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Impact of single nucleotide polymorphisms on P450 oxidoreductase and peroxisome proliferator-activated receptor alpha on tacrolimus pharmacokinetics in renal transplant recipients

The Pharmacogenomics Journal volume 19, pages 42–52 (2019)Cite this article

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Abstract

The P450 oxidoreductase (POR) and peroxisome proliferator-activated receptor alpha (PPARA) genes are associated with the activity of cytochrome P450 enzymes in vivo. We aimed to investigate the impact of single nucleotide polymorphisms (SNPs) in the POR and PPARA genes on the pharmacokinetics of tacrolimus (TAC) in renal transplant recipients. A total of 220 recipients were assessed and 105 recipients were included for final quantitative analysis. Blood samples were collected and DNA was extracted. Targeting sequencing based on next-generation sequencing was applied to detect the SNPs in the POR and PPARA genes. In addition, 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. 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. No significant association was observed in the combined effect analysis of CYP3A4*1G and CYP3A5*3 with three significant SNPs in the POR gene. Age, post-transplant duration, and the use of sirolimus were identified as the most important factors that influenced the TAC concentrations. A meta-analysis of four studies results and our cohort indicated that compared with recipients carrying the CT or TT genotypes, recipients carrying the CC genotypes of POR*28 showed significantly higher TAC concentrations. Our study suggested the positive influence of mutations in the POR gene on TAC exposure at 3 months after kidney transplantation.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China [grant numbers 81570676, 81100532, 81470981], the National Key R&D Plan for Precision Medicine [grant number 2017YFC0910001], the Science and Education Health Project of Jiangsu Province for Important Talent [grant number RC2011055], the “333 High Level Talents Project” in Jiangsu Province, China [grant numbers BRA2015469, BRA2016514 (2011 and 2013)], the Standardized Diagnosis and Treatment Research Program of Key Diseases in Jiangsu Province, China [grant number BE2016791], the Open Project Program of Health Department of Jiangsu Province, China [grant number JSY-2–2016–099], the Jiangsu Province Six Talents Peak from Department of Human Resources, Social Security Office of Jiangsu Province, China [grant numbers 2010WSN-56, 2011-WS-033], the General Program of Health Department of Jiangsu Province, China [grant number H2009907], and the Priority Academic Program Development of Jiangsu Higher Education Institutions [grant number JX10231801].

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  1. These authors contributed equally: Shuhui Si, Zijie Wang, Haiwei Yang.

Authors and Affiliations

  1. Department of Urology, Nanjing Medical University First Affiliated Hospital, Nanjing, 210029, China

    Shuhui Si, Zijie Wang, Haiwei Yang, Zhijian Han, Jun Tao, Hao Chen, Ke Wang, Ruoyun Tan, Ji-Fu Wei & Min Gu

  2. Research Division of Clinical Pharmacology, Nanjing Medical University First Affiliated Hospital, Nanjing, 210029, China

    Shuhui Si, Miao Guo & Ji-Fu Wei

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  1. Shuhui Si
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Si, S., Wang, Z., Yang, H. et al. Impact of single nucleotide polymorphisms on P450 oxidoreductase and peroxisome proliferator-activated receptor alpha on tacrolimus pharmacokinetics in renal transplant recipients. Pharmacogenomics J 19, 42–52 (2019). https://doi.org/10.1038/s41397-018-0061-1

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