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Journal of Zhejiang University SCIENCE B
ISSN 1673-1581(Print), 1862-1783(Online), Monthly
2017 Vol.18 No.1 P.37-47
Haplotype of platelet receptor P2RY12 gene is associated with residual clopidogrel on-treatment platelet reactivity
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.
Key words: P2RY12, CYP2C19, Haplotype, Single nucleotide polymorphism (SNP), Clopidogrel, Thromboelastography
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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DOI:
10.1631/jzus.B1600333
CLC number:
R543.3
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On-line Access:
2017-01-03
Received:
2016-07-21
Revision Accepted:
2016-10-20
Crosschecked:
2016-12-14