Rudez Goran, Bouman Heleen J, van Werkum Jochem W, Leebeek Frank W G, Kruit Adrian, Ruven Hendrik J T, ten Berg Jurriën M, de Maat Moniek P M, Hackeng Christian M
Department of Hematology, Erasmus University Medical Center, Rotterdam, The Netherlands.
Circ Cardiovasc Genet. 2009 Oct;2(5):515-21. doi: 10.1161/CIRCGENETICS.109.861799. Epub 2009 Jul 24.
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.
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).
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.
氯吡格雷的临床疗效因个体间血小板抑制的巨大差异而受到影响。P2RY12受体基因多态性被认为是导致这种差异的原因之一，但以往研究纳入的患者数量相对较少，且未完全涵盖P2RY12基因的常见变异。本研究的目的是在一大群患者中，全面调查整个P2RY12基因座的常见变异与通过两种常用血小板功能检测方法测得的氯吡格雷治疗后残余血小板反应性大小之间的可能关联。
共纳入1031例计划进行择期经皮冠状动脉介入治疗的冠心病连续患者。通过ADP诱导的透光率聚集法和VerifyNow P2Y12检测法评估血小板功能。精心挑选了6个单倍型标签单核苷酸多态性，以全面涵盖P2RY12基因及其侧翼调控区域的所有常见变异。从这些单倍型标签单核苷酸多态性推断出6种常见单倍型（表示为A至F）。与参考单倍型A相比，单倍型F与氯吡格雷治疗后残余血小板反应性显著降低相关。在ADP诱导的透光率聚集法中，每个单倍型等位基因的这种效应大小约为5%的聚集率（P<0.05），在VerifyNow P2Y12检测法中为11个P2Y12反应单位（P<0.05）。
P2RY12基因的常见变异是冠心病患者氯吡格雷治疗后残余血小板反应性个体间差异的重要决定因素。
