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

Abstract

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.

Pregnane X Receptor (PXR) Polymorphisms and Cancer Treatment

“…NR1I2 polymorphisms detected in patients who received cyclosporin (CsA) after their first renal transplantation were correlated with altered CsA C0/D and C2/D after the first month of transplantation, as the haplotype cluster PXR*1B tagged by NR1I2 rs2276707 and rs3814058 was correlated with increased CsA C2/D [77]. A study also indicated the importance of NR1I2 rs13059232 (T > C) as a biomarker for clopidogrel therapy in acute ischemic stroke (IS) patients, since patients carrying the CC genotype exhibited poorer clinical outcome than patients carrying the T allele, while comparable results were not observed in the aspirin cohort [78]. HIVpositive patients treated with atazanavir and ritonavir and carrying the G allele of NR1I2 rs1523130 (T > G) exhibited higher ritonavir intracellular concentrations [79].…”

Plasma brain natriuretic peptide, platelet parameters, and cardiopulmonary function in chronic obstructive pulmonary disease

“…PDW indicates the variability in platelet size, while MPV reflects megakaryocyte and platelet generation. The parameters PDW, PCT, and MPV are markers of thrombopoiesis, wherein a high level of MPV was confirmed to be an independent risk factor of myocardial infarction in patients with coronary heart disease and thus can predict adverse cardiovascular events with high sensitivity[ 15 , 16 ]. Our study revealed that PDW and MPV exhibited a declining trend in the pulmonary heart disease, COPD, and control groups, although PLT and PCT showed an increasing trend.…”

Effects of precision antiplatelet therapy based on CYP2C19/11-dhTxB2 variability in prognosis of ischemic stroke/TIA patients: study protocol for a multicenter randomized controlled trial

“…Three single-nucleotide polymorphisms (SNPs) for CYP2C19 (National Center for Biotechnology Information [NCBI] Genome build 37.1, GenBank NG_008384), including CYP2C19*2 (681G>A, dbSNP rs4244285), CYP2C19*3 (636G>A, dbSNP rs4986893), and CYP2C19*17 (−806C>T, dbSNP rs12248560) [26][27][28][29] , will be genotyped in 3000 participants. Genotyping of the 3 SNPs is performed using the PCR+MassARRAY (flight mass spectrometry).…”