Impact of Single Nucleotide Polymorphisms on P450 Oxidoreductase and Peroxisome Proliferator-Activated Receptor Alpha on Tacrolimus Pharmacokinetics in Renal Transplant Recipients

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Abstract

The P450 oxidoreductase (POR) and peroxisome proliferator-activated receptor alpha (PPARA) genes have been reported to be associated with the activity of cytochrome P450 enzymes in vivo. We aimed to investigate the impact of single nucleotide polymorphisms (SNP) in the POR and PPARA genes on the pharmacokinetics of tacrolimus (TAC) in renal transplant recipients. We enrolled 105 recipients in this cohort. Whole exome sequencing technology was applied to detect the SNPs on POR and PPARA gene. A systematic review and meta-analysis was performed to comprehensively evaluate the influence of POR and PPARA mutations on the TAC concentrations. A total of 81 SNPs were obtained. Mutations on three SNPs (POR*28, Chr7:75619677 and Chr7:75614288) were found to be significantly associated with the TAC pharmacokinetics at 3 months, 6 months and more than 12 months. The age, post-transplant duration and the usage of sirolimus were identified as the most important factors influencing the TAC concentrations. Meta-analysis results reported that recipients carrying CC genotypes of POR*28 showed significantly higher TAC concentrations compared to those with CT or TT genotypes. Our study suggested the positive influence of mutations on POR gene on the TAC exposure after 3 months of kidney transplantation.

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