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Haplotype of platelet receptor P2RY12 gene is associated with residual clopidogrel on-treatment platelet reactivity

P2RY12 基因单倍体分型对急性冠脉综合征患者氯吡格雷用药后血小板反应性的影响

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Abstract

Objective

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).

Methods

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.

Results

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 H0 to H5) according to the linkage disequilibrium R square (except for rs2046934). Haplotype H1 showed a significantly lower incidence of HTPR than the reference haplotype (H0) in the total study population while haplotypes H1 and H2 showed significantly lower incidences of HTPR than H0 in the nonsmoker subgroup after adjusting for CYP2C19 effects and demographic characteristics. rs2046934 (T744C) did not show any significant association with HTPR.

Conclusions

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.

概要

目 的

评估血小板受体基因P2RY12 常见突变位点单倍体分型对急性冠脉综合征患者氯吡格雷用药后血小板反应性的影响。

创新点

首次在中国人群中对包含调控基因在内的五个常见P2RY12 突变位点进行单倍体分析, 并且校正了CYP2C19 基因多态性的影响, 发现P2RY12 常见基因位点联合突变可降低氯吡格雷用药后血小板高反应性发生率, 且作用在不吸烟人群中更明显。

方 法

连续入选180 例接受氯吡格雷药物治疗的急性冠脉综合征患者, 利用血栓弹力图法检测患者用药后血小板反应性, 将用药后血小板抑制率<30%定义为血小板高反应性(HTPR)。用多重连接酶检测反应(LDR)技术, 对覆盖P2RY12 调控基因在内的五个基因位点( rs6798347 、rs6787801、rs6801273、rs6785930 和rs2046934)以及CYP2C19 常见的三个等位基因(*2、*3 和*17)进行基因分型。根据连锁不平衡系数和基因分布频率进行单倍体分析, 观察在校正CYP2C19 基因多态性影响后, 不同P2RY12 单倍体分型对氯吡格雷用药后HTPR 的影响。

结 论

将P2RY12 基因rs6798347、rs6787801、rs6801273和rs6785930 四个紧密连锁的单核苷酸多态性(SNP)分为六个常见单倍体分析(H0~H5, 表4)。单倍体分型与氯吡格雷用药后HTPR发生率显著相关, 与H0 型相比, H1 型HTPR 发生率显著降低, 而rs2046934 对HTPR 发生率无显著影响(表5), 且在不吸烟组中单倍体分型对HTPR 影响更明显(图1)。综上所述, P2RY12 基因rs6798347、rs6787801、rs6801273 和rs6785930单倍体分型与氯吡格雷用药后HTPR 显著相关。

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Authors and Affiliations

  1. School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing, 100191, China

    Xiao-yan Nie, Jun-lei Li, Yu Fu, Guang-kai Liang & Lu-wen Shi

  2. Department of Cardiology, Peking University People’s Hospital, Beijing, 100044, China

    Yong Zhang & Jian Liu

  3. School of Public Health, Peking University Health Science Center, Beijing, 100191, China

    Yang Xu

  4. Department of Epidemiology, Fuwai Hospital, Beijing, 100037, China

    Xue-li Yang

  5. Department of Pharmacy, Hennepin County Medical Center, Minneapolis, Minnesota, 55415, USA

    Yun Lu

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Correspondence to Xiao-yan Nie, Jian Liu or Lu-wen Shi.

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Project supported by the Beijing Higher Education Young Elite Teacher Project (No. YETP0064), China

ORCID: Xiao-yan NIE, http://orcid.org/0000-0002-1443-2176

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Nie, Xy., Li, Jl., Zhang, Y. et al. Haplotype of platelet receptor P2RY12 gene is associated with residual clopidogrel on-treatment platelet reactivity. J. Zhejiang Univ. Sci. B 18, 37–47 (2017). https://doi.org/10.1631/jzus.B1600333

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