Liu Rui, Zhou Zi-Yi, Chen Yi-Bei, Li Jia-Li, Yu Wei-Bang, Chen Xin-Meng, Zhao Min, Zhao Yuan-Qi, Cai Ye-Feng, Jin Jing, Huang Min
Institute of Clinical Pharmacology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
Guangdong Provincial Hospital of Traditional Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine, Guangzhou 510120, China.
Acta Pharmacol Sin. 2016 Jul;37(7):882-8. doi: 10.1038/aps.2016.41. Epub 2016 May 2.
There is a high incidence of the antiplatelet drug clopidogrel resistance (CR) in Asian populations. Because clopidogrel is a prodrug, polymorphisms of genes encoding the enzymes involved in its biotransformation may be the primary influential factors. The goal of this study was to investigate the associations of polymorphisms of CYP3A4, NR1I2, CYP2C19 and P2RY12 genes with CR in Chinese patients with ischemic stroke.
A total of 191 patients with ischemic stroke were enrolled. The patients were treated with clopidogrel for at least 5 days. Platelet function was measured by light transmission aggregometry. The SNPs NR1I2 (rs13059232), CYP3A4()1G (rs2242480), CYP2C19()2 (rs4244285) and P2RY12 (rs2046934) were genotyped.
The CR rate in this population was 36%. The CYP2C19()2 variant was a risk factor for CR (()2/()2+wt/()2 vs wt/wt, OR: 2.366, 95% CI: 1.180-4.741, P=0.014), whereas the CYP3A4()1G variant had a protective effect on CR (()1/()1 vs ()1G/()1G+()1/(*)1G, OR: 2.360, 95% CI: 1.247-4.468, P=0.008). The NR1I2 (rs13059232) polymorphism was moderately associated with CR (CC vs TT+TC, OR: 0.533, 95% CI: 0.286-0.991, P=0.046). The C allele in P2RY12 (rs2046934) was predicted to be a protective factor for CR (CC+TC vs
TT, OR: 0.407, 95% CI: 0.191-0.867, P=0.018). In addition, an association was found between hypertension and CR (P=0.022).
The individuals with both the CYP2C19()2 allele and hypertension are at high risk of CR during anti-thrombosis therapy. The CYP3A4()1G allele, P2RY12 (rs2046934) C allele and NR1I2 (rs13059232) CC genotype may be protective factors for CR. The associated SNPs studied may be useful to predict clopidogrel resistance in Chinese patients with ischemic stroke.
亚洲人群中抗血小板药物氯吡格雷抵抗（CR）的发生率较高。由于氯吡格雷是一种前体药物，编码参与其生物转化的酶的基因多态性可能是主要影响因素。本研究的目的是探讨CYP3A4、NR1I2、CYP2C19和P2RY12基因多态性与中国缺血性脑卒中患者CR的相关性。
共纳入191例缺血性脑卒中患者。患者接受氯吡格雷治疗至少5天。采用光透射聚集法测定血小板功能。对NR1I2（rs13059232）、CYP3A4（）1G（rs2242480）、CYP2C19（）2（rs4244285）和P2RY12（rs2046934）进行基因分型。
该人群的CR率为36%。CYP2C19（）2变异是CR的危险因素（（）2/（）2+wt/（）2与wt/wt相比，OR：2.366，95%CI：1.180 - 4.741，P = 0.014），而CYP3A4（）1G变异对CR有保护作用（（）1/（）1与（）1G/（）1G+（）1/（*）1G相比，OR：2.360，95%CI：1.247 - 4.468，P = 0.008）。NR1I2（rs13059232）多态性与CR中度相关（CC与TT+TC相比，OR：0.533，95%CI：0.286 - 0.991，P = 0.046）。P2RY12（rs2046934）中的C等位基因预计是CR的保护因素（CC+TC与TT相比，OR：0.407，95%CI：0.191 - 0.867，P = 0.018）。此外，发现高血压与CR之间存在关联（P = 0.022）。
携带CYP2C19（）2等位基因且患有高血压的个体在抗血栓治疗期间发生CR的风险较高。CYP3A4（）1G等位基因、P2RY12（rs2046934）C等位基因和NR1I2（rs13059232）CC基因型可能是CR的保护因素。所研究的相关单核苷酸多态性可能有助于预测中国缺血性脑卒中患者的氯吡格雷抵抗。
