Skip to main content

Advertisement

SpringerLink
Log in

Meta-analysis of the associations of IMPDH and UGT1A9 polymorphisms with rejection in kidney transplant recipients taking mycophenolic acid

  • Pharmacodynamics
  • Published:
European Journal of Clinical Pharmacology Aims and scope Submit manuscript

Abstract

Purpose

To investigate the associations of IMPDH and UGT1A9 polymorphisms with rejection in kidney transplant recipients taking mycophenolic acid (MPA).

Methods

PubMed, Web of Science, Embase, Cochrane Library, Wanfang Data, and the China Academic Journal Network Publishing Database were systematically searched for studies investigating the associations of IMPDH1, IMPDH2, and UGT1A9 polymorphisms with rejection in kidney transplant recipients taking MPA. Associations were evaluated by pooled odds ratios (ORs) and effect sizes (ESs) with 95% confidence intervals (CIs).

Results

Twelve studies were included in the analysis, including a total of 2342 kidney transplant recipients. The results showed that compared with the TC + CC variant genotypes, the TT genotype of IMPDH2 3757 T > C was significantly associated with a higher risk of rejection (ES = 1.60, 95% CI = 1.07–2.40, P = 0.021), while there was no significant association of the IMPDH2 3757 T > C polymorphism with acute rejection within 1 year in kidney transplant recipients (OR = 1.49, 95% CI = 0.79–2.80, P = 0.217; ES = 1.44, 95% CI = 0.88–2.36, P = 0.142). The GG genotypes of IMPDH1 125G > A and IMPDH1 106G > A were significantly associated with a higher risk of rejection (ES = 1.91, 95% CI = 1.11–3.28, P = 0.019) and acute rejection within 1 year (ES = 2.12, 95% CI = 1.45–3.10, P < 0.001) than the variant genotypes GA + AA. The TT genotype of UGT1A9 275 T > A showed a decreased risk of rejection compared with the variant genotypes TA + AA (ES = 0.44, 95% CI = 0.23–0.84, P = 0.013).

Conclusions

IMPDH1, IMPDH2, and UGT1A9 polymorphisms were associated with rejection in kidney transplant recipients, and the genetic backgrounds of patients should be considered when using MPA.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

Data availability

Data and materials will be available from the authors upon reasonable request.

References

  1. Dalal P, Grafals M, Chhabra D, Gallon L (2009) Mycophenolate mofetil: safety and efficacy in the prophylaxis of acute kidney transplantation rejection. Ther Clin Risk Manag 5(1):139–149. https://doi.org/10.2147/tcrm.s3068

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Sollinger HW (1995) Mycophenolate mofetil for the prevention of acute rejection in primary cadaveric renal allograft recipients. U.S. Renal Transplant Mycophenolate Mofetil Study Group. Transplantation 60(3):225–232. https://doi.org/10.1097/00007890-199508000-00003

  3. Kaufman DB, Shapiro R, Lucey MR, CherikhR TB, Dyke DB, WS (2004) Immunosuppression: practice and trends. Am J Transplant Off J Am Soc Transplant Am Soc Transplant Surg 4(Suppl 9):38–53. https://doi.org/10.1111/j.1600-6135.2004.00397.x

    Article  Google Scholar 

  4. Picard N, Ratanasavanh D, Premaud A, Le Meur Y, Marquet P (2005) Identification of the UDP-glucuronosyltransferase isoforms involved in mycophenolic acid phase II metabolism. Drug Metab Dispos 33(1):139–146. https://doi.org/10.1124/dmd.104.001651

    Article  CAS  PubMed  Google Scholar 

  5. Bernard O, Guillemette C (2004) The main role of UGT1A9 in the hepatic metabolism of mycophenolic acid and the effects of naturally occurring variants. Drug Metab Dispos 32(8):775–778. https://doi.org/10.1124/dmd.32.8.775

    Article  CAS  PubMed  Google Scholar 

  6. Bernard O, Tojcic J, Journault K, Perusse L, Guillemette C (2006) Influence of nonsynonymous polymorphisms of UGT1A8 and UGT2B7 metabolizing enzymes on the formation of phenolic and acyl glucuronides of mycophenolic acid. Drug Metab Dispos 34(9):1539–1545. https://doi.org/10.1124/dmd.106.010553

    Article  CAS  PubMed  Google Scholar 

  7. Patel CG, Ogasawara K, Akhlaghi F (2013) Mycophenolic acid glucuronide is transported by multidrug resistance-associated protein 2 and this transport is not inhibited by cyclosporine, tacrolimus or sirolimus. Xenobiotica 43(3):229–235. https://doi.org/10.3109/00498254.2012.713531

    Article  CAS  PubMed  Google Scholar 

  8. Westley IS, Brogan LR, Morris RG, Evans AM, Sallustio BC (2006) Role of Mrp2 in the hepatic disposition of mycophenolic acid and its glucuronide metabolites: effect of cyclosporine. Drug Metab Dispos 34(2):261–266. https://doi.org/10.1124/dmd.105.006122

    Article  CAS  PubMed  Google Scholar 

  9. Picard N, Bergan S, Marquet P, van Gelder T, Wallemacq P, Hesselink DA, Haufroid V (2016) Pharmacogenetic biomarkers predictive of the pharmacokinetics and pharmacodynamics of immunosuppressive drugs. Ther Drug Monit 38(Suppl 1):S57-69. https://doi.org/10.1097/FTD.0000000000000255

    Article  PubMed  Google Scholar 

  10. Fujiyama N, Miura M, Kato S, Sone T, Isobe M, Satoh S (2010) Involvement of carboxylesterase 1 and 2 in the hydrolysis of mycophenolate mofetil. Drug Metab Dispos 38(12):2210–2217. https://doi.org/10.1124/dmd.110.034249

    Article  CAS  PubMed  Google Scholar 

  11. Kiang TKL, Partovi N, Shapiro RJ, Berman JM, Collier AC, Ensom MHH (2018) Regression and genomic analyses on the association between dose-normalized mycophenolic acid exposure and absolute neutrophil count in steroid-free, de novo kidney transplant recipients. Clin Drug Investig 38(11):1011–1022. https://doi.org/10.1007/s40261-018-0694-5

    Article  CAS  PubMed  Google Scholar 

  12. Neri A, Scalzotto E, Corradi V, Caprara C, Salin A, Cannone M, De Cal M, Romano G, Tulissi P, Cussigh AR, Montanaro D, Frigo A, Giavarina D, Chiaramonte S, Ronco C (2019) Acute rejection in kidney transplantation and the evaluation of associated polymorphisms (SNPs): the importance of sample size. Diagnosis 6(3):287–295. https://doi.org/10.1515/dx-2018-0110

    Article  PubMed  Google Scholar 

  13. Pouche L, Stojanova J, Marquet P, Picard N (2016) New challenges and promises in solid organ transplantation pharmacogenetics: the genetic variability of proteins involved in the pharmacodynamics of immunosuppressive drugs. Pharmacogenomics 17(3):277–296. https://doi.org/10.2217/pgs.15.169

    Article  CAS  PubMed  Google Scholar 

  14. Grinyó J, Vanrenterghem Y, Nashan B, Vincenti F, Ekberg H, Lindpaintner K, Rashford M, Nasmyth-Miller C, Voulgari A, Spleiss O, Truman M, Essioux L (2008) Association of four DNA polymorphisms with acute rejection after kidney transplantation. Transpl Int 21(9):879–891. https://doi.org/10.1111/j.1432-2277.2008.00679.x

    Article  CAS  PubMed  Google Scholar 

  15. Ciftci HS, Demir E, Karadeniz MS, Tefik T, Nane I, Oguz FS, Aydin F, Turkmen A (2018) Influence of uridine diphosphate-glucuronosyltransferases (1A9) polymorphisms on mycophenolic acid pharmacokinetics in patients with renal transplant. Ren Fail 40(1):395–402. https://doi.org/10.1080/0886022X.2018.1489285

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Wang J, Yang JW, Zeevi A, Webber SA, Girnita DM, Selby R, Fu J, Shah T, Pravica V, Hutchinson IV, Burckart GJ (2008) IMPDH1 gene polymorphisms and association with acute rejection in renal transplant patients. Clin Pharmacol Ther 83(5):711–717. https://doi.org/10.1038/sj.clpt.6100347

    Article  CAS  PubMed  Google Scholar 

  17. Pazik J, Oldak M, Podgorska M, Lewandowski Z, Sitarek E, Ploski R, Szmidt J, Chmura A, Durlik M, Malejczyk J (2011) Lymphocyte counts in kidney allograft recipients are associated with IMPDH2 3757T>C gene polymorphism. Transpl Proc 43(8):2943–2945. https://doi.org/10.1016/j.transproceed.2011.08.037

    Article  CAS  Google Scholar 

  18. Sombogaard F, van Schaik RH, Mathot RA, Budde K, van der Werf M, Vulto AG, Weimar W, Glander P, Essioux L, van Gelder T (2009) Interpatient variability in IMPDH activity in MMF-treated renal transplant patients is correlated with IMPDH type II 3757T > C polymorphism. Pharmacogenet Genomics 19(8):626–634. https://doi.org/10.1097/FPC.0b013e32832f5f1b

    Article  CAS  PubMed  Google Scholar 

  19. Woillard J-B, Picard N, Thierry A, Touchard G, Marquet P (2014) Associations between polymorphisms in target, metabolism, or transport proteins of mycophenolate sodium and therapeutic or adverse effects in kidney transplant patients. Pharmacogenet Genomics 24(5):256–262. https://doi.org/10.1097/fpc.0000000000000045

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Kagaya H, Miura M, Saito M, Habuchi T, Satoh S (2010) Correlation of IMPDH1 gene polymorphisms with subclinical acute rejection and mycophenolic acid exposure parameters on day 28 after renal transplantation. Basic Clin Pharmacol Toxicol 107(2):631–636. https://doi.org/10.1111/j.1742-7843.2010.00542.x

    Article  CAS  PubMed  Google Scholar 

  21. Sohani ZN, Meyre D, de Souza RJ, Joseph PG, Gandhi M, Dennis BB, Norman G, Anand SS (2015) Assessing the quality of published genetic association studies in meta-analyses: the quality of genetic studies (Q-Genie) tool. BMC Genet 16:50. https://doi.org/10.1186/s12863-015-0211-2

    Article  PubMed  PubMed Central  Google Scholar 

  22. Cheng L, Wang Y, Li X, Feng W, Weng B, Yuan Q, Xia P, Sun F (2020) Meta-analysis of the associations of CYP2B6-516G>T polymorphisms with efavirenz-induced central nervous system side effects and virological outcome in HIV-infected adults. Pharmacogenomics J 20(2):246–259. https://doi.org/10.1038/s41397-019-0112-2

    Article  CAS  PubMed  Google Scholar 

  23. Sun F, Chen Z, Yao P, Weng B, Liu Z, Cheng L (2021) Meta-analysis of ABCG2 and ABCB1 polymorphisms with sunitinib-induced toxicity and efficacy in renal cell carcinoma. Front Pharmacol 12:641075. https://doi.org/10.3389/fphar.2021.641075

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Ciliao HL, Camargo-Godoy RBO, Souza MF, Zanuto A, Delfino VDA, Colus IMS (2018) Polymorphisms in IMPDH2, UGT2B7, and CES2 genes influence the risk of graft rejection in kidney transplant recipients taking mycophenolate mofetil. Mutat Res, Genet Toxicol Environ Mutagen 836(Pt B):97–102. https://doi.org/10.1016/j.mrgentox.2018.06.008

    Article  CAS  Google Scholar 

  25. Sun M, He J, Qi X, Ding Z, Qiu Q, Zhang J, Wei X, Hu L, Zhang X, Hou J (2014) Correlation of inosine monophosphate dehydrogenase gene polymorphisms and acute rejection in renal transplantation. Chin J Exp Surg 31(12):2678–2781. https://doi.org/10.3760/ema.j.issn.1001-9030.2014.12.014

    Article  CAS  Google Scholar 

  26. Gensburger O, Van Schaik RHN, Picard N, Le Meur Y, Rousseau A, Woillard J-B, Van Gelder T, Marquet P (2010) Polymorphisms in type I and II inosine monophosphate dehydrogenase genes and association with clinical outcome in patients on mycophenolate mofetil. Pharmacogenet Genomics 20(9):537–543. https://doi.org/10.1097/FPC.0b013e32833d8cf5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Michelon H, König J, Durrbach A, Quteineh L, Verstuyft C, Furlan V, Ferlicot S, Letierce A, Charpentier B, Fromm MF, Becquemont L (2010) SLCO1B1 genetic polymorphism influences mycophenolic acid tolerance in renal transplant recipients. Pharmacogenomics 11(12):1703–1713. https://doi.org/10.2217/pgs.10.132

    Article  CAS  PubMed  Google Scholar 

  28. Pazik J, Oldak M, Dabrowski M, Lewandowski Z, Sitarek E, Podgorska M, Wazna E, Ploski R, Szmidt J, Chmura A, Durlik M, Malejczyk J (2011) Association of UDP-glucuronosyltransferase 1A9 (UGT1A9) gene polymorphism with kidney allograft function. Ann Transplant 16(4):69–73. https://doi.org/10.12659/aot.882221

    Article  CAS  PubMed  Google Scholar 

  29. van Schaik RH, van Agteren M, de Fijter JW, Hartmann A, Schmidt J, Budde K, Kuypers D, Le Meur Y, van der Werf M, Mamelok R, van Gelder T (2009) UGT1A9 -275T>A/-2152C>T polymorphisms correlate with low MPA exposure and acute rejection in MMF/tacrolimus-treated kidney transplant patients. Clin Pharmacol Ther 86(3):319–327. https://doi.org/10.1038/clpt.2009.83

    Article  CAS  PubMed  Google Scholar 

  30. Little J, Higgins JP, Ioannidis JP, Moher D, Gagnon F, von Elm E, Khoury MJ, Cohen B, Davey-Smith G, Grimshaw J, Scheet P, Gwinn M, Williamson RE, Zou GY, Hutchings K, Johnson CY, Tait V, Wiens M, Golding J, van Duijn C, McLaughlin J, Paterson A, Wells G, Fortier I, Freedman M, Zecevic M, King R, Infante-Rivard C, Stewart A, Birkett Studies Stroga, N (2009) STrengthening the Reporting of Genetic Association Studies (STREGA): an extension of the STROBE statement. PLoS Med 6(2):e22. https://doi.org/10.1371/journal.pmed.1000022

  31. Shah S, Harwood SM, Dohler B, Opelz G, Yaqoob MM (2012) Inosine monophosphate dehydrogenase polymorphisms and renal allograft outcome. Transplantation 94(5):486–491. https://doi.org/10.1097/TP.0b013e31825b7654

    Article  CAS  PubMed  Google Scholar 

  32. Winnicki W, Weigel G, Sunder-Plassmann G, Bajari T, Winter B, Herkner H, Sengoelge G (2010) An inosine 5′-monophosphate dehydrogenase 2 single-nucleotide polymorphism impairs the effect of mycophenolic acid. Pharmacogenomics J 10(1):70–76. https://doi.org/10.1038/tpj.2009.43

    Article  CAS  PubMed  Google Scholar 

  33. Wu TY, Peng Y, Pelleymounter LL, Moon I, Eckloff BW, Wieben ED, Yee VC, Weinshilboum RM (2010) Pharmacogenetics of the mycophenolic acid targets inosine monophosphate dehydrogenases IMPDH1 and IMPDH2: gene sequence variation and functional genomics. Br J Pharmacol 161(7):1584–1598. https://doi.org/10.1111/j.1476-5381.2010.00987.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Na Takuathung M, Sakuludomkan W, Koonrungsesomboon N (2021) The impact of genetic polymorphisms on the pharmacokinetics and pharmacodynamics of mycophenolic acid: systematic review and meta-analysis. Clin Pharmacokinet 60(10):1291–1302. https://doi.org/10.1007/s40262-021-01037-7

    Article  CAS  PubMed  Google Scholar 

  35. Djebli N, Picard N, Rerolle JP, Le Meur Y, Marquet P (2007) Influence of the UGT2B7 promoter region and exon 2 polymorphisms and comedications on Acyl-MPAG production in vitro and in adult renal transplant patients. Pharmacogenet Genomics 17(5):321–330. https://doi.org/10.1097/FPC.0b013e32801430f8

    Article  CAS  PubMed  Google Scholar 

  36. Ting LS, Benoit-Biancamano MO, Bernard O, Riggs KW, Guillemette C, Ensom MH (2010) Pharmacogenetic impact of UDP-glucuronosyltransferase metabolic pathway and multidrug resistance-associated protein 2 transport pathway on mycophenolic acid in thoracic transplant recipients: an exploratory study. Pharmacotherapy 30(11):1097–1108. https://doi.org/10.1592/phco.30.11.1097

    Article  CAS  PubMed  Google Scholar 

  37. Pazik J, Oldak M, Lewandowski Z, Podgorska M, Sitarek E, Ploski R, Galazka Z, Kwiatkowski A, Malejczyk J, Durlik M (2013) Uridine diphosphate glucuronosyltransferase 2B7 variant p.His268Tyr as a predictor of kidney allograft early acute rejection. Transplant Proc 45(4):1516–1519. https://doi.org/10.1016/j.transproceed.2013.01.010

  38. Dhaouadi T, Sfar I, Bardi R, Jendoubi-Ayed S, Abdallah TB, Ayed K, Gorgi Y (2013) Cytokine gene polymorphisms in kidney transplantation. Transpl Proc 45(6):2152–2157. https://doi.org/10.1016/j.transproceed.2012.12.006

    Article  CAS  Google Scholar 

  39. Nafar M, Sahraei Z, Salamzadeh J, Samavat S, Vaziri ND (2011) Oxidative stress in kidney transplantation: causes, consequences, and potential treatment. Iran J Kidney Dis 5(6):357–372

    PubMed  Google Scholar 

  40. Djamali A (2007) Oxidative stress as a common pathway to chronic tubulointerstitial injury in kidney allografts. Am J Physiol Renal Physiol 293(2):F445-455. https://doi.org/10.1152/ajprenal.00037.2007

    Article  CAS  PubMed  Google Scholar 

  41. Kim SK, Park HJ, Seok H, Jeon HS, Lee TW, Lee SH, Moon JY, Ihm CG, Kim TH, Kim YH, Kang SW, Park SJ, Jeong KH, Chung J-H (2014) Association studies of cytochrome P450, family 2, subfamily E, polypeptide 1 (CYP2E1) gene polymorphisms with acute rejection in kidney transplantation recipients. Clin Transplant 28(6):707–712. https://doi.org/10.1111/ctr.12369

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pharmacy, The First Affiliated Hospital of Third Military Medical University (Army Medical University), Chongqing, 400038, China

    Lin Cheng, Pu Yao, Bangbi Weng & Qian Wang

  2. Department of Pharmacy, The Affiliated Hospital of North Sichuan Medical College, Nanchong, 637000, China

    Ming Yang

Authors
  1. Lin Cheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Pu Yao
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Bangbi Weng
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ming Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Qian Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

CL: conceptualization, methodology, investigation, data curation, formal analysis, writing; YP, WB: data curation; YM, WQ: writing—review and editing.

Corresponding authors

Correspondence to Ming Yang or Qian Wang.

Ethics declarations

Conflict of interest

The authors declare no competing interests.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (PDF 95 KB)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Cheng, L., Yao, P., Weng, B. et al. Meta-analysis of the associations of IMPDH and UGT1A9 polymorphisms with rejection in kidney transplant recipients taking mycophenolic acid. Eur J Clin Pharmacol 78, 1227–1238 (2022). https://doi.org/10.1007/s00228-022-03311-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00228-022-03311-4

Keywords

Search

Navigation