Thiopurine S-methyltransferase Activity in Three Major Asian Populations: a Population-based Study in Singapore

Overview

Journal Eur J Clin Pharmacol

Specialty Pharmacology

Date 2008 Jan 15

PMID 18193212

Citations 19

Authors

Shirley Kow Yin Kham

Chin Kok Soh

Te Chih Liu

Yiong Huak Chan

Hany Ariffin

Poh Lin Tan

Allen Eng Juh Yeoh

Affiliations

Soon will be listed here.

Abstract

Objective: The distribution of thiopurine methyltransferase (TPMT) activity in Asian populations has not been well documented. We studied the TPMT phenotype in three major Asian ethnic groups in Singapore, namely the Chinese (Ch), Malays (Mal) and Indians (Ind), with the aim of carrying out a comprehensive survey of the distribution of TPMT activity in Asians.

Methods: A radiochemical assay was used to measure the enzymatic activity of TPMT in the red blood cells (RBCs) of 479 healthy adults (Ch=153, Mal=163 and Ind=163). Cut-off points for intermediate TPMT activity were validated using a receiver operating curve (ROC) analysis. PCR-based methods were used to screen for the TPMT*3C, TPMT*3A and TPMT*6 variants.

Results: The histogram of the combined population cohort showed a bimodal distribution of TPMT activity, with no subject having low TPMT activity (<5 units). In total, TPMT variants were detected in 14 subjects (*1/*3C in 13 subjects; *1/*3A in one subject). We observed significant inter-ethnic differences in terms of TPMT activity (p<0.001), with the Malays showing a higher median activity than the Chinese or Indians (17.8 units vs 16.4 units). The Malays also showed a higher methylation rate--with a cut-off point for intermediate TPMT activity of 11.3 units--than the Chinese (9.9 units) or Indians (9.4 units). A high phenotype-genotype correlation of >97% was observed in all three races. We also genotyped 418 childhood leukaemias. The combined analysis of subjects participating in this and a previous study--1585 subjects--showed that 4.7% of Chinese (n=30/644), 4.4% of Malays (n=24/540) and 2.7% of Indians (n=11/401) were heterozygous at the TPMT gene locus.

Conclusion: This is the first comprehensive TPMT phenotype and genotype study in Asian populations, particularly in the Malays and Indians.

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References

Weinshilboum R, Raymond F, Pazmino P . Human erythrocyte thiopurine methyltransferase: radiochemical microassay and biochemical properties. Clin Chim Acta. 1978; 85(3):323-33. DOI: 10.1016/0009-8981(78)90311-x. View

Lennard L . The clinical pharmacology of 6-mercaptopurine. Eur J Clin Pharmacol. 1992; 43(4):329-39. DOI: 10.1007/BF02220605. View

Otterness D, Szumlanski C, Lennard L, Klemetsdal B, Aarbakke J, Iven H . Human thiopurine methyltransferase pharmacogenetics: gene sequence polymorphisms. Clin Pharmacol Ther. 1997; 62(1):60-73. DOI: 10.1016/S0009-9236(97)90152-1. View

Krynetski E, Evans W . Drug methylation in cancer therapy: lessons from the TPMT polymorphism. Oncogene. 2003; 22(47):7403-13. DOI: 10.1038/sj.onc.1206944. View

Jang I, Shin S, Lee K, Yim D, Lee M, Koo H . Erythrocyte thiopurine methyltransferase activity in a Korean population. Br J Clin Pharmacol. 1996; 42(5):638-41. DOI: 10.1111/j.1365-2125.1996.tb00122.x. View

Weinshilboum R, Sladek S . Mercaptopurine pharmacogenetics: monogenic inheritance of erythrocyte thiopurine methyltransferase activity. Am J Hum Genet. 1980; 32(5):651-62. PMC: 1686086. View

Mason M, Currey H, Barnes C, Dunne J, Hazleman B, Strickland I . Azathioprine in rheumatoid arthritis. Br Med J. 1969; 1(5641):420-2. PMC: 1981902. DOI: 10.1136/bmj.1.5641.420. View

Chang J, Lee L, Chen C, Shih M, Wu M, Tsai F . Molecular analysis of thiopurine S-methyltransferase alleles in South-east Asian populations. Pharmacogenetics. 2002; 12(3):191-5. DOI: 10.1097/00008571-200204000-00003. View

Salavaggione O, Wang L, Wiepert M, Yee V, Weinshilboum R . Thiopurine S-methyltransferase pharmacogenetics: variant allele functional and comparative genomics. Pharmacogenet Genomics. 2005; 15(11):801-15. DOI: 10.1097/01.fpc.0000174788.69991.6b. View

10.

Tai H, Krynetski E, Yates C, Loennechen T, Fessing M, Krynetskaia N . 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. 1996; 58(4):694-702. PMC: 1914689. View

11.

Relling M, Hancock M, Rivera G, Sandlund J, Ribeiro R, Krynetski E . Mercaptopurine therapy intolerance and heterozygosity at the thiopurine S-methyltransferase gene locus. J Natl Cancer Inst. 1999; 91(23):2001-8. DOI: 10.1093/jnci/91.23.2001. View

12.

Kham S, Tan P, Tay A, Heng C, Yeoh A, Quah T . Thiopurine methyltransferase polymorphisms in a multiracial asian population and children with acute lymphoblastic leukemia. J Pediatr Hematol Oncol. 2002; 24(5):353-9. DOI: 10.1097/00043426-200206000-00006. View

13.

Reis M, Santoro A, Suarez-Kurtz G . Thiopurine methyltransferase phenotypes and genotypes in Brazilians. Pharmacogenetics. 2003; 13(6):371-3. DOI: 10.1097/00008571-200306000-00009. View

14.

Kubota T, Nishida A, Takeuchi K, Iida T, Yokota H, Higashi K . Frequency distribution of thiopurine S-methyltransferase activity in red blood cells of a healthy Japanese population. Ther Drug Monit. 2004; 26(3):319-21. DOI: 10.1097/00007691-200406000-00017. View

15.

Lu H, Shih M, Chang Y, Chang J, Ko Y, Chang S . Molecular analysis of thiopurine S-methyltransferase alleles in Taiwan aborigines and Taiwanese. J Clin Pharm Ther. 2006; 31(1):93-8. DOI: 10.1111/j.1365-2710.2006.00707.x. View

16.

Fessing M, Krynetski E, Zambetti G, Evans W . Functional characterization of the human thiopurine S-methyltransferase (TPMT) gene promoter. Eur J Biochem. 1998; 256(3):510-7. DOI: 10.1046/j.1432-1327.1998.2560510.x. View

17.

Tiede I, Fritz G, Strand S, Poppe D, Dvorsky R, Strand D . CD28-dependent Rac1 activation is the molecular target of azathioprine in primary human CD4+ T lymphocytes. J Clin Invest. 2003; 111(8):1133-45. PMC: 152932. DOI: 10.1172/JCI16432. View

18.

Rossi A, Bianchi M, Guarnieri C, Barale R, Pacifici G . Genotype-phenotype correlation for thiopurine S-methyltransferase in healthy Italian subjects. Eur J Clin Pharmacol. 2001; 57(1):51-4. DOI: 10.1007/s002280000246. View

19.

Jun J, Cho D, Kang C, Bae S . Thiopurine S-methyltransferase polymorphisms and the relationship between the mutant alleles and the adverse effects in systemic lupus erythematosus patients taking azathioprine. Clin Exp Rheumatol. 2006; 23(6):873-6. View

20.

Evans W, Hon Y, Bomgaars L, Coutre S, Holdsworth M, Janco R . Preponderance of thiopurine S-methyltransferase deficiency and heterozygosity among patients intolerant to mercaptopurine or azathioprine. J Clin Oncol. 2001; 19(8):2293-301. DOI: 10.1200/JCO.2001.19.8.2293. View