Influences of an NR1I2 polymorphism on heterogeneous antiplatelet reactivity responses to clopidogrel and clinical outcomes in acute ischemic stroke patients

Authors: Yi-bei Chen1, Zi-yi Zhou2, Guo-min Li2, Can-xing Xiao1, Wei-bang Yu1, Shi-long Zhong3, Ye-feng Cai2, Jing Jin1, Min Huang1
1 Institute of Clinical Pharmacology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China
2 Guangdong Provincial Hospital of Chinese Medicine, Guangzhou 510120, China
3 Medical Research Center of Guangdong General Hospital, Guangzhou 510080, China
Correspondence to: Shi-long Zhong:, Ye-feng Cai:, Jing Jin:,
DOI: 10.1038/s41401-018-0178-4
Received: 13 June 2018
Accepted: 26 September 2018
Advance online: 28 November 2018


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.
Keywords: acute ischemic stroke; anti-platelet medication; clopidogrel; aspirin; NR1I2; individualized medication

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