Clinical Chemistry (A.K., H.J.T.R., C.M.H.), St. Antonius Hospital, Nieuwegein, The Netherlands.

Correspondence to Moniek P.M. de Maat, PhD, Erasmus University Medical Center, Department of Hematology, L-431, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands. E-mail m.demaat{at}erasmusmc.nl

Received February 28, 2009; accepted June 2, 2009.

Background— The clinical efficacy of clopidogrel is hampered by a large interindividual variability in platelet inhibition. Polymorphisms in the P2RY12 receptor gene have been suggested to contribute to this variability, but previous studies included a relatively small number of patients and incompletely covered the common variation in the P2RY12 gene. The aim of this study was to comprehensively investigate the possible association between common variation in the entire P2RY12 locus and the magnitude of residual on-clopidogrel platelet reactivity measured by 2 commonly used platelet function assays in a large cohort of patients.

Methods and Results— A total of 1031 consecutive patients with coronary artery disease who were scheduled for elective percutaneous coronary interventions were enrolled. Platelet function was assessed by means of ADP-induced light-transmittance aggregometry and the VerifyNow P2Y12 assay. Six haplotype-tagging single nucleotide polymorphisms were carefully selected to comprehensively cover the total common variation in the P2RY12 gene and its flanking regulatory regions. Six common haplotypes were inferred from these haplotype-tagging single nucleotide polymorphisms (denoted A to F). Haplotype F was associated with significantly lower residual on-clopidogrel platelet reactivity compared with the reference haplotype A. The size of this effect per haplotype allele was approximately 5% aggregation in the ADP-induced light-transmittance aggregometry (P<0.05) and 11 P2Y12 reaction units in the VerifyNow P2Y12 assay (P<0.05).

Conclusions— Common variation in the P2RY12 gene is a significant determinant of the interindividual variability in residual on-clopidogrel platelet reactivity in patients with coronary artery disease.

Key Words: P2Y12 • haplotypes • platelets • clopidogrel • revascularization

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CLINICAL PERSPECTIVE

Drs Rude and Bouman contributed equally to this work.

The online-only Data Supplement is available at http://circgenetics.ahajournals.org/cgi/content/full/CIRCGENETICS.109.861799.