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Association between interleukin-18 promoter variants and tacrolimus pharmacokinetics in Chinese renal transplant patients

European Journal of Clinical Pharmacology volume 71, pages 191–198 (2015)Cite this article

Abstract

Purpose

Interleukin 18 (IL-18) is a potent proinflammatory cytokine thought to down-regulate cytochrome P450 (CYP) enzyme activities. This study aimed to assess the potential influence of two functional single nucleotide polymorphisms (SNPs) in the IL-18 promoter region on the tacrolimus pharmacokinetics in Chinese renal transplant patients.

Methods

We enrolled 96 renal allograft recipients receiving tacrolimus-based immunosuppressive regiments. Two functional SNPs in the IL-18 gene promoter region at the positions –137G/C (rs187283) and –607A/C (rs1946518) and one SNP (rs776746) of CYP3A5 were genotyped using a Mass ARRAY platform. Tacrolimus daily doses (mg/day) and trough tacrolimus concentration (ng/ml) were continuously recorded for 1 month after transplantation.

Results

The tacrolimus C/D ratio was significantly associated with the IL-18 rs1946518 gene polymorphism in the first month after transplantation (P = 0.0225). We studied the influence of its polymorphism on tacrolimus C/D ratios in subjects with different CYP3A5 genotype backgrounds, and among patients with CYP3A5 expressers, the difference among the three genotypes was even more striking (P < 0.001). We did not find significant differences in tacrolimus C/D ratios between the IL-18 rs187238 genotypes, either nominally or according to the CYP3A5 genotype. In a simple linear regression model, age, hemoglobin (Hb), CYP3A5 gene polymorphisms, and IL-18 A-607C gene polymorphisms were associated with log-transformed tacrolimus C/D ratios (P < 0.05). In the final multiple linear regression model, CYP3A5 polymorphisms were the most important variant, accounting for 19.5 % of total variation involved in tacrolimus pharmacokinetics.

Conclusion

Our findings suggest that a combined analysis of CYP3A5 and IL-18 promoter polymorphisms may help clinicians develop individualized tacrolimus treatment, which is based on determining CYP3A5 genotype.

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Fig. 1
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Abbreviations

CYP3A5:

cytochrome P450, family 3, subfamily A, polypeptide 5

IL-18:

interleukin-18

SNP:

single nucleotide polymorphisms

References

  1. Picard N, Marquet P (2011) The influence of pharmacogenetics and cofactors on clinical outcomes in kidney transplantation. Expert Opin Drug Metab Toxicol 7(6):731–743

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  2. Rossetto A, Bitetto D, Bresadola V, Lorenzin D, Baccarani U, De Anna D, Bresadola F, Adani GL (2010) Cardiovascular risk factors and immunosuppressive regimen after liver transplantation. Transplant Proc 42:2576–2578

    CAS  PubMed  Article  Google Scholar 

  3. Georges-Philippe P, Stéphanie F, Hassan B, Michael B, Assenat E (2009) Long-term outcomes of liver transplantation: diabetes mellitus. Liver Transpl 15:79–82

    Article  Google Scholar 

  4. Wallemacq P, Armstrong VW, Brunet M, Haufroid V, Holt DW, Johnston A, Kuypers D et al (2009) Opportunities to optimize tacrolimus therapy in solid organ transplantation: report of the European consensus conference. Ther Drug Monit 31:139–152

    CAS  PubMed  Article  Google Scholar 

  5. Barry A, Levine M (2010) A systematic review of the effect of CYP3A5 genotype on the apparent oral clearance of tacrolimus in renal transplant recipients. Ther Drug Monit 32(6):708–714

    CAS  PubMed  Article  Google Scholar 

  6. Tang H-L, Xie H-G, Yao Yao HY-F (2011) Lower tacrolimus daily dose requirements and acute rejection rates in the CYP3A5 nonexpressers than expressers. Pharmacogenet Genomics 21:713–720

    CAS  PubMed  Article  Google Scholar 

  7. Satoh S, Saito M, Inoue T, Kagaya H, Miura M, Inoue K, Komatsuda A, Tsuchiya N, Suzuki T, Habuchi T (2009) CYP3A5*1 allele associated with tacrolimus trough concentrations but not subclinical acute rejection or chronic allograft nephropathy in Japanese renal transplant recipients. Eur J Clin Pharmacol 65:473–481

    CAS  PubMed  Article  Google Scholar 

  8. Li C-J, Li L, Li Lin H-XJ, Zhong Z-Y, Li W-M, Zhang Y-J, Zheng P, Tan X-H, Zhou L (2014) Impact of the CYP3A5, CYP3A4, COMT, IL-10 and POR genetic polymorphisms on tacrolimus metabolism in Chinese renal transplant recipients. Plos One 9(1):e86206

    PubMed Central  PubMed  Article  Google Scholar 

  9. Chen D, Fan J, Guo F, Qin S, Wang Z, Peng Z (2013) Novel single nucleotide polymorphisms in interleukin 6 affect tacrolimus metabolism in liver transplant patients. Plos One 8(8):e73405

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  10. Lee C-M, Pohl J, Morgan ET (2009) Dual mechanisms of CYP3A protein regulation by proinflammatory cytokine stimulation in primary hepatocyte cultures. Drug Metab Dispos 37:865–872

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  11. Aitken AE, Morgan ET (2007) Gene-Specific effects of inflammatory cytokines on cytochrome P450 2C, 2B6 and 3A4 mRNA levels in human hepatocytes. Drug Metab Dispos 35:1687–1693

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  12. Dickmann LJ, Patel SK, Wienkers LC, Slatter JG (2012) Effects of interleukin 1 (IL-1) and IL-1/interleukin 6 (IL-6) combinations on drug metabolizing enzymes in human hepatocyte culture. Curr Drug Metab 13:930–937

    CAS  PubMed  Article  Google Scholar 

  13. Tsutsui H, Nakanishi K (2012) Immunotherapeutic applications of IL-18. Immunotherapy 4(12):1883–1894

    CAS  PubMed  Article  Google Scholar 

  14. Hakkola J, Hu Y, Ingelman-Sundberg M (2003) Mechanisms of down-regulation of CYP2E1 expression by inflammatory cytokines in rat hepatoma cells. J Pharmacol Exp Ther 304(3):1048–1054

    CAS  PubMed  Article  Google Scholar 

  15. Kalsotra A, Anakk S, Brommer CL, Kikuta Y, Morgan ET, Strobel HW (2007) Catalytic characterization and cytokine mediated regulation of cytochrome P450 4Fs in rat hepatocytes. Arch Biochem Biophys 461:104–112

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  16. Lebel-Binay S, Berger A, Zinzindohoué F, Cugnenc P-H, Thiounn N, Fridman WH, Pagès F (2000) Interleukin-18: biological properties and clinical implications. Eur Cytokine Netw 11(1):15–26

    CAS  PubMed  Google Scholar 

  17. Giedraitis V, He B, Huang W-X, Hillert J (2001) Cloning and mutation analysis of the human IL-18 promoter: a possible role of polymorphisms in expression regulation. J Neuroimmunol 112:146–152

    CAS  PubMed  Article  Google Scholar 

  18. Kalina U, Ballas K, Koyama N, Kauschat D, Miething C, Arnemann J, Martin H, Hoelzer D, Ottmann OG (2000) Genomic organization and regulation of the human interleukin-18 gene. Scand J Immunol 52:525–530

    CAS  PubMed  Article  Google Scholar 

  19. Chen DY, Hsieh CW, Chen KS, Chen YM, Lin FJ, Lan J (2009) Association of interleukin-18 promoter polymorphisms with WHO pathological classes and serum IL-18 levels in Chinese patients with lupus nephritis. Lupus 18:29–37

    CAS  PubMed  Article  Google Scholar 

  20. Khripko OP, Sennikova NS, Lopatnikova JA, Khripko JI, Filipenko ML, Khrapov EA et al (2008) Association of single nucleotide polymorphisms in the IL-18 gene with production of IL-18 protein by mononuclear cells from healthy donors. Mediat Inflamm 2008:1–6

    Google Scholar 

  21. Wang Z, Shaohan W, Chen D, Guo F, Zhong L, Fan J, Peng Z (2014) Influence of TLR4 rs1927907 locus polymorphisms on tacrolimus pharmacokinetics in the early stage after liver transplantation. Eur J Clin Pharmacol. doi:10.1007/s00228-014-1673-2

    PubMed Central  Google Scholar 

  22. Miura M, Satoh S, Kagaya H, Saito M, Numakura K et al (2011) Impact of the CYP3A4*1G polymorphism and its combination with CYP3A5 genotypes on tacrolimus pharmacokinetics in renal transplant patients. Pharmacogenomics 12(7):977–984

    CAS  PubMed  Article  Google Scholar 

  23. Meng X, Guo C, Feng G, Zhao Y et al (2012) Association of CYP3A polymorphisms with the pharmacokinetics of cyclosporine A in early post-renal transplant recipients in China. Acta Pharmacol Sin 33:1563–1570

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  24. Gabriel S, Ziaugra L, Tabbaa D (2009) SNP genotyping using the Sequenom MassARRAY iPLEX platform. Current protocols in human genetics/editorial board, Jonathan L Haines [et al.], Chapter 2: Unit 2.12

  25. Shi YY, He L (2005) SHEsis, a powerful software platform for analyses of linkage disequilibrium, haplotype construction, and genetic association at polymorphism loci. Cell Res 15:97–98

    CAS  PubMed  Article  Google Scholar 

  26. Chen D, Guo F, Shi J, Zhang C, Wang Z, Fan J, Peng Z (2014) Association of hemoglobin levels, CYP3A5, and NR1I3 gene polymorphisms with tacrolimus pharmacokinetics in liver transplant patients. Drug Metab Pharmacokinet 29(3):249–253

    CAS  PubMed  Article  Google Scholar 

  27. Jin-Tai Y, Tan L, Song J-H, Sun Y-P, Chen W, Miao D, Tian Y (2009) Interleukin-18 promoter polymorphisms and risk of late onset Alzheimer’s disease. Brain Res 1253:169–175

    Article  Google Scholar 

  28. Zhanga N, Jin-Tai Y, Nan-Nan Y, Rui-Chun L, Ma T, Wang N-D, Miaoa D, Song J-H, Tan L (2010) Interleukin-18 promoter polymorphisms and risk of ischemic stroke. Brain Res Bull 81:590–594

    Article  Google Scholar 

  29. Xiang X, Dequan L, Qing H, Jing G, Biao C, Xie A (2011) Interleukin-18 promoter polymorphisms and risk of Parkinson’s disease in a Han Chinese population. Brain Res 1381:90–94

    Article  Google Scholar 

  30. Liu J, Liu J, Zhou Y, Li S, Li Y, Song X, Wang J, Wang L, Ying B (2011) Association between promoter variants of interleukin-18 and schizophrenia in a Han Chinese population. DNA Cell Biol 0(11):913–917

    Article  Google Scholar 

  31. SÂenz-LÔpez P, Carretero R, Vazquez F, Martin J, SÂnchez E, Talladab M et al (2010) Impact of interleukin-18 polymorphisms-607 and −137 on clinical characteristics of renal cell carcinoma patients. Hum Immunol 71:309–313

    PubMed  Article  Google Scholar 

  32. Babar M, Ryan AW, Anderson LA, Segurado R, Turner G, Liam J et al (2012) Genes of the interleukin-18 pathway are associated with susceptibility to Barrett’s esophagus and esophageal adenocarcinoma. Am J Gastroenterol 107:1331–1341

    CAS  PubMed  Article  Google Scholar 

  33. Pratesi C, Bortolin MT, Bidoli E, Tedeschi R, Vaccher E, Dolcetti R, Guidoboni M, Franchin G et al (2006) Interleukin-10 and interleukin-18 promoter polymorphisms in an Italian cohort of patients with undifferentiated carcinoma of nasopharyngeal type. Cancer Immunol Immunother: CII 55(1):23–30

    CAS  PubMed  Article  Google Scholar 

  34. Li Y, Zou Y, Cai B, Yang B, Ying B, Shi Y, Wang L (2012) The associations of IL-18 serum levels and promoter polymorphism with tacrolimus pharmacokinetics and hepatic allograft dysfunction in Chinese liver transplantation recipients. Gene 491:251–255

    CAS  PubMed  Article  Google Scholar 

  35. Zhang X, Wang Z, Fan J, Liu G, Peng Z (2010) Impact of interleukin-10 gene polymorphisms on tacrolimus dosing requirements in Chinese liver transplant patients during the early posttransplantation period. Eur J Clin Pharmacol 67:803–813

    Article  Google Scholar 

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Acknowledgments

This work was supported by the developing Project of Science and Technology Commission of Shandong Province (2012G0021825), the 863 Program (2012AA021002), and the National Natural Science Foundation of China (Grant Number 81202609).

Declaration of interest

The authors declare no conflicts of interest and claim responsibility for the content and writing of this paper.

Author information

Affiliations

  1. Department of Urology Surgery, Shandong Qianfoshan Hospital, School of Medicine, Taishan Medical College, Shandong, China

    Jiazhen Xing

  2. Department of Pharmacy, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China

    Xiaoqing Zhang

  3. Department of Hepatobiliary Pancreatic Surgery, Shanghai First People’s Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China

    Junwei Fan

  4. Department of Urology Surgery, Shandong Qianfoshan Hospital, School of Medicine, Shandong University, Shandong, China

    Bin Shen, Tongyi Men & Jianning Wang

  5. No.16766, Jingshi Road, Jinan City, China

    Tongyi Men & Jianning Wang

Authors
  1. Jiazhen Xing
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  2. Xiaoqing Zhang
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  3. Junwei Fan
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  4. Bin Shen
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Corresponding authors

Correspondence to Tongyi Men or Jianning Wang.

Additional information

J. Xing, X. Zhang, and J. Fan are co-first authors with the same contribution to the paper.

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Xing, J., Zhang, X., Fan, J. et al. Association between interleukin-18 promoter variants and tacrolimus pharmacokinetics in Chinese renal transplant patients. Eur J Clin Pharmacol 71, 191–198 (2015). https://doi.org/10.1007/s00228-014-1785-8

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  • DOI: https://doi.org/10.1007/s00228-014-1785-8

Keywords

  • CYP3A5
  • IL-18
  • SNPs
  • Tacrolimus pharmacokinetics
  • Renal transplantation