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Analysis of common polymorphisms within NR1I2 and NR1I3 genes and tacrolimus dose-adjusted concentration in stable kidney transplant recipients

Kurzawski, Mateusza; Malinowski, Damianb; Dziewanowski, Krzysztofc; Droździk, Mareka

doi: 10.1097/FPC.0000000000000301
ORIGINAL ARTICLES
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Objectives Several genetic factors were identified to be responsible for interidividual variability in tacrolimus (TAC) pharmacokinetics, with the predominant role of CYP3A5 and CYP3A4 polymorphisms. In this study, genetic variants of NR1I2 and NR1I3 nuclear receptors (responsible for the regulation of drug-metabolizing enzymes and transporters at the transcriptional level) were evaluated for their potential association with altered TAC concentrations.

Materials and methods Two hundred and forty White kidney transplant patients were genotyped for five single-nucleotide polymorphisms (rs3814055, rs6785049, rs2276707, rs2307424, and rs2307418) in NR1I2 and NR1I3 genes. Genetic data were analyzed in relation to TAC dose-adjusted trough concentration measured 6 months after transplantation (unadjusted and adjusted for patient’s CYP3A5 expresser status).

Results There were significant differences in TAC concentrations between patients with different NR1I2 rs3814055:C>T genotypes (mean values: 121.3 ng/ml mg/kg in major CC homozygotes, 169.6 ng/ml mg/kg in CT heterozygotes, and 186.0 ng/ml mg/kg in patients homozygous for the minor T allele) that remained significant after excluding CYP3A5 expressers from analysis. The TAC dose administered to minor T allele carriers (CT or TT genotype) was significantly lower (~22%) compared with CC homozygotes. For all the other loci analyzed, no significant associations were noted.

Conclusion Our results support the previous data on the functionality of NR1I2 rs3814055 single-nucleotide polymorphism that points to its association with interindividual differences in activity and inducibility of a broad range of drug-metabolizing enzymes and drug transporters.

Departments of aExperimental and Clinical Pharmacology

bPharmacokinetics and Therapeutic Drug Monitoring, Pomeranian Medical University

cClinical Department of Nephrology and Dialysis, Marie Curie Regional Hospital, Szczecin, Poland

Correspondence to Mateusz Kurzawski, PhD, Department of Experimental and Clinical Pharmacology, Pomeranian Medical University, Powstancow Wlkp. 72, 70-111 Szczecin, Poland Tel: +48 914 661 589; fax: +48 914 661 600; e-mail: mkurz@pum.edu.pl

Received March 10, 2017

Accepted July 10, 2017

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