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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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References

  1. Rodriguez-Peralvarez M, Germani G, Darius T, Lerut J, Tsochatzis E, Burroughs AK. Tacrolimus trough levels, rejection and renal impairment in liver transplantation: a systematic review and meta-analysis. Am J Transplant. 2012;12:2797–814.

    Article  CAS  Google Scholar 

  2. Piotti G, Cremaschi E, Maggiore U. Once-daily prolonged-release tacrolimus formulations for kidney transplantation: what the nephrologist needs to know. J Nephrol. 2017;30:53–61.

    Article  CAS  Google Scholar 

  3. Caillard S, Moulin B, Buron F, Mariat C, Audard V, Grimbert P, et al. Advagraf((R)), a once-daily prolonged release tacrolimus formulation, in kidney transplantation: literature review and guidelines from a panel of experts. Transplant Int. 2016;29:860–9.

    Article  Google Scholar 

  4. Chen YH, Zheng KL, Chen LZ, Dai YP, Fei JG, Qiu J, et al. Clinical pharmacokinetics of tacrolimus after the first oral administration in combination with mycophenolate mofetil and prednisone in Chinese renal transplant recipients. Transplant Proc. 2005;37:4246–50.

    Article  CAS  Google Scholar 

  5. Li CJ, Li L. Tacrolimus in preventing transplant rejection in Chinese patients--optimizing use. Drug Des Devel Ther. 2015;9:473–85.

    Article  CAS  Google Scholar 

  6. Kuypers DR. Immunosuppressive drug monitoring - what to use in clinical practice today to improve renal graft outcome. Transplant Int. 2005;18:140–50.

    Article  CAS  Google Scholar 

  7. Elens L, Bouamar R, Shuker N, Hesselink DA, van Gelder T, van Schaik RH. Clinical implementation of pharmacogenetics in kidney transplantation: calcineurin inhibitors in the starting blocks. Br J Clin Pharmacol. 2014;77:715–28.

    Article  Google Scholar 

  8. Liu MZ, He HY, Zhang YL, Hu YF, He FZ, Luo JQ, et al. IL-3 and CTLA4 gene polymorphisms may influence the tacrolimus dose requirement in Chinese kidney transplant recipients. Acta Pharmacol Sin. 2017;38:415–23.

    Article  CAS  Google Scholar 

  9. Kamdem LK, Streit F, Zanger UM, Brockmoller J, Oellerich M, Armstrong VW, et al. Contribution of CYP3A5 to the in vitro hepatic clearance of tacrolimus. Clin Chem. 2005;51:1374–81.

    Article  CAS  Google Scholar 

  10. Shuker N, van Gelder T, Hesselink DA. Intra-patient variability in tacrolimus exposure: causes, consequences for clinical management. Transplant Rev. 2015;29:78–84.

    Article  Google Scholar 

  11. Zong YP, Wang ZJ, Zhou WL, Zhou WM, Ma TL, Huang ZK, et al. Effects of CYP3A5 polymorphisms on tacrolimus pharmacokinetics in pediatric kidney transplantation: a systematic review and meta-analysis of observational studies. World J Pediatr. 2017.

  12. Shi WL, Tang HL, Zhai SD. Effects of the CYP3A4*1B genetic polymorphism on the pharmacokinetics of tacrolimus in adult renal transplant recipients: a meta-analysis. PLoS ONE. 2015;10:e0127995.

    Article  Google Scholar 

  13. Rojas L, Neumann I, Herrero MJ, Boso V, Reig J, Poveda JL, et al. Effect of CYP3A5*3 on kidney transplant recipients treated with tacrolimus: a systematic review and meta-analysis of observational studies. Pharm J. 2015;15:38–48.

    CAS  Google Scholar 

  14. Golubovic B, Prostran M, Miljkovic B, Vucicevic K, Radivojevic D, Grabnar I. Population pharmacokinetic approach of immunosuppressive therapy in kidney transplant patients. Curr Med Chem. 2016;23:1998–2011.

    Article  CAS  Google Scholar 

  15. Hesselink DA, Bouamar R, Elens L, van Schaik RH, van Gelder T. The role of pharmacogenetics in the disposition of and response to tacrolimus in solid organ transplantation. Clin Pharmacokinet. 2014;53:123–39.

    Article  CAS  Google Scholar 

  16. Klein K, Thomas M, Winter S, Nussler AK, Niemi M, Schwab M, et al. PPARA: a novel genetic determinant of CYP3A4 in vitro and in vivo. Clin Pharmacol Ther. 2012;91:1044–52.

    Article  CAS  Google Scholar 

  17. Tang JT, Andrews LM, van Gelder T, Shi YY, van Schaik RH, Wang LL, et al. Pharmacogenetic aspects of the use of tacrolimus in renal transplantation: recent developments and ethnic considerations. Expert Opin Drug Metab Toxicol. 2016;12:555–65.

    Article  CAS  Google Scholar 

  18. Olfson E, Saccone NL, Johnson EO, Chen LS, Culverhouse R, Doheny K, et al. Rare, low frequency and common coding variants in CHRNA5 and their contribution to nicotine dependence in European and African Americans. Mol Psychiatry. 2016;21:601–7.

    Article  CAS  Google Scholar 

  19. Zhang JJ, Liu SB, Xue L, Ding XL, Zhang H, Miao LY. The genetic polymorphisms of POR*28 and CYP3A5*3 significantly influence the pharmacokinetics of tacrolimus in Chinese renal transplant recipients. Int J Clin Pharmacol Ther. 2015;53:728–36.

    Article  CAS  Google Scholar 

  20. Lunde I, Bremer S, Midtvedt K, Mohebi B, Dahl M, Bergan S, et al. The influence of CYP3A, PPARA, and POR genetic variants on the pharmacokinetics of tacrolimus and cyclosporine in renal transplant recipients. Eur J Clin Pharmacol. 2014;70:685–93.

    Article  CAS  Google Scholar 

  21. Kuypers DR, de Loor H, Naesens M, Coopmans T, de Jonge H. Combined effects of CYP3A5*1, POR*28, and CYP3A4*22 single nucleotide polymorphisms on early concentration-controlled tacrolimus exposure in de-novo renal recipients. Pharm Genom. 2014;24:597–606.

    Article  CAS  Google Scholar 

  22. Jannot AS, Vuillemin X, Etienne I, Buchler M, Hurault de Ligny B, Choukroun G, et al. A lack of significant effect of POR*28 allelic variant on tacrolimus exposure in kidney transplant recipients. Ther Drug Monit. 2016;38:223–9.

    Article  CAS  Google Scholar 

  23. Elens L, Hesselink DA, Bouamar R, Budde K, de Fijter JW, De Meyer M, et al. Impact of POR*28 on the pharmacokinetics of tacrolimus and cyclosporine A in renal transplant patients. Ther Drug Monit. 2014;36:71–9.

    CAS  PubMed  Google Scholar 

  24. Kurzawski M, Malinowski D, Dziewanowski K, Drozdzik M. Impact of PPARA and POR polymorphisms on tacrolimus pharmacokinetics and new-onset diabetes in kidney transplant recipients. Pharm Genom. 2014;24:397–400.

    CAS  Google Scholar 

  25. Li CJ, Li L, Lin L, Jiang HX, Zhong ZY, Li WM, et al. Impact of the CYP3A5, CYP3A4, COMT, IL-10 and POR genetic polymorphisms on tacrolimus metabolism in Chinese renal transplant recipients. PLoS ONE. 2014;9:e86206.

    Article  Google Scholar 

  26. de Jonge H, Metalidis C, Naesens M, Lambrechts D, Kuypers DR. The P450 oxidoreductase *28 SNP is associated with low initial tacrolimus exposure and increased dose requirements in CYP3A5-expressing renal recipients. Pharmacogenomics. 2011;12:1281–91.

    Article  Google Scholar 

  27. Liu S, Chen RX, Li J, Zhang Y, Wang XD, Fu Q, et al. The POR rs1057868-rs2868177 GC-GT diplotype is associated with high tacrolimus concentrations in early post-renal transplant recipients. Acta Pharmacol Sin. 2016;37:1251–8.

    Article  Google Scholar 

  28. Bruckmueller H, Werk AN, Renders L, Feldkamp T, Tepel M, Borst C, et al. Which genetic determinants should be considered for tacrolimus dose optimization in kidney transplantation? A combined analysis of genes affecting the CYP3A locus. Ther Drug Monit. 2015;37:288–95.

    Article  CAS  Google Scholar 

  29. Trojan K, Unterrainer C, Weimer R, Bulut N, Morath C, Aly M, et al. Helios expression and Foxp3 TSDR methylation of IFNy+and IFNy- Treg from kidney transplant recipients with good long-term graft function. PLoS ONE. 2017;12:e0173773.

    Article  Google Scholar 

  30. Fennell K, Hoffman R, Yoshida K, Iwamoto S, Govender L, Vather K, et al. Effect on gene expression of three allelic variants in GATA motifs of ABO, RHD, and RHCE regulatory elements. Transfusion. 2017.

  31. Bicknell AA, Cenik C, Chua HN, Roth FP, Moore MJ. Introns in UTRs: why we should stop ignoring them. Bioessays. 2012;34:1025–34.

    Article  CAS  Google Scholar 

  32. Cenik C, Chua HN, Zhang H, Tarnawsky SP, Akef A, Derti A, et al. Genome analysis reveals interplay between 5’UTR introns and nuclear mRNA export for secretory and mitochondrial genes. PLoS Genet. 2011;7:e1001366.

    Article  CAS  Google Scholar 

  33. Huh KH, Lee JG, Ha J, Oh CK, Ju MK, Kim CD, et al. De novo low-dose sirolimus versus mycophenolate mofetil in combination with extended-release tacrolimus in kidney transplant recipients: a multicentre, open-label, randomized, controlled, non-inferiority trial. Nephrol, Dial, Transplant. 2017;32:1415–24.

    Article  CAS  Google Scholar 

  34. Cruzado JM, Pascual J, Sanchez-Fructuoso A, Seron D, Diaz JM, Rengel M, et al. Controlled randomized study comparing the cardiovascular profile of everolimus with tacrolimus in renal transplantation. Transplant Int. 2016;29:1317–28.

    Article  CAS  Google Scholar 

  35. Scheel J, Reber S, Stoessel L, Waldmann E, Jank S, Eckardt KU, et al. Patient-reported non-adherence and immunosuppressant trough levels are associated with rejection after renal transplantation. BMC Nephrol. 2017;18:107.

    Article  Google Scholar 

  36. Xue W, Tian P, Xiang H, Ding X, Pan X, Yan H, et al. Outcomes for primary kidney transplantation from donation after Citizens’ death in China: a single center experience of 367 cases. BMC Health Serv Res. 2017;17:250.

    Article  Google Scholar 

Download references

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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