Pregnane X receptor (PXR) is a member of nuclear receptor subfamily 1 (NR1I2) that is a transcriptional regulator of several metabolic enzymes involved in clopidogrel metabolism. In this study we identified and evaluated the contributions of single nucleotide polymorphisms (SNPs) in NR1I2 and cytochrome P450 (CYP) 2C19 alleles to clopidogrel resistance (CR) and long-term clinical outcomes in acute ischemic stroke (IS) patients. A total of 634 patients with acute IS were recruited, who received antiplatelet medication (clopidogrel or aspirin) every day and completed a 1-year follow-up. The selected SNPs were genotyped, and platelet function was measured. Modified Rankin Scale (mRS) scores and main adverse cardiovascular and cerebrovascular events (MACCE) were noted to assess the prognosis. We showed that SNPs NR1I2 rs13059232 and CYP2C19 alleles (2*/3*) were related to CR. SNP NR1I2 (rs13059232) was identified as an independent risk factor for the long-term clinical outcomes in the clopidogrel cohorts (P < 0.001), but similar results were not observed in a matched aspirin cohort (P > 0.05). Our results suggest that NR1I2 variant (rs13059232) could serve as biomarker for clopidogrel therapy and individualized antiplatelet medications in the treatment of acute IS patients.

中文翻译：

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NR1I2基因多态性对急性缺血性卒中患者对氯吡格雷的异种抗血小板反应性和临床结局的影响。

孕烷X受体（PXR）是核受体亚家族1（NR1I2）的成员，该家族是参与氯吡格雷代谢的几种代谢酶的转录调节剂。在这项研究中，我们确定并评估了NR1I2和细胞色素P450（CYP）2C19等位基因中的单核苷酸多态性（SNP）对氯吡格雷抵抗（CR）和急性缺血性中风（IS）患者长期临床结局的贡献。总共招募了634例急性IS患者，他们每天接受抗血小板药物（氯吡格雷或阿司匹林）治疗，并完成了1年的随访。对选择的SNP进行基因分型，并测量血小板功能。记录了改良的Rankin量表（mRS）评分和主要的不良心血管和脑血管事件（MACCE），以评估预后。我们显示SNPs NR1I2 rs13059232和CYP2C19等位基因（2 * / 3 *）与CR相关。SNP NR1I2（rs13059232）被确定为氯吡格雷队列的长期临床结果的独立危险因素（P <0.001），但在匹配的阿司匹林队列中未观察到类似的结果（P> 0.05）。我们的结果表明，NR1I2变异体（rs13059232）可以作为氯吡格雷治疗和个体化抗血小板药物在急性IS患者治疗中的生物标志物。