Skip to main content
SpringerLink
Log in

Distribution of TPMT risk alleles for thioupurine toxicity in the Israeli population

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

Abstract

Background and objective

Individuals with intermediate or no thiopurine S-methyltransferase (TPMT) activity are at risk of hematotoxicity when treated with standard doses of thiopurines, thus, pretreatment identification of these individuals is of major importance. The purpose of this study was to determine the frequency and distribution of TPMT polymorphic variants, known to functionally impair TPMT activity, in the highly heterogeneous Israeli population.

Methods

TPMT genotyping of individuals representing three major demographic groups in Israel was carried out by PCR restriction fragment length polymorphism and high-resolution melting.

Results

Frequencies of TPMT risk alleles differed significantly among the screened Israeli subpopulations: Druze showed fivefold and twofold higher frequencies than Jews and Moslems, respectively. Specifically, allelic frequencies of TPMT*3A were 0.73% (95% CI 0.34-1.45%), 0.79% (95% CI 0.16-2.39%), and 3.19% (95% CI 1.78-5.58%) in Jews, Moslems, and Druze, respectively. Although not found in Jews, TPMT*3C was found at an allelic frequency of 1.05% (95% CI 0.31-2.76%) and 0.75% (95% CI 0.02-2.84%) in Moslems and Druze. TPMT*2 and TPMT*3B were not detected in any of the Israeli subpopulations studied.

Conclusion

These data indicate that the Israeli population displays a distinct TPMT genetic variability that is comprised of a mix of three major genetically diverse subpopulations, each with its unique TPMT allelic frequency distribution pattern and likelihood of developing an adverse reaction to thiopurine drugs.

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

Similar content being viewed by others

References

  1. Sahasranaman S, Howard D, Roy S (2008) Clinical pharmacology and pharmacogenetics of thiopurines. Eur J Clin Pharmacol 64(8):753–767

    Article  PubMed  CAS  Google Scholar 

  2. Krynetski E, Evans WE (2003) Drug methylation in cancer therapy: lessons from the TPMT polymorphism. Oncogene 22(47):7403–7413

    Article  PubMed  CAS  Google Scholar 

  3. Tassaneeyakul W, Srimarthpirom S, Reungjui S, Chansung K, Romphruk A, Tassaneeyakul W (2003) Azathioprine-induced fatal myelosuppression in a renal-transplant recipient who carried heterozygous TPMT*1/*3C. Transplantation 76(1):265–266

    Article  PubMed  Google Scholar 

  4. Slanar O, Chalupna P, Novotny A, Bortlik M, Krska Z, Lukas M (2008) Fatal myelotoxicity after azathioprine treatment. Nucleosides Nucleotides Nucleic Acids 27(6):661–665

    Article  PubMed  CAS  Google Scholar 

  5. Relling MV, Hancock ML, Rivera GK, Sandlund JT, Ribeiro RC, Krynetski EY, Pui CH, Evans WE (1999) Mercaptopurine therapy intolerance and heterozygosity at the thiopurine S-methyltransferase gene locus. J Natl Cancer Inst 91(23):2001–2008

    Article  PubMed  CAS  Google Scholar 

  6. Black AJ, McLeod HL, Capell HA, Powrie RH, Matowe LK, Pritchard SC, Collie-Duguid ES, Reid DM (1998) Thiopurine methyltransferase genotype predicts therapy-limiting severe toxicity from azathioprine. Ann Int Med 129(9):716–718

    PubMed  CAS  Google Scholar 

  7. Evans WE, Hon YY, Bomgaars L, Coutre S, Holdsworth M, Janco R, Kalwinsky D, Keller F, Khatib Z, Margolin J, Murray J, Quinn J, Ravindranath Y, Ritchey K, Roberts W, Rogers ZR, Schiff D, Steuber C, Tucci F, Kornegay N, Krynetski EY, Relling MV (2001) Preponderance of thiopurine S-methyltransferase deficiency and heterozygosity among patients intolerant to mercaptopurine or azathioprine. J Clin Oncol 19(8):2293–2301

    PubMed  CAS  Google Scholar 

  8. Evans WE (2004) Pharmacogenetics of thiopurine S-methyltransferase and thiopurine therapy. Ther Drug Monit 26(2):186–191

    Article  PubMed  CAS  Google Scholar 

  9. Rutherford K, Daggett V (2008) Four human thiopurine s-methyltransferase alleles severely affect protein structure and dynamics. J Mol Biol 379(4):803–814

    Article  PubMed  CAS  Google Scholar 

  10. Pierik M, Rutgeerts P, Vlietinck R, Vermeire S (2006) Pharmacogenetics in inflammatory bowel disease. World J Gastroenterol 12(23):3657–3667

    PubMed  CAS  Google Scholar 

  11. Ganiere-Monteil C, Medard Y, Lejus C, Bruneau B, Pineau A, Fenneteau O, Bourin M, Jacqz-Aigrain E (2004) Phenotype and genotype for thiopurine methyltransferase activity in the French Caucasian population: impact of age. Eur J Clin Pharm 60(2):89–96

    Article  CAS  Google Scholar 

  12. Park-Hah JO, Klemetsdal B, Lysaa R, Choi KH, Aarbakke J (1996) Thiopurine methyltransferase activity in a Korean population sample of children. Clin Pharm Ther 60(1):68–74

    Article  CAS  Google Scholar 

  13. Hiratsuka M, Inoue T, Omori F, Agatsuma Y, Mizugaki M (2000) Genetic analysis of thiopurine methyltransferase polymorphism in a Japanese population. Mutation Res 448(1):91–95

    PubMed  CAS  Google Scholar 

  14. Chang JG, Lee LS, Chen CM, Shih MC, Wu MC, Tsai FJ, Liang DC (2002) Molecular analysis of thiopurine S-methyltransferase alleles in South-east Asian populations. Pharmacogenetics 12(3):191–195

    Article  PubMed  CAS  Google Scholar 

  15. Ameyaw MM, Collie-Duguid ES, Powrie RH, Ofori-Adjei D, McLeod HL (1999) Thiopurine methyltransferase alleles in British and Ghanaian populations. Human Mol Gen 8(2):367–370

    Article  CAS  Google Scholar 

  16. Alves S, Rocha J, Amorim A, Prata MJ (2004) Tracing the origin of the most common thiopurine methyltransferase (TPMT) variants: preliminary data from the patterns of haplotypic association with two CA repeats. Ann Human Gen 68(Pt 4):313–323

    Article  CAS  Google Scholar 

  17. Collie-Duguid ES, Pritchard SC, Powrie RH, Sludden J, Collier DA, Li T, McLeod HL (1999) The frequency and distribution of thiopurine methyltransferase alleles in Caucasian and Asian populations. Pharmacogenetics 9(1):37–42

    Article  PubMed  CAS  Google Scholar 

  18. Hon YY, Fessing MY, Pui CH, Relling MV, Krynetski EY, Evans WE (1999) Polymorphism of the thiopurine S-methyltransferase gene in African-Americans. Human Mol Gen 8(2):371–376

    Article  CAS  Google Scholar 

  19. Jang IJ, Shin SG, Lee KH, Yim DS, Lee MS, Koo HH, Kim HK, Sohn DR (1996) Erythrocyte thiopurine methyltransferase activity in a Korean population. Brit J Clin Pharm 42(5):638–641

    PubMed  CAS  Google Scholar 

  20. Rossi AM, Bianchi M, Guarnieri C, Barale R, Pacifici GM (2001) Genotype-phenotype correlation for thiopurine S-methyltransferase in healthy Italian subjects. Eur J Clin Pharm 57(1):51–54

    Article  CAS  Google Scholar 

  21. Schaeffeler E, Fischer C, Brockmeier D, Wernet D, Moerike K, Eichelbaum M, Zanger UM, Schwab M (2004) Comprehensive analysis of thiopurine S-methyltransferase phenotype-genotype correlation in a large population of German-Caucasians and identification of novel TPMT variants. Pharmacogenetics 14(7):407–417

    Article  PubMed  CAS  Google Scholar 

  22. Zhang JP, Guan YY, Xu AL, Zhou SF, Wu JH, Wei H, Huang M (2004) Gene mutation of thiopurine S-methyltransferase in Uygur Chinese. Eur J Clin Pharm 60(1):1–3

    Article  CAS  Google Scholar 

  23. Kubota T, Chiba K (2001) Frequencies of thiopurine S-methyltransferase mutant alleles (TPMT*2, *3A, *3B and *3C) in 151 healthy Japanese subjects and the inheritance of TPMT*3C in the family of a propositus. Brit J Clin Pharm 51(5):475–477

    Article  PubMed  CAS  Google Scholar 

  24. Zhang JP, Guan YY, Wu JH, Jiang WQ, Huang M (2003) [Genetic polymorphism of the thiopurine S-methyltransferase of healthy Han Chinese]. Aizheng Chin J Cancer 22(4):385–388

    CAS  Google Scholar 

  25. Krynetski EY, Tai HL, Yates CR, Fessing MY, Loennechen T, Schuetz JD, Relling MV, Evans WE (1996) Genetic polymorphism of thiopurine S-methyltransferase: clinical importance and molecular mechanisms. Pharmacogenetics 6(4):279–290

    Article  PubMed  CAS  Google Scholar 

  26. McLeod HL, Krynetski EY, Relling MV, Evans WE (2000) Genetic polymorphism of thiopurine methyltransferase and its clinical relevance for childhood acute lymphoblastic leukemia. Leukemia 14(4):567–572

    Article  PubMed  CAS  Google Scholar 

  27. McLeod HL, Lin JS, Scott EP, Pui CH, Evans WE (1994) Thiopurine methyltransferase activity in American white subjects and black subjects. Clin Pharm Ther 55(1):15–20

    CAS  Google Scholar 

  28. Lowenthal A, Meyerstein N, Ben-Zvi Z (2001) Thiopurine methyltransferase activity in the Jewish population of Israel. Eur J Clin Pharm 57(1):43–46

    Article  CAS  Google Scholar 

  29. Hammer MF, Redd AJ, Wood ET, Bonner MR, Jarjanazi H, Karafet T, Santachiara-Benerecetti S, Oppenheim A, Jobling MA, Jenkins T, Ostrer H, Bonne-Tamir B (2000) Jewish and Middle Eastern non-Jewish populations share a common pool of Y-chromosome biallelic haplotypes. Proc Natl Acad Sci USA 97(12):6769–6774

    Article  PubMed  CAS  Google Scholar 

  30. Schwab M, Schaeffeler E, Marx C, Zanger U, Aulitzky W, Eichelbaum M (2001) Shortcoming in the diagnosis of TPMT deficiency in a patient with Crohn′s disease using phenotyping only. Gastroenterology 121:499–498

    Article  Google Scholar 

  31. Rossino R, Vincis C, Alves S, Prata MJ, Macis MD, Nucaro AL, Schirru E, Congia M (2006) Frequency of the thiopurine S-methyltransferase alleles in the ancient genetic population isolate of Sardinia. J Clin Pharm Ther 31(3):283–287

    Article  PubMed  CAS  Google Scholar 

  32. Boson WL, Romano-Silva MA, Correa H, Falcao RP, Teixeira-Vidigal PV, De Marco L (2003) Thiopurine methyltransferase polymorphisms in a Brazilian population. Pharmacogenomics J 3(3):178–182

    Article  PubMed  CAS  Google Scholar 

  33. Haglund S, Lindqvist M, Almer S, Peterson C, Taipalensuu J (2004) Pyrosequencing of TPMT alleles in a general Swedish population and in patients with inflammatory bowel disease. Clin Chem 50(2):288–295

    Article  PubMed  CAS  Google Scholar 

  34. Kurzawski M, Gawronska-Szklarz B, Drozdzik M (2004) Frequency distribution of thiopurine S-methyltransferase alleles in a Polish population. Ther Drug Monit 26(5):541–545

    Article  PubMed  CAS  Google Scholar 

  35. Milek M, Murn J, Jaksic Z, Lukac Bajalo J, Jazbec J, Mlinaric Rascan I (2006) Thiopurine S-methyltransferase pharmacogenetics: genotype to phenotype correlation in the Slovenian population. Pharmacology 77(3):105–114

    Article  PubMed  CAS  Google Scholar 

  36. Larovere LE, de Kremer RD, Lambooy LH, De Abreu RA (2003) Genetic polymorphism of thiopurine S-methyltransferase in Argentina. Ann Clin Biochem 40(Pt 4):388–393

    Article  PubMed  CAS  Google Scholar 

  37. Isaza C, Henao J, Lopez AM, Cacabelos R (2003) Allelic variants of the thiopurine methyltransferase (TPMT) gene in the Colombian population. Meth Findings Exp Clin Pharmacol 25(6):423–429

    Article  CAS  Google Scholar 

  38. Hamdy SI, Hiratsuka M, Narahara K, Endo N, El-Enany M, Moursi N, Ahmed MS, Mizugaki M (2003) Genotype and allele frequencies of TPMT, NAT2, GST, SULT1A1 and MDR-1 in the Egyptian population. Brit J Clin Pharm 55(6):560–569

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

We wish to thank Prof. Karl Skorecki for helpful comments.

Author information

Authors and Affiliations

  1. Center for Translational Genetics, B. Rappaport Institute for Research in the Medical Sciences, Faculty of Medicine, Technion - Israel Institute of Technology and Rambam Health Care Campus, Haifa, Israel

    Edna Efrati, Lior Adler & Eli Sprecher

  2. Clinical Pharmacology Institute, Division of Medicine, Rambam Health Care Campus, B. Rappaport Institute for Research in the Medical Sciences, Faculty of Medicine, Technion - Israel Institute of Technology Haifa, Haifa, Israel

    Norberto Krivoy

Authors
  1. Edna Efrati
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Lior Adler
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Norberto Krivoy
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Eli Sprecher
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Edna Efrati.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Efrati, E., Adler, L., Krivoy, N. et al. Distribution of TPMT risk alleles for thioupurine toxicity in the Israeli population. Eur J Clin Pharmacol 65, 257–262 (2009). https://doi.org/10.1007/s00228-008-0590-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00228-008-0590-7

Keywords

Search

Navigation