Pharmacogenetics of Thiopurine Drugs: Role of Thiopurine S-Methyltransferase and Nucleoside Diphosphate-Linked Moiety X Motif 15 Genetic Polymorphisms on Drugs-induced Myelosuppression
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Published:
Jun 30, 2019
Keywords:
myelosupression thiopurine S-methyltransferase (TPMT) nucleoside diphosphate–linked moiety X-type motif 15 (NUDT15) 6 -mercaptopurine (6-MP) azathioprine (AZA) 6-thioguanine (6-TG)
Main Article Content
Abstract
ยากลุ่ม thiopurines ได้แก่ 6-mercaptopurine (6-MP), 6-thioguanine (6-TG) และ azathioprine (AZA) เป็นยาที่ใช้อย่างแพร่หลายในการรักษาโรคมะเร็ง เช่น มะเร็งเม็ดเลือดขาวเฉียบพลันชนิดลิมโฟบลาสติก มะเร็งเม็ดเลือดขาวเรื้อรังชนิดมัยอีลอยด์ มะเร็งเม็ดเลือดขาวเฉียบพลันชนิดมัยอีลอยด์ มะเร็งต่อมน้ำเหลือง รวมไปถึงใช้ในการรักษาโรคภูมิต้านเนื้อเยื่อของตนเองและโรคที่เกิดจากการอักเสบ อย่างไรก็ตาม เป็นที่ทราบกันดีว่ายาในกลุ่มนี้ทำให้เกิดพิษรุนแรง โดยเฉพาะอย่างยิ่งภาวะกดไขกระดูก ปัจจุบัน มีรายงานว่าความหลากหลายทางพันธุกรรมของยีน thiopurine S-methyltransferase (TPMT) และ nucleoside diphosphate-linked moiety X-type motif 15 (NUDT15) มีความสัมพันธ์อย่างมากกับการเกิดภาวะกดไขกระดูกของยากลุ่มนี้ ซึ่ง TPMT และ NUDT15 เป็นเอนไซม์หลักที่เกี่ยวข้องในกระบวนการเมแทบอลิซึม ของยา thiopurines บทความนี้เป็นการทบทวนวรรณกรรมเกี่ยวกับความหลากหลายทางพันธุกรรมของเอนไซม์เหล่านี้ และความสัมพันธ์กับการเกิดภาวะกดไขกระดูกของยากลุ่ม thiopurines โดยเน้นถึงความแตกต่างกันในประชากรแต่ละเชื้อชาติ
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References
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6. Kakuta Y, Kinouchi Y, Shimosegawa T. Pharmacogenetics of thiopurines for inflammatory bowel disease in East Asia: prospects for clinical application of NUDT15 genotyping. J Gastroenterol. 2018 Feb;53(2):172-80.
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8. Ameyaw MM, Collie-Duguid ES, Powrie RH, Ofori-Adjei D, McLeod HL. Thiopurine methyltransferase alleles in British and Ghanaian populations. Hum Mol Genet. 1999 Feb;8(2):367-70.
9. Salavaggione OE, Wang L, Wiepert M, Yee VC, Weinshilboum RM. Thiopurine S-methyltransferase pharmacogenetics: variant allele functional and comparative genomics. Pharmacogenet Genomics. 2005 Nov;15(11):801-15.
10. Wang L, Pelleymounter L, Weinshilboum R, Johnson JA, Hebert JM, Altman RB, et al. Very important pharmacogene summary: thiopurine S-methyltransferase. Pharmacogenet Genomics. 2010 Jun;20(6):401-5.
11. Kumagai K, Hiyama K, Ishioka S, Sato H, Yamanishi Y, McLeod HL, et al. Allelotype frequency of the thiopurine methyltransferase (TPMT) gene in Japanese. Pharmacogenetics. 2001 Apr;11(3):275-8.
12. Chang JG, Lee LS, Chen CM, Shih MC, Wu MC, Tsai FJ, et al. Molecular analysis of thiopurine S-methyltransferase alleles in South-east Asian populations. Pharmacogenetics. 2002 Apr;12(3):191-5.
13. Collie-Duguid ES, Pritchard SC, Powrie RH, Sludden J, Collier DA, Li T, et al. The frequency and distribution of thiopurine methyltransferase alleles in Caucasian and Asian populations. Pharmacogenetics. 1999 Feb;9(1):37-42.
14. Cheon JH, Kim JH, Kim BY, Kim SW, Hong SY, Eun CS, et al. Allele frequency of thiopurine methyltransferase and inosine triphosphate pyro-phosphatase gene polymorphisms in Korean patients with inflammatory bowel diseases. Hepatogastroenterology. 2009 Mar-Apr;56(90):421-3.
15. Spire-Vayron de la Moureyre C, Debuysere H, Mastain B, Vinner E, Marez D, Lo Guidice JM, et al. Genotypic and phenotypic analysis of the polymorphic thiopurine S-methyltransferase gene (TPMT) in a European population. Br J Pharmacol. 1998 Oct;125(4):879-87.
16. Relling MV, Gardner EE, Sandborn WJ, Schmiegelow K, Pui CH, Yee SW, et al. Clinical Pharmacogenetics Implementation Consortium guidelines for thiopurine methyltransferase genotype and thiopurine dosing. Clin Pharmacol Ther. 2011 Mar;89(3):387-91.
17. Lennard L, Van Loon JA, Lilleyman JS, Weinshilboum RM. Thiopurine pharmaco- genetics in leukemia: correlation of erythrocyte thiopurine methyltransferase activity and 6-thioguanine nucleotide concentrations. Clin Pharmacol Ther. 1987 Jan;41(1):18-25.
18. Lennard L, Lilleyman JS, Van Loon J, Weinshilboum RM. Genetic variation in response to 6-mercaptopurine for childhood acute lymphoblastic leukaemia. Lancet. 1990 Jul 28;336(8709):225-9.
19. Evans WE, Horner M, Chu YQ, Kalwinsky D, Roberts WM. Altered mercapto-purine metabolism, toxic effects, and dosage requirement in a thiopurine methyltransferase-deficient child with acute lymphocytic leukemia. J Pediatr. 1991 Dec;119(6):985-9.
20. Lennard L, Gibson BE, Nicole T, Lilleyman JS. Congenital thiopurine methyl-transferase deficiency and 6-mercaptopurine toxicity during treatment for acute lymphoblastic leukaemia. Arch Dis Child. 1993 Nov;69(5):577-9.
21. McLeod HL, Miller DR, Evans WE. Azathioprine-induced myelosuppression in thiopurine methyltransferase deficient heart transplant recipient. Lancet. 1993 May 1;341(8853):1151.
22. Relling MV, Hancock ML, Rivera GK, Sandlund JT, Ribeiro RC, Krynetski EY, et al. Mercaptopurine therapy intolerance and heterozygosity at the thiopurine S-methyltransferase gene locus. J Natl Cancer Inst. 1999 Dec 1;91(23):2001-8.
23. McLeod HL, Coulthard S, Thomas AE, Pritchard SC, King DJ, Richards SM, et al. Analysis of thiopurine methyltransferase variant alleles in childhood acute lymphoblastic leukaemia. Br J Haematol. 1999 Jun;105(3):696-700.
24. Evans WE, Hon YY, Bomgaars L, Coutre S, Holdsworth M, Janco R, et al. Preponderance of thiopurine S-methyltransferase deficiency and heterozygosity among patients intolerant to mercaptopurine or azathioprine. J Clin Oncol. 2001 Apr15;19(8):2293-301.
25. Lennard L, Cartwright CS, Wade R, Vora A. Thiopurine dose intensity and treatment outcome in childhood lymphoblastic leukaemia: the influence of thiopurine methyltransferase pharmacogenetics. Br J Haematol. 2015 Apr;169(2):228-40.
26. Srimartpirom S. Genetic polymorphism of thiopurine S-methyltransferase in a northeastern Thai population [master's thesis]. Khon Kaen, Khon Kaen University; 2002.
27. Schutz E, Gummert J, Mohr FW, Armstrong VW, Oellerich M. Should 6-thioguanine nucleotides be monitored in heart transplant recipients given azathioprine? Ther Drug Monit. 1996 Jun;18(3):228-33.
28. Vannaprasaht S, Angsuthum S, Avihingsanon Y, Sirivongs D, Pongskul C, Makarawate P, et al. Impact of the heterozygous TPMT*1/*3C genotype on azathioprine-induced myelosuppression in kidney transplant recipients in Thailand. Clin Ther. 2009 Jul;31(7):1524-33.
29. Snow JL, Gibson LE. The role of genetic variation in thiopurine methyl-transferase activity and the efficacy and/or side effects of azathioprine therapy in dermatologic patients. Arch Dermatol. 1995 Feb;131(2):193-7.
30. Stolk JN, Boerbooms AM, de Abreu RA, de Koning DG, van Beusekom HJ, Muller WH, et al. Reduced thiopurine methyltransferase activity and development of side effects of azathioprine treatment in patients with rheumatoid arthritis. Arthritis Rheum. 1998 Oct;41(10):1858-66.
31. Takatsu N, Matsui T, Murakami Y, Ishihara H, Hisabe T, Nagahama T, et al. Adverse reactions to azathioprine cannot be predicted by thiopurine S-methyl-transferase genotype in Japanese patients with inflammatory bowel disease. J Gastroenterol Hepatol. 2009 July;24(7):1258-64.
32. Zhu X, Wang XD, Chao K, Zhi M, Zheng H, Ruan HL, et al. NUDT15 polymorphisms are better than thiopurine S-methyltransferase as predictor of risk for thiopurine-induced leukopenia in Chinese patients with Crohn's disease. Aliment Pharmacol Ther. 2016 Nov;44(9):967-75.
33. Vora A, Mitchell CD, Lennard L, Eden TO, Kinsey SE, Lilleyman J, et al. Toxicity and efficacy of 6-thioguanine versus 6-mercaptopurine in childhood lymphoblastic leukaemia: a randomised trial. Lancet. 2006 Oct 14;368(9544): 1339-48.
34. Erb N, Harms DO, Janka-Schaub G. Pharmacokinetics and metabolism of thio-purines in children with acute lymphoblastic leukemia receiving 6-thioguanine versus 6-mercaptopurine. Cancer Chemother Pharmacol. 1998;42(4):266-72.
35. McBride KL, Gilchrist GS, Smithson WA, Weinshilboum RM, Szmulanski C. Severe 6-thioguanine-induced marrow aplasia in a child with acute lymphoblastic leukemia and inherited thiopurine methyltransferase deficiency. J Pediatr Hematol Oncol. 2000 Sep-Oct;22(5):441-5.
36. Maki H, Sekiguchi M. MutT protein specifically hydrolyses a potent mutagenic substrate for DNA synthesis. Nature. 1992 Jan 16;355(6357):273-5.
37. Khaeso Kanyarat, Komwilaisak Patcharee, Nakkam Nontaya, Kanjanawart Sirimas, Vannaprasaht Suda, Tassaneeyakul W. Genetic polymorphism of Genes involved in 6-mercaptopurine-induced hematopoietic toxicity in Thai children with acute lymphoblastic leukemia. In: Phumala Morales Noppawan, Pornpun V, editors. The 40th Pharmacological and Therapeutic Society of Thailand Meeting; 2018 April 26-28; Faculty of Science, Mahidol University, Bangkok, Thailand; 2018. p. 40-8.
38. Chiengthong K, Ittiwut C, Muensri S, Sophonphan J, Sosothikul D, Seksan P, et al. NUDT15 c.415C>T increases risk of 6-mercaptopurine induced myelo-suppression during maintenance therapy in children with acute lymphoblastic leukemia. Haematologica. 2016 Jan;101(1):e24-6.
39. Yang JJ, Landier W, Yang W, Liu C, Hageman L, Cheng C, et al. Inherited NUDT15 variant is a genetic determinant of mercaptopurine intolerance in children with acute lymphoblastic leukemia. J Clin Oncol. 2015 Apr 10;33(11):1235-42.
40. Yang SK, Hong M, Baek J, Choi H, Zhao W, Jung Y, et al. A common missense variant in NUDT15 confers susceptibility to thiopurine-induced leukopenia. Nat Genet. 2014 Sep;46(9):1017-20.
41. Tanaka Y, Kato M, Hasegawa D, Urayama KY, Nakadate H, Kondoh K, et al. Susceptibility to 6-MP toxicity conferred by a NUDT15 variant in Japanese children with acute lymphoblastic leukaemia. Br J Haematol. 2015 Oct;171(1): 109-15.
42. Lee YJ, Hwang EH, Park JH, Shin JH, Kang B, Kim SY. NUDT15 variant is the most common variant associated with thiopurine-induced early leukopenia and alopecia in Korean pediatric patients with Crohn's disease. Eur J Gastroenterol Hepatol. 2016 Apr;28(4):475-8.
43. Asada A, Nishida A, Shioya M, Imaeda H, Inatomi O, Bamba S, et al. NUDT15 R139C-related thiopurine leukocytopenia is mediated by 6-thioguanine nucleotide-independent mechanism in Japanese patients with inflammatory bowel disease. J Gastroenterol. 2016 Jan;51(1):22-9.
44. Liang DC, Yang CP, Liu HC, Jaing TH, Chen SH, Hung IJ, et al. NUDT15 gene polymorphism related to mercaptopurine intolerance in Taiwan Chinese children with acute lymphoblastic leukemia. Pharmacogenomics J. 2016 Nov; 16(6):536-9.
45. Cargnin S, Genazzani AA, Canonico PL, Terrazzino S. Diagnostic accuracy of NUDT15 gene variants for thiopurine-induced leukopenia: a systematic review and meta-analysis. Pharmacol Res. 2018 Sep;135:102-11.
2. Moriyama T, Nishii R, Perez-Andreu V, Yang W, Klussmann FA, Zhao X, et al. NUDT15 polymorphisms alter thiopurine metabolism and hematopoietic toxicity. Nat Genet. 2016 Apr;48(4):367-73.
3. Ritter CA, Jedlitschky G, Meyer zu Schwabedissen H, Grube M, Kock K, Kroemer HK. Cellular export of drugs and signaling molecules by the ATP-binding cassette transporters MRP4 (ABCC4) and MRP5 (ABCC5). Drug Metab Rev. 2005;37(1):253-78.
4. Deininger M, Szumlanski CL, Otterness DM, Van Loon J, Ferber W, Weinshilboum RM. Purine substrates for human thiopurine methyltransferase. Biochem Pharmacol. 1994 Nov 29;48(11):2135-8.
5. Weinshilboum RM, Sladek SL. Mercaptopurine pharmacogenetics: monogenic inheritance of erythrocyte thiopurine methyltransferase activity. Am J Hum Genet. 1980 Sep;32(5):651-62.
6. Kakuta Y, Kinouchi Y, Shimosegawa T. Pharmacogenetics of thiopurines for inflammatory bowel disease in East Asia: prospects for clinical application of NUDT15 genotyping. J Gastroenterol. 2018 Feb;53(2):172-80.
7. Srimartpirom S, Tassaneeyakul W, Kukongviriyapan V, Tassaneeyakul W. Thiopurine S-methyltransferase genetic polymorphism in the Thai population. Br J Clin Pharmacol. 2004 July;58(1):66-70.
8. Ameyaw MM, Collie-Duguid ES, Powrie RH, Ofori-Adjei D, McLeod HL. Thiopurine methyltransferase alleles in British and Ghanaian populations. Hum Mol Genet. 1999 Feb;8(2):367-70.
9. Salavaggione OE, Wang L, Wiepert M, Yee VC, Weinshilboum RM. Thiopurine S-methyltransferase pharmacogenetics: variant allele functional and comparative genomics. Pharmacogenet Genomics. 2005 Nov;15(11):801-15.
10. Wang L, Pelleymounter L, Weinshilboum R, Johnson JA, Hebert JM, Altman RB, et al. Very important pharmacogene summary: thiopurine S-methyltransferase. Pharmacogenet Genomics. 2010 Jun;20(6):401-5.
11. Kumagai K, Hiyama K, Ishioka S, Sato H, Yamanishi Y, McLeod HL, et al. Allelotype frequency of the thiopurine methyltransferase (TPMT) gene in Japanese. Pharmacogenetics. 2001 Apr;11(3):275-8.
12. Chang JG, Lee LS, Chen CM, Shih MC, Wu MC, Tsai FJ, et al. Molecular analysis of thiopurine S-methyltransferase alleles in South-east Asian populations. Pharmacogenetics. 2002 Apr;12(3):191-5.
13. Collie-Duguid ES, Pritchard SC, Powrie RH, Sludden J, Collier DA, Li T, et al. The frequency and distribution of thiopurine methyltransferase alleles in Caucasian and Asian populations. Pharmacogenetics. 1999 Feb;9(1):37-42.
14. Cheon JH, Kim JH, Kim BY, Kim SW, Hong SY, Eun CS, et al. Allele frequency of thiopurine methyltransferase and inosine triphosphate pyro-phosphatase gene polymorphisms in Korean patients with inflammatory bowel diseases. Hepatogastroenterology. 2009 Mar-Apr;56(90):421-3.
15. Spire-Vayron de la Moureyre C, Debuysere H, Mastain B, Vinner E, Marez D, Lo Guidice JM, et al. Genotypic and phenotypic analysis of the polymorphic thiopurine S-methyltransferase gene (TPMT) in a European population. Br J Pharmacol. 1998 Oct;125(4):879-87.
16. Relling MV, Gardner EE, Sandborn WJ, Schmiegelow K, Pui CH, Yee SW, et al. Clinical Pharmacogenetics Implementation Consortium guidelines for thiopurine methyltransferase genotype and thiopurine dosing. Clin Pharmacol Ther. 2011 Mar;89(3):387-91.
17. Lennard L, Van Loon JA, Lilleyman JS, Weinshilboum RM. Thiopurine pharmaco- genetics in leukemia: correlation of erythrocyte thiopurine methyltransferase activity and 6-thioguanine nucleotide concentrations. Clin Pharmacol Ther. 1987 Jan;41(1):18-25.
18. Lennard L, Lilleyman JS, Van Loon J, Weinshilboum RM. Genetic variation in response to 6-mercaptopurine for childhood acute lymphoblastic leukaemia. Lancet. 1990 Jul 28;336(8709):225-9.
19. Evans WE, Horner M, Chu YQ, Kalwinsky D, Roberts WM. Altered mercapto-purine metabolism, toxic effects, and dosage requirement in a thiopurine methyltransferase-deficient child with acute lymphocytic leukemia. J Pediatr. 1991 Dec;119(6):985-9.
20. Lennard L, Gibson BE, Nicole T, Lilleyman JS. Congenital thiopurine methyl-transferase deficiency and 6-mercaptopurine toxicity during treatment for acute lymphoblastic leukaemia. Arch Dis Child. 1993 Nov;69(5):577-9.
21. McLeod HL, Miller DR, Evans WE. Azathioprine-induced myelosuppression in thiopurine methyltransferase deficient heart transplant recipient. Lancet. 1993 May 1;341(8853):1151.
22. Relling MV, Hancock ML, Rivera GK, Sandlund JT, Ribeiro RC, Krynetski EY, et al. Mercaptopurine therapy intolerance and heterozygosity at the thiopurine S-methyltransferase gene locus. J Natl Cancer Inst. 1999 Dec 1;91(23):2001-8.
23. McLeod HL, Coulthard S, Thomas AE, Pritchard SC, King DJ, Richards SM, et al. Analysis of thiopurine methyltransferase variant alleles in childhood acute lymphoblastic leukaemia. Br J Haematol. 1999 Jun;105(3):696-700.
24. Evans WE, Hon YY, Bomgaars L, Coutre S, Holdsworth M, Janco R, et al. Preponderance of thiopurine S-methyltransferase deficiency and heterozygosity among patients intolerant to mercaptopurine or azathioprine. J Clin Oncol. 2001 Apr15;19(8):2293-301.
25. Lennard L, Cartwright CS, Wade R, Vora A. Thiopurine dose intensity and treatment outcome in childhood lymphoblastic leukaemia: the influence of thiopurine methyltransferase pharmacogenetics. Br J Haematol. 2015 Apr;169(2):228-40.
26. Srimartpirom S. Genetic polymorphism of thiopurine S-methyltransferase in a northeastern Thai population [master's thesis]. Khon Kaen, Khon Kaen University; 2002.
27. Schutz E, Gummert J, Mohr FW, Armstrong VW, Oellerich M. Should 6-thioguanine nucleotides be monitored in heart transplant recipients given azathioprine? Ther Drug Monit. 1996 Jun;18(3):228-33.
28. Vannaprasaht S, Angsuthum S, Avihingsanon Y, Sirivongs D, Pongskul C, Makarawate P, et al. Impact of the heterozygous TPMT*1/*3C genotype on azathioprine-induced myelosuppression in kidney transplant recipients in Thailand. Clin Ther. 2009 Jul;31(7):1524-33.
29. Snow JL, Gibson LE. The role of genetic variation in thiopurine methyl-transferase activity and the efficacy and/or side effects of azathioprine therapy in dermatologic patients. Arch Dermatol. 1995 Feb;131(2):193-7.
30. Stolk JN, Boerbooms AM, de Abreu RA, de Koning DG, van Beusekom HJ, Muller WH, et al. Reduced thiopurine methyltransferase activity and development of side effects of azathioprine treatment in patients with rheumatoid arthritis. Arthritis Rheum. 1998 Oct;41(10):1858-66.
31. Takatsu N, Matsui T, Murakami Y, Ishihara H, Hisabe T, Nagahama T, et al. Adverse reactions to azathioprine cannot be predicted by thiopurine S-methyl-transferase genotype in Japanese patients with inflammatory bowel disease. J Gastroenterol Hepatol. 2009 July;24(7):1258-64.
32. Zhu X, Wang XD, Chao K, Zhi M, Zheng H, Ruan HL, et al. NUDT15 polymorphisms are better than thiopurine S-methyltransferase as predictor of risk for thiopurine-induced leukopenia in Chinese patients with Crohn's disease. Aliment Pharmacol Ther. 2016 Nov;44(9):967-75.
33. Vora A, Mitchell CD, Lennard L, Eden TO, Kinsey SE, Lilleyman J, et al. Toxicity and efficacy of 6-thioguanine versus 6-mercaptopurine in childhood lymphoblastic leukaemia: a randomised trial. Lancet. 2006 Oct 14;368(9544): 1339-48.
34. Erb N, Harms DO, Janka-Schaub G. Pharmacokinetics and metabolism of thio-purines in children with acute lymphoblastic leukemia receiving 6-thioguanine versus 6-mercaptopurine. Cancer Chemother Pharmacol. 1998;42(4):266-72.
35. McBride KL, Gilchrist GS, Smithson WA, Weinshilboum RM, Szmulanski C. Severe 6-thioguanine-induced marrow aplasia in a child with acute lymphoblastic leukemia and inherited thiopurine methyltransferase deficiency. J Pediatr Hematol Oncol. 2000 Sep-Oct;22(5):441-5.
36. Maki H, Sekiguchi M. MutT protein specifically hydrolyses a potent mutagenic substrate for DNA synthesis. Nature. 1992 Jan 16;355(6357):273-5.
37. Khaeso Kanyarat, Komwilaisak Patcharee, Nakkam Nontaya, Kanjanawart Sirimas, Vannaprasaht Suda, Tassaneeyakul W. Genetic polymorphism of Genes involved in 6-mercaptopurine-induced hematopoietic toxicity in Thai children with acute lymphoblastic leukemia. In: Phumala Morales Noppawan, Pornpun V, editors. The 40th Pharmacological and Therapeutic Society of Thailand Meeting; 2018 April 26-28; Faculty of Science, Mahidol University, Bangkok, Thailand; 2018. p. 40-8.
38. Chiengthong K, Ittiwut C, Muensri S, Sophonphan J, Sosothikul D, Seksan P, et al. NUDT15 c.415C>T increases risk of 6-mercaptopurine induced myelo-suppression during maintenance therapy in children with acute lymphoblastic leukemia. Haematologica. 2016 Jan;101(1):e24-6.
39. Yang JJ, Landier W, Yang W, Liu C, Hageman L, Cheng C, et al. Inherited NUDT15 variant is a genetic determinant of mercaptopurine intolerance in children with acute lymphoblastic leukemia. J Clin Oncol. 2015 Apr 10;33(11):1235-42.
40. Yang SK, Hong M, Baek J, Choi H, Zhao W, Jung Y, et al. A common missense variant in NUDT15 confers susceptibility to thiopurine-induced leukopenia. Nat Genet. 2014 Sep;46(9):1017-20.
41. Tanaka Y, Kato M, Hasegawa D, Urayama KY, Nakadate H, Kondoh K, et al. Susceptibility to 6-MP toxicity conferred by a NUDT15 variant in Japanese children with acute lymphoblastic leukaemia. Br J Haematol. 2015 Oct;171(1): 109-15.
42. Lee YJ, Hwang EH, Park JH, Shin JH, Kang B, Kim SY. NUDT15 variant is the most common variant associated with thiopurine-induced early leukopenia and alopecia in Korean pediatric patients with Crohn's disease. Eur J Gastroenterol Hepatol. 2016 Apr;28(4):475-8.
43. Asada A, Nishida A, Shioya M, Imaeda H, Inatomi O, Bamba S, et al. NUDT15 R139C-related thiopurine leukocytopenia is mediated by 6-thioguanine nucleotide-independent mechanism in Japanese patients with inflammatory bowel disease. J Gastroenterol. 2016 Jan;51(1):22-9.
44. Liang DC, Yang CP, Liu HC, Jaing TH, Chen SH, Hung IJ, et al. NUDT15 gene polymorphism related to mercaptopurine intolerance in Taiwan Chinese children with acute lymphoblastic leukemia. Pharmacogenomics J. 2016 Nov; 16(6):536-9.
45. Cargnin S, Genazzani AA, Canonico PL, Terrazzino S. Diagnostic accuracy of NUDT15 gene variants for thiopurine-induced leukopenia: a systematic review and meta-analysis. Pharmacol Res. 2018 Sep;135:102-11.