Common variation in the platelet receptor P2RY12 gene is associated with residual on-clopidogrel platelet reactivity in patients undergoing elective percutaneous coronary interventions.
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.


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.
Rudez
Goran
G
Department of Hematology, Erasmus University Medical Center, Rotterdam, The Netherlands.
Bouman
Heleen J
HJ
van Werkum
Jochem W
JW
Leebeek
Frank W G
FW
Kruit
Adrian
A
Ruven
Hendrik J T
HJ
ten Berg
Jurriën M
JM
de Maat
Moniek P M
MP
Hackeng
Christian M
CM
D000368:Aged; D001792:Blood Platelets / Q000187:drug effects / Q000502:physiology*; D000077144:Clopidogrel; D015331:Cohort Studies; D003324:Coronary Artery Disease / Q000601:surgery*; D014644:Genetic Variation; D006801:Humans; D007431:Intraoperative Complications / Q000097:blood / Q000188:drug therapy* / Q000517:prevention & control; D008297:Male; D008875:Middle Aged; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage*; D020641:Polymorphism, Single Nucleotide; D011292:Premedication; D018048:Receptors, Purinergic P2 / Q000235:genetics*; D058925:Receptors, Purinergic P2Y12; D013988:Ticlopidine / Q000008:administration & dosage / Q000031:analogs & derivatives*
C548576:P2RY12 protein, human; D010975:Platelet Aggregation Inhibitors; D018048:Receptors, Purinergic P2; D058925:Receptors, Purinergic P2Y12; D000077144:Clopidogrel; D013988:Ticlopidine