Skip to main content

Advertisement

SpringerLink
Log in

TPMT but not ITPA gene polymorphism influences the risk of azathioprine intolerance in renal transplant recipients

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

Abstract

Purpose

Thiopurine drugs have to be withdrawn in 10–30% of cases due to side effects, and it has been presented that genetic factors may be responsible for some of reported toxicity cases. Among polymorphic enzymes of thiopurines’ metabolic pathway, thiopurine S-methyltransferase (TPMT) has been studied most extensively, and some recent studies point to inosine triphosphate pyrophosphohydrolase (ITPA) polymorphism as an additional toxicity risk factor.

Methods

The aim of the current study was to evaluate an association between TPMT and ITPA gene polymorphisms and drug intolerance in a cohort of 157 renal transplant recipients treated with azathioprine (AZA). Each subject was genotyped for the presence of variant TPMT (*2, *3A, *3B, and *3C) and ITPA (94C>A and IVS2+21A>C) alleles.

Results

Mean AZA dose, mean white-blood-cell count, and platelet count in the course of treatment were lower in carriers of variant TPMT alleles compared to patients with TPMT wild-type genotype. Leukocyte numbers fell below 4.0 × 109/L in 41.2% of TPMT heterozygous renal transplant recipients, compared to only 18.0% of wild-type patients (P < 0.01). In contrast, ITPA genotype did not influence AZA dose, hematological parameters, or leucopenia risk.

Conclusions

Our results suggest that routine genotyping of renal transplant recipients for TPMT variants may be useful in reducing the risk of AZA-related myelotoxicity, but there is not enough evidence to introduce ITPA testing into clinical practice.

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

References

  1. Gardiner SJ, Begg EJ, Barclay ML, Kirkpatrick CM (2000) Genetic polymorphism and outcomes with azathioprine and 6-mercaptopurine. Adverse Drug React Toxicol Rev 19:293–312

    PubMed  CAS  Google Scholar 

  2. McLeod HL, Siva C (2002) The thiopurine S-methyltransferase gene locus – implication for clinical pharmacogenomics. Pharmacogenomics 3:89–98

    Article  PubMed  CAS  Google Scholar 

  3. Lennard L, Gibson BES, Nicole T, Lilleyman JS (1993) Congenital thiopurine methyltransferase deficiency and 6-mercaptopurine toxicity during treatment for acute lymphoblastic leukaemia. Arch Dis Child 69:577–579

    Article  PubMed  CAS  Google Scholar 

  4. Krynetski EY, Evans WE (1996) Genetic polymorphism of thiopurine S-methyltransferase: clinical importance and molecular mechanisms. Pharmacogenetics 6:279–290

    Article  PubMed  CAS  Google Scholar 

  5. Weinshilboum R, Sladek S (1980) Mercaptopurine pharmacogenetics: monogenic inheritance of erythrocyte thiopurine methyltransferase activity. Am J Hum Genet 32:651–662

    PubMed  CAS  Google Scholar 

  6. Kurzawski M, Chrzanowska M, Kuehn M, Januszkiewicz-Lewandowska D, Oko A, Peregud-Pogorzelski J et al (2007) Thiopurine S-methyltransferase (TPMT) pharmacogenetics: risk of genetically determined intolerance of thiopurine drugs in a Polish population. Probl Ter Monitorowanej 18:21–27

    Google Scholar 

  7. Zhou S (2006) Clinical pharmacogenomics of thiopurine S-methyltransferase. Curr Clin Pharmacol 1:119–128

    PubMed  CAS  Google Scholar 

  8. von Ahsen N, Oellerich M, Armstrong VW (2008) Characterization of the inosine triphosphatase (ITPA) gene: haplotype structure, haplotype-phenotype correlation and promoter function. Ther Drug Monit 30:16–22

    Article  CAS  Google Scholar 

  9. Sumi S, Marinaki AM, Arenas M, Fairbanks L, Shobowale-Bakre M, Rees DC et al (2002) Genetic basis of inosine triphosphate pyrophosphohydrolase deficiency. Hum Genet 111:360–367

    Article  PubMed  CAS  Google Scholar 

  10. Atanasova S, Shipkova M, Svinarov D, Mladenova A, Genova M, Wieland E et al (2007) Analysis of ITPA phenotype-genotype correlation in the Bulgarian population revealed a novel gene variant in exon 6. Ther Drug Monit 29:6–10

    Article  PubMed  CAS  Google Scholar 

  11. Kurzawski M, Dziewanowski K, Gawrońska-Szklarz B, Domański L, Droździk M (2005) The impact of thiopurine S-methyltransferase polymorphism on azathioprine-induced myelotoxicity in renal transplant recipients. Ther Drug Monit 27:435–441

    Article  PubMed  CAS  Google Scholar 

  12. Kurzawski M, Gawronska-Szklarz B, Drozdzik M (2004) Frequency distribution of thiopurine S-methyltransferase alleles in a Polish population. Ther Drug Monit 26:541–545

    Article  PubMed  CAS  Google Scholar 

  13. Marinaki AM, Ansari A, Duley JA, Arenas M, Sumi S, Lewis CM et al (2004) Adverse drug reactions to azathioprine therapy are associated with polymorphism in the gene encoding inosine triphosphate pyrophosphatase (ITPase). Pharmacogenetics 14:181–187

    Article  PubMed  CAS  Google Scholar 

  14. Evans WE, Hon YY, Bomgaars L, Coutre S, Holdsworth M, Janco R et al (2001) Preponderance of thiopurine S-methyltransferase deficiency and heterozygosity among patients intolerant to mercaptopurine or azathioprine. J Clin Oncol 19:2293–2301

    PubMed  CAS  Google Scholar 

  15. Fabre MA, Jones DC, Bunce M, Morris PJ, Friend PJ, Welsh KI et al (2004) The impact of thiopurine S-methyltransferase polymorphisms on azathioprine dose 1 year after renal transplantation. Transpl Int 17:531–539

    Article  PubMed  CAS  Google Scholar 

  16. Zelinkova Z, Derijks LJ, Stokkers PC, Vogels EW, van Kampen AH, Curvers WL et al (2006) Inosine triphosphate pyrophosphatase and thiopurine S-methyltransferase genotypes relationship to azathioprine-induced myelosuppression. Clin Gastroenterol Hepatol 4:44–49

    Article  PubMed  CAS  Google Scholar 

  17. Ansari A, Arenas M, Greenfield SM, Morris D, Lindsay J, Gilshenan K et al (2008) Prospective evaluation of the pharmacogenetics of azathioprine in the treatment of inflammatory bowel disease. Aliment Pharmacol Ther 28:973–983

    Article  PubMed  CAS  Google Scholar 

  18. Gearry RB, Roberts RL, Barclay ML, Kennedy MA (2004) Lack of association between the ITPA 94C>A polymorphism and adverse effects from azathioprine. Pharmacogenetics 14:779–781

    Article  PubMed  CAS  Google Scholar 

  19. Allorge D, Hamdan R, Broly F, Libersa C, Colombel JF (2005) ITPA genotyping test does not improve detection of Crohn’s disease patients at risk of azathioprine/6-mercaptopurine induced myelosuppression. Gut 54:565

    Article  PubMed  CAS  Google Scholar 

  20. van Dieren JM, van Vuuren AJ, Kusters JG, Nieuwenhuis EE, Kuipers EJ, van der Woude CJ (2005) ITPA genotyping is not predictive for the development of side effects in AZA treated inflammatory bowel disease patients. Gut 54:1664

    PubMed  Google Scholar 

  21. von Ahsen N, Armstrong VW, Behrens C, von Tirpitz C, Stallmach A, Herfarth H et al (2005) Association of inosine triphosphatase 94C>A and thiopurine S-methyltransferase deficiency with adverse events and study drop-outs under azathioprine therapy in a prospective Crohn disease study. Clin Chem 51:2282–2288

    Article  CAS  Google Scholar 

  22. Stocco G, Cheok M, Crews K, Dervieux T, French D, Pei D et al (2008) Genetic polymorphism of iInosine triphosphate pyrophosphatase is a determinant of mercaptopurine metabolism and toxicity during treatment for acute lymphoblastic leukemia. Clin Pharmacol Ther doi:10.1038/clpt.2008.154

  23. De Ridder L, Van Dieren JM, Van Deventer HJ, Stokkers PC, Van der Woude JC, Van Vuuren AJ et al (2006) Pharmacogenetics of thiopurine therapy in paediatric IBD patients. Aliment Pharmacol Ther 23:1137–1141

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

Dr. Mateusz Kurzawski is supported in part by The Foundation for Polish Science (Warsaw, Poland).

Author information

Authors and Affiliations

  1. Department of Pharmacology, Pomeranian Medical University, Powstancow Wlkp. 72, 70-111, Szczecin, Poland

    Mateusz Kurzawski, Agnieszka Lener & Marek Drozdzik

  2. Clinical Department of Nephrology and Dialysis, Regional Hospital, Szczecin, Poland

    Krzysztof Dziewanowski

Authors
  1. Mateusz Kurzawski
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Krzysztof Dziewanowski
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Agnieszka Lener
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Marek Drozdzik
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Mateusz Kurzawski.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kurzawski, M., Dziewanowski, K., Lener, A. et al. TPMT but not ITPA gene polymorphism influences the risk of azathioprine intolerance in renal transplant recipients. Eur J Clin Pharmacol 65, 533–540 (2009). https://doi.org/10.1007/s00228-009-0630-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00228-009-0630-y

Keywords

Search

Navigation