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

Abstract

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 (PϽ0.05) and 11 P2Y12 reaction units in the VerifyNow P2Y12 assay (PϽ0.05). Conclusions-Common

Associations of CYP3A4, NR1I2, CYP2C19 and P2RY12 polymorphisms with clopidogrel resistance in Chinese patients with ischemic stroke

“…Genetic polymorphisms of the P2Y12 ADP receptor might alter the receptor activation induced by ADP or the response to platelet inhibitors in patients [36] . Goran et al reported that P2RY12 (rs2046934) was consistently associated with a higher platelet reactivity in patients on clopidogrel in the ADP-induced LTA and the VerifyNow P2Y12 assay; this may provide protection against atherothrombotic events [16] . Robert et al provided evidence for an association between the P2RY12 haplotype H2 (composed of dbSNP rs10935838, rs2046934, rs5853517 and rs6809699) and a lower risk of DVT/PE [37] .…”

“…In addition, the P2RY12 gene encodes the P2Y12 ADP receptor, and genetic variants of P2RY12 have been associated with alterations in the platelet inhibition response in patients [13] . Many studies have focused on the association between genetic polymorphisms and clopidogrel resistance [14][15][16] . According to the clopidogrel black box warning released by the US FDA, CYP2C19 genotyping now allows clinicians to adjust the treatment therapy for an individual patient.…”

Cardiovascular pharmacogenetics

“…CYP2C19*3 is also prevalent in Eastern (8.7%) and Southern (4.6%) Asia as well as in Melanesia (15.7%) and Australia (14.3%) (Sistonen et al, 2009) Although an increased risk for neurovascular events associated with the C34T P2RY 12 SNP was found (Table 5) (Simon et al, 2009;Ziegler et al, 2005), an association between this SNP and adverse outcomes associated with clopidogrel has not been observed (Simon et al, 2009). However, the 2739T>C SNP which occurs with relatively high frequency in intron 1 has been correlated with clopidogrel poor responsiveness in a study (n = 245) using ex vivo aggregmometry (Rudez et al, 2009). It would appear that research concerning the P2RY12 gene has provided inconsistent results which need to be resolved before considering mutations in this gene as pharmacogenetically relevant.…”

Molecular defects of the platelet P2 receptors

“…Several studies tested the hypothesis that common polymorphisms of the P2Y 12 gene might interfere with the antiplatelet effects of drugs inhibiting the P2Y 12 receptor, accounting for the well known individual variability in the response to these agents [52,53]. The vast majority of these studies, with few exceptions, reported that P2Y 12 polymorphisms are not associated with altered platelet function inhibition by P2Y 12 antagonists [54][55][56][57][58][59][60][61]. …”