Skip to main content
SpringerLink
Log in

Genetic analysis of thiopurine methyltransferase polymorphism in the Jordanian population

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

Abstract

 

This study provides the first analysis of the TPMT mutant allele frequency in a sample of the Jordanian population and indicates that TPMT*3A is the most common allele in Jordanian subjects.

Purpose

Thiopurine methyltransferase TPMT catalyses the S-methylation of thiopurine drugs such as 6-mercaptopurine, 6-thioguanine, and azathiopurine. Thiopurine methyltransferase (TPMT) polymorphisms are the major determinants of interindividual differences in the severe haematological toxicity of 6-mercaptopurine. Several variants in the TPMT gene have been identified that correlate with a low activity phenotype. Four variant alleles, TPMT*2, TPMT*3A, TPMT*3B and TPMT*3C, are responsible for over 80% of the low or undetectable enzyme activity. The allelic frequency of TPMT variants has been established in many populations.

Methods

In this study, the frequencies of four (TPMT*2, TPMT*3A, TPMT*3B and TPMT*3C) variants were investigated in 169 healthy Jordanian men (18–45 years of age). Single nucleotide polymorphisms (SNPs) were genotyped using the Sequenom® MassARRAY technology (Sequenom®; San Diego, CA, USA).

Results

TPMT*3A and TPMT*3C were the only deficiency alleles detected in the Jordanian population with an allele frequency of 0.59% and 0.30% respectively. The TPMT*3A allele frequency is found to be lower than in the European Caucasian population.

Conclusion

TPMT*3A and TPMT*3C were the only deficiency alleles detected in the Jordanian population with an allele frequency of 0.59% and 0.30% respectively. The TPMT*3A allele frequency is found to be lower than in the European Caucasian population.

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

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 64:753–767

    Article  CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  3. Rutherford K, Daggett V (2008) Four human thiopurine smethyltransferase alleles severely affect protein structure and dynamics. J Mol Biol 379:803–814

    Article  CAS  PubMed  Google Scholar 

  4. Fargher EA, Tricker K, Newman W, Elliott R, Roberts SR, Shaffer HL, Bruce I, Payne K (2007) Current use of pharmacogenetic testing: a national survey of thiopurine methyltransferase testing prior to azathioprine prescription. J Clin Pharm Ther 32:187–195

    Article  CAS  PubMed  Google Scholar 

  5. McLeod HL, Lin JS, Scott EP, Pui CH, Evans WE (1194) Thiopurine methyltransferase activity in American white subjects and black subjects. Clin Pharmacol Ther 55:15–20

    Article  Google Scholar 

  6. Kham SK, Soh CK, Aw DC, Yeoh AE (2009) TPMT*26 (208F–>L), a novel mutation detected in a Chinese. Br J Clin Pharmacol 68(1):120–123

    Article  CAS  PubMed  Google Scholar 

  7. Yates CR, Krynetski EY, Loennechen T (1997) Molecular diagnosis of thiopurine S-methyl transferase deficiency: genetic basis for azathioprine and mercaptopurine intolerance. Ann Intern Med 126:608–616

    CAS  PubMed  Google Scholar 

  8. 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 14:407–417

    Article  CAS  PubMed  Google Scholar 

  9. Tai HL, Krynetski EY, Yates CR, Loennechen T, Fessing MY, Krynetskaia NF, Evans WE (1996) Thiopurine S-methyltransferase deficiency: two nucleotide transitions define the most prevalent mutant allele associated with loss of catalytic activity in Caucasians. Am J Hum Genet 58:694–702

    CAS  PubMed  Google Scholar 

  10. 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 8:371–376

    Article  CAS  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  Google Scholar 

  14. 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 60:1–3

    Article  Google Scholar 

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

    Article  CAS  Google Scholar 

  16. Efrati E, Adler L, Krivoy N, Sprecher E (2009) Distribution of TPMT risk alleles for thioupurine toxicity in the Israeli population. Eur J Clin Pharmacol 65:257–262

    Article  CAS  PubMed  Google Scholar 

  17. 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. Br J Clin Pharm 55:560–569

    Article  CAS  Google Scholar 

  18. 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 Pharmacol 60:89–96

    Article  CAS  PubMed  Google Scholar 

  19. 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 57:51–54

    Article  CAS  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  21. Wei H, Zhou S, Li C, Zhang J, Wu J, Huang M (2005) Phenotyping and genotyping studies of thiopurine S-methyltransferase in Kazaks. Pharm Res 22:1762–1766

    Article  CAS  PubMed  Google Scholar 

  22. 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 Hum Genet 68:313–323

    Article  CAS  PubMed  Google Scholar 

  23. 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  CAS  PubMed  Google Scholar 

  24. Samochatova EV, Chupova NV, Rudneva A, Makarova O, Nasedkina TN, Fedorova OE et al (2008) TPMT genetic variations in populations of the Russian Federation. Pediatr Blood Cancer 52:203–208

    Article  Google Scholar 

  25. 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 77:105–114

    Article  CAS  PubMed  Google Scholar 

  26. 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 50:288–295

    Article  CAS  PubMed  Google Scholar 

  27. 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 12:191–195

    Article  CAS  PubMed  Google Scholar 

  28. Tumer TB, Ulusoy G, Adali O, Sahin G, Gozdasoglu S, Arinc E (2007) The low frequency of defective TPMT alleles in Turkish population: a study on pediatric patients with acute lymphoblastic leukemia. Am J Hematol 82:906–910

    Article  CAS  PubMed  Google Scholar 

  29. 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 9:37–42

    Article  CAS  PubMed  Google Scholar 

  30. Sánchez-Velasco P, Karadsheh NS, García-Martín A, de Alegría CR, Leyva-Cobián F (2001) Molecular analysis of HLA allelic frequencies and haplotypes in Jordanians and comparison with other related populations. Hum Immunol 62:901–909

    Article  PubMed  Google Scholar 

  31. Oliveira E, Quental S, Alves S, Amorim A, Prata MJ (2007) Do the distribution patterns of polymorphisms at the thiopurine S-methyltransferase locus in sub-Saharan populations need revision? Hints from Cabinda and Mozambique. Eur J Clin Pharmacol 63:703–706

    Article  CAS  PubMed  Google Scholar 

  32. Banerjee B, Saha N, Daoud ZF, Khalaf FH, Qudah H (1981) A genetic study of the Jordanians. Hum Hered 31:65–69

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

Funding for this study was provided by the Department of Health Pharmacogenetics Initiative (TARGET study) Ref. PHGX09A. The Newman laboratory is supported by the Manchester Academic Health Sciences Centre (MAHSC) and the NIHR Manchester Biomedical Research Centre.

Author information

Authors and Affiliations

  1. Faculty of Pharmacy, University of Jordan, Amman, 11942, Jordan

    Nancy Hakooz

  2. Jordan Center for Pharmaceutical Research, Amman, 11195, Jordan

    Tawfiq Arafat

  3. Centre for Integrated Genomic Medical Research (CIGMR), University of Manchester, Manchester, UK

    Debbie Payne & William Ollier

  4. Medical Genetics, Manchester Academic Health Sciences Centre (MAHSC), St Mary’s Hospital, University of Manchester, Manchester, UK

    Sudeep Pushpakom & William Newman

  5. School of Pharmacy, University of Manchester, Manchester, UK

    Julie Andrews

Authors
  1. Nancy Hakooz
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Tawfiq Arafat
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Debbie Payne
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. William Ollier
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Sudeep Pushpakom
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Julie Andrews
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. William Newman
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Nancy Hakooz.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hakooz, N., Arafat, T., Payne, D. et al. Genetic analysis of thiopurine methyltransferase polymorphism in the Jordanian population. Eur J Clin Pharmacol 66, 999–1003 (2010). https://doi.org/10.1007/s00228-010-0826-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00228-010-0826-1

Keywords

Search

Navigation