Nie Xiao-Yan, Li Jun-Lei, Zhang Yong, Xu Yang, Yang Xue-Li, Fu Yu, Liang Guang-Kai, Lu Yun, Liu Jian, Shi Lu-Wen
School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing 100191, China.
Department of Cardiology, Peking University People's Hospital, Beijing 100044, China.
J Zhejiang Univ Sci B. 2017;18(1):37-47. doi: 10.1631/jzus.B1600333.
To investigate a possible association between common variations of the P2RY12 and the residual clopidogrel on-treatment platelet reactivity after adjusting for the influence of CYP2C19 tested by thromboelastography (TEG).
One hundred and eighty patients with acute coronary syndrome (ACS) treated with clopidogrel and aspirin were included and platelet function was assessed by TEG. Five selected P2RY12 single nucleotide polymorphisms (SNPs; rs6798347, rs6787801, rs6801273, rs6785930, and rs2046934), which cover the common variations in the P2RY12 gene and its regulatory regions, and three CYP2C19 SNPs (2,3,17) were genotyped and possible haplotypes were analyzed.
The high on-treatment platelet reactivity (HTPR) prevalence defined by a platelet inhibition rate <30% by TEG in adenosine diphosphate (ADP)-channel was 69 (38.33%). Six common haplotypes were inferred from four of the selected P2RY12 SNPs (denoted H to H) according to the linkage disequilibrium R square (except for rs2046934). Haplotype H showed a significantly lower incidence of HTPR than the reference haplotype (H) in the total study population while haplotypes H and H showed significantly lower incidences of HTPR than H in the nonsmoker subgroup after adjusting for CYP2C19 effects and demographic characteristics. rs2046934 (T744C) did not show any significant association with HTPR.
The combination of common P2RY12 variations including regulatory regions rather than rs2046934 (T744C) that related to pharmacodynamics of clopidogrel in patients with ACS was independently associated with residual on-clopidogrel platelet reactivity. This is apart from the established association of the CYP2C19. This association seemed more important in the subgroup defined by smoking.
在通过血栓弹力图（TEG）检测调整CYP2C19影响后，研究P2RY12常见变异与氯吡格雷治疗期间残余血小板反应性之间的可能关联。
纳入180例接受氯吡格雷和阿司匹林治疗的急性冠脉综合征（ACS）患者，通过TEG评估血小板功能。对涵盖P2RY12基因及其调控区域常见变异的5个选定P2RY12单核苷酸多态性（SNP；rs6798347、rs6787801、rs6801273、rs6785930和rs2046934）以及3个CYP2C19 SNP（2、3、17）进行基因分型，并分析可能的单倍型。
在二磷酸腺苷（ADP）通道中，TEG检测血小板抑制率<30%定义的高治疗期血小板反应性（HTPR）患病率为69例（38.33%）。根据连锁不平衡R平方（rs2046934除外），从4个选定的P2RY12 SNP中推断出6种常见单倍型（记为H到H）。在调整CYP2C19效应和人口统计学特征后，单倍型H在总研究人群中的HTPR发生率显著低于参考单倍型（H），而在非吸烟亚组中，单倍型H和H的HTPR发生率显著低于H。rs2046934（T744C）与HTPR无任何显著关联。
包括调控区域在内的P2RY12常见变异组合而非与ACS患者氯吡格雷药效学相关的rs2046934（T744C）与氯吡格雷治疗期间残余血小板反应性独立相关。这与已确定的CYP2C19关联不同。这种关联在吸烟定义的亚组中似乎更为重要。
