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Journal of Gastroenterology
Published in: Journal of Gastroenterology 2/2018

Open Access 01-02-2018 | Review

Pharmacogenetics of thiopurines for inflammatory bowel disease in East Asia: prospects for clinical application of NUDT15 genotyping

Authors: Yoichi Kakuta, Yoshitaka Kinouchi, Tooru Shimosegawa

Published in: Journal of Gastroenterology | Issue 2/2018

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Abstract

The thiopurine drugs 6-mercaptopurine (6-MP) and azathiopurine (AZA) are widely used to treat inflammatory bowel disease. However, the incidence of adverse reactions is high, particularly in Asia, and the mechanisms of toxicity in Asian populations remain unclear. Thiopurine S-methyltransferase (TPMT) is a well-known enzyme that inactivates AZA or 6-MP through methylation and is one of the few pharmacogenetic predictors used in clinical settings in Western countries. Individuals carrying TPMT-deficient genetic variants require reduced drug doses, but this treatment modification is are not applicable to East Asian populations. Several genes code thiopurine-metabolizing enzymes, including TPMT, multidrug-resistance protein 4, and inosine triphosphatase. These genes have been studied as candidate pharmacogenetic markers; however, it remains unclear why Asian populations seem to be more intolerant than other ethnic groups to a full dose of thiopurines. A genome-wide association approach to identify Asian-specific pharmacogenetic markers in Korean patients with Crohn’s disease revealed that a non-synonymous single nucelotide polymorphism in nucleoside diphosphate-linked moiety X-type motif 15 (NUDT15) which causes p.Arg139Cys was strongly associated with thiopurine-induced early leukopenia. Six common haplotypes of NUDT15 were reported, and five variants showed medium-to-low enzyme activities, compared with the wild haplotype. NUDT15 hydrolyzes the thiopurine active metabolites 6-thio-GTP and 6-thio-dGTP; variants of NUDT15 had lower enzyme activities, causing higher levels of thiopurine active metabolites, resulting in thiopurine-induced leukopenia. In clinical application, NUDT15 genotyping is a good candidate for predicting thiopurine toxicity in East Asian populations. However, the association of NUDT15 diplotypes with thiopurine toxicity remains unclear. Further analyses with large cohorts to confirm the clinical effects of each haplotype are planned.
Literature
1.
2.
Pearson DC, May GR, Fick GH, et al. Azathioprine and 6-mercaptopurine in Crohn disease. A meta-analysis. Ann Intern Med. 1995;123:132–42.CrossRefPubMed
3.
Hibi T, Naganuma M, Kitahora T, et al. Low-dose azathioprine is effective and safe for maintenance of remission in patients with ulcerative colitis. J Gastroenterol. 2003;38:740–6.CrossRefPubMed
4.
Gisbert JP, Nino P, Cara C, et al. Comparative effectiveness of azathioprine in Crohn’s disease and ulcerative colitis: prospective, long-term, follow-up study of 394 patients. Aliment Pharmacol Ther. 2008;28:228–38.CrossRefPubMed
5.
Khan KJ, Dubinsky MC, Ford AC, et al. Efficacy of immunosuppressive therapy for inflammatory bowel disease: a systematic review and meta-analysis. Am J Gastroenterol. 2011;106:630–42.CrossRefPubMed
6.
7.
Panaccione R, Ghosh S, Middleton S, et al. Combination therapy with infliximab and azathioprine is superior to monotherapy with either agent in ulcerative colitis. Gastroenterology. 2014;146:392–400.CrossRefPubMed
8.
Colombel JF, Sandborn WJ, Reinisch W, et al. Infliximab, azathioprine, or combination therapy for Crohn’s disease. N Engl J Med. 2010;362:1383–95.CrossRefPubMed
9.
Qiu Y, Mao R, Chen BL, et al. Effects of combination therapy with immunomodulators on trough levels and antibodies against tumor necrosis factor antagonists in patients with inflammatory bowel disease: a meta-analysis. Clin Gastroenterol Hepatol. 2017;15:1359–72.CrossRefPubMed
10.
Jun JB, Cho DY, Kang C, et al. 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. 2005;23:873–6.PubMed
11.
Qiu Y, Mao R, Zhang SH, et al. Safety profile of thiopurines in Crohn disease: analysis of 893 patient-years follow-up in a Southern China cohort. Medicine. 2015;94:e1513.CrossRefPubMedPubMedCentral
12.
Takatsu N, Matsui T, Murakami Y, et al. Adverse reactions to azathioprine cannot be predicted by thiopurine S-methyltransferase genotype in Japanese patients with inflammatory bowel disease. J Gastroenterol Hepatol. 2009;24:1258–64.CrossRefPubMed
13.
Palmieri O, Latiano A, Bossa F, et al. Sequential evaluation of thiopurine methyltransferase, inosine triphosphate pyrophosphatase, and HPRT1 genes polymorphisms to explain thiopurines’ toxicity and efficacy. Aliment Pharmacol Ther. 2007;26:737–45.CrossRefPubMed
14.
Gearry RB, Barclay ML, Burt MJ, et al. Thiopurine drug adverse effects in a population of New Zealand patients with inflammatory bowel disease. Pharmacoepidemiol Drug Saf. 2004;13:563–7.CrossRefPubMed
15.
Ruemmele FM, Veres G, Kolho KL, et al. Consensus guidelines of ECCO/ESPGHAN on the medical management of pediatric Crohn’s disease. J Crohns Colitis. 2014;8:1179–207.CrossRefPubMed
16.
Dubinsky MC, Lamothe S, Yang HY, et al. Pharmacogenomics and metabolite measurement for 6-mercaptopurine therapy in inflammatory bowel disease. Gastroenterology. 2000;118:705–13.CrossRefPubMed
17.
Haglund S, Taipalensuu J, Peterson C, et al. IMPDH activity in thiopurine-treated patients with inflammatory bowel disease-relation to TPMT activity and metabolite concentrations. Br J Clin Pharmacol. 2008;65:69–77.CrossRefPubMed
18.
Lennard L, Van Loon JA, Lilleyman JS, et al. Thiopurine pharmacogenetics in leukemia: correlation of erythrocyte thiopurine methyltransferase activity and 6-thioguanine nucleotide concentrations. Clin Pharmacol Ther. 1987;41:18–25.CrossRefPubMed
19.
Schutz E, Gummert J, Armstrong VW, et al. Azathioprine pharmacogenetics: the relationship between 6-thioguanine nucleotides and thiopurine methyltransferase in patients after heart and kidney transplantation. Eur J Clin Chem Clin Biochem. 1996;34:199–205.PubMed
20.
Lorenz M, Weise A, Prause S, et al. Development and validation of a rapid and reliable method for TPMT genotyping using real-time PCR. Clin Lab. 2012;58:959–71.PubMed
21.
Nasedkina TV, Fedorova OE, Glotov AS, et al. Rapid genotyping of common deficient thiopurine S-methyltransferase alleles using the DNA-microchip technique. Eur J Hum Genet. 2006;14:991–8.CrossRefPubMed
22.
Relling MV, Gardner EE, Sandborn WJ, et al. Clinical Pharmacogenetics Implementation Consortium guidelines for thiopurine methyltransferase genotype and thiopurine dosing. Clin Pharmacol Ther. 2011;89:387–91.CrossRefPubMedPubMedCentral
23.
Derijks LJ, Gilissen LP, Engels LG, et al. Pharmacokinetics of 6-thioguanine in patients with inflammatory bowel disease. Ther Drug Monit. 2006;28:45–50.CrossRefPubMed
24.
Kurtovic S, Grehn L, Karlsson A, et al. Glutathione transferase activity with a novel substrate mimics the activation of the prodrug azathioprine. Anal Biochem. 2008;375:339–44.CrossRefPubMed
25.
Derijks LJ, Wong DR. Pharmacogenetics of thiopurines in inflammatory bowel disease. Curr Pharm Des. 2010;16:145–54.CrossRefPubMed
26.
Moon W, Loftus EV Jr. Review article: recent advances in pharmacogenetics and pharmacokinetics for safe and effective thiopurine therapy in inflammatory bowel disease. Aliment Pharmacol Ther. 2016;43:863–83.CrossRefPubMed
27.
Nelson JA, Carpenter JW, Rose LM, et al. Mechanisms of action of 6-thioguanine, 6-mercaptopurine, and 8-azaguanine. Cancer Res. 1975;35:2872–8.PubMed
28.
Fairchild CR, Maybaum J, Kennedy KA. Concurrent unilateral chromatid damage and DNA strand breakage in response to 6-thioguanine treatment. Biochem Pharmacol. 1986;35:3533–41.CrossRefPubMed
29.
Poppe D, Tiede I, Fritz G, et al. Azathioprine suppresses ezrin-radixin-moesin-dependent T cell-APC conjugation through inhibition of Vav guanosine exchange activity on Rac proteins. J Immunol. 2006;176:640–51.CrossRefPubMedPubMedCentral
30.
Weinshilboum RM, Sladek SL. Mercaptopurine pharmacogenetics: monogenic inheritance of erythrocyte thiopurine methyltransferase activity. Am J Hum Genet. 1980;32:651–62.PubMedPubMedCentral
31.
Krynetski EY, Tai HL, Yates CR, et al. Genetic polymorphism of thiopurine S-methyltransferase: clinical importance and molecular mechanisms. Pharmacogenetics. 1996;6:279–90.CrossRefPubMed
32.
Colombel JF, Ferrari N, Debuysere H, et al. Genotypic analysis of thiopurine S-methyltransferase in patients with Crohn’s disease and severe myelosuppression during azathioprine therapy. Gastroenterology. 2000;118:1025–30.CrossRefPubMed
33.
Al Hadithy AF, de Boer NK, Derijks LJ, et al. Thiopurines in inflammatory bowel disease: pharmacogenetics, therapeutic drug monitoring and clinical recommendations. Dig Liver Dis. 2005;37:282–97.CrossRefPubMed
34.
Seidman EG. Clinical use and practical application of TPMT enzyme and 6-mercaptopurine metabolite monitoring in IBD. Rev Gastroenterol Disord. 2003;3:S30–8.PubMed
35.
Nygaard U, Toft N, Schmiegelow K. Methylated metabolites of 6-mercaptopurine are associated with hepatotoxicity. Clin Pharmacol Ther. 2004;75:274–81.CrossRefPubMed
36.
Kopylov U, Amre D, Theoret Y, et al. Thiopurine metabolite ratios for monitoring therapy in pediatric Crohn disease. J Pediatr Gastroenterol Nutr. 2014;59:511–5.CrossRefPubMed
37.
Ansari A, Hassan C, Duley J, et al. Thiopurine methyltransferase activity and the use of azathioprine in inflammatory bowel disease. Aliment Pharmacol Ther. 2002;16:1743–50.CrossRefPubMed
38.
de la Moureyre CS, Debuysere H, Sabbagh N, et al. Detection of known and new mutations in the thiopurine S-methyltransferase gene by single-strand conformation polymorphism analysis. Hum Mutat. 1998;12:177–85.CrossRef
39.
Iu YPH, Helander S, Kahlin AZ, et al. One amino acid makes a difference—characterization of a new TPMT allele and the influence of SAM on TPMT stability. Sci Rep. 2017;7:46428.CrossRefPubMedPubMedCentral
40.
Ujiie S, Sasaki T, Mizugaki M, et al. Functional characterization of 23 allelic variants of thiopurine S-methyltransferase gene (TPMT*2-*24). Pharmacogenet Genomics. 2008;18:887–93.CrossRefPubMed
41.
Winter JW, Gaffney D, Shapiro D, et al. Assessment of thiopurine methyltransferase enzyme activity is superior to genotype in predicting myelosuppression following azathioprine therapy in patients with inflammatory bowel disease. Aliment Pharmacol Ther. 2007;25:1069–77.CrossRefPubMed
42.
Schaeffeler E, Eichelbaum M, Reinisch W, et al. Three novel thiopurine S-methyltransferase allelic variants (TPMT*20, *21, *22)-association with decreased enzyme function. Hum Mutat. 2006;27:976.CrossRefPubMed
43.
Lindqvist M, Haglund S, Almer S, et al. Identification of two novel sequence variants affecting thiopurine methyltransferase enzyme activity. Pharmacogenetics. 2004;14:261–5.CrossRefPubMed
44.
Roberts RL, Gearry RB, Bland MV, et al. Trinucleotide repeat variants in the promoter of the thiopurine S-methyltransferase gene of patients exhibiting ultra-high enzyme activity. Pharmacogenet Genomics. 2008;18:434–8.CrossRefPubMed
45.
Yan L, Zhang S, Eiff B, et al. Thiopurine methyltransferase polymorphic tandem repeat: genotype-phenotype correlation analysis. Clin Pharmacol Ther. 2000;68:210–9.CrossRefPubMed
46.
Brouwer C, De Abreu RA, Keizer-Garritsen JJ, et al. Thiopurine methyltransferase in acute lymphoblastic leukaemia: biochemical and molecular biological aspects. Eur J Cancer. 2005;41:613–23.CrossRefPubMed
47.
Charasson V, Hillaire-Buys D, Solassol I, et al. Involvement of gene polymorphisms of the folate pathway enzymes in gene expression and anticancer drug sensitivity using the NCI-60 panel as a model. Eur J Cancer. 2009;45:2391–401.CrossRefPubMed
48.
Karas-Kuzelicki N, Milek M, Mlinaric-Rascan I. MTHFR and TYMS genotypes influence TPMT activity and its differential modulation in males and females. Clin Biochem. 2010;43:37–42.CrossRefPubMed
49.
Dorababu P, Naushad SM, Linga VG, et al. Genetic variants of thiopurine and folate metabolic pathways determine 6-MP-mediated hematological toxicity in childhood ALL. Pharmacogenomics. 2012;13:1001–8.CrossRefPubMed
50.
Nagasaki M, Yasuda J, Katsuoka F, et al. Rare variant discovery by deep whole-genome sequencing of 1,070 Japanese individuals. Nat Commun. 2015;6:8018.CrossRefPubMedPubMedCentral
51.
Yamaguchi-Kabata Y, Nariai N, Kawai Y, et al. iJGVD: an integrative Japanese genome variation database based on whole-genome sequencing. Hum Genome Var. 2015;2:15050.CrossRefPubMedPubMedCentral
52.
Uchiyama K, Nakamura M, Kubota T, et al. Thiopurine S-methyltransferase and inosine triphosphate pyrophosphohydrolase genes in Japanese patients with inflammatory bowel disease in whom adverse drug reactions were induced by azathioprine/6-mercaptopurine treatment. J Gastroenterol. 2009;44:197–203.CrossRefPubMed
53.
54.
Sasaki T, Goto E, Konno Y, et al. Three novel single nucleotide polymorphisms of the human thiopurine S-methyltransferase gene in Japanese individuals. Drug Metab Pharmacokinet. 2006;21:332–6.CrossRefPubMed
55.
Ban H, Andoh A, Tanaka A, et al. Analysis of thiopurine S-methyltransferase genotypes in Japanese patients with inflammatory bowel disease. Intern Med. 2008;47:1645–8.CrossRefPubMed
56.
Wielinga PR, Reid G, Challa EE, et al. Thiopurine metabolism and identification of the thiopurine metabolites transported by MRP4 and MRP5 overexpressed in human embryonic kidney cells. Mol Pharmacol. 2002;62:1321–31.CrossRefPubMed
57.
Krishnamurthy P, Schwab M, Takenaka K, et al. Transporter-mediated protection against thiopurine-induced hematopoietic toxicity. Cancer Res. 2008;68:4983–9.CrossRefPubMedPubMedCentral
58.
Ban H, Andoh A, Imaeda H, et al. The multidrug-resistance protein 4 polymorphism is a new factor accounting for thiopurine sensitivity in Japanese patients with inflammatory bowel disease. J Gastroenterol. 2010;45:1014–21.CrossRefPubMed
59.
Tanaka Y. Susceptibility to 6-mercaptopurine toxicity related with NUDT15 and ABCC4 variants in Japanese childhood acute lymphoblastic leukemia. Rinsho Ketsueki. 2017;58:950–6.PubMed
60.
61.
Holmes SL, Turner BM, Hirschhorn K. Human inosine triphosphatase: catalytic properties and population studies. Clin Chim Acta. 1979;97:143–53.CrossRefPubMed
62.
Lin S, McLennan AG, Ying K, et al. Cloning, expression, and characterization of a human inosine triphosphate pyrophosphatase encoded by the ITPA gene. J Biol Chem. 2001;276:18695–701.CrossRefPubMed
63.
Marinaki AM, Ansari A, Duley JA, et al. Adverse drug reactions to azathioprine therapy are associated with polymorphism in the gene encoding inosine triphosphate pyrophosphatase (ITPase). Pharmacogenetics. 2004;14:181–7.CrossRefPubMed
64.
Stocco G, Crews KR, Evans WE. Genetic polymorphism of inosine-triphosphate-pyrophosphatase influences mercaptopurine metabolism and toxicity during treatment of acute lymphoblastic leukemia individualized for thiopurine-S-methyl-transferase status. Expert Opin Drug Saf. 2010;9:23–37.CrossRefPubMed
65.
Gearry RB, Roberts RL, Barclay ML, et al. Lack of association between the ITPA 94C>A polymorphism and adverse effects from azathioprine. Pharmacogenetics. 2004;14:779–81.CrossRefPubMed
66.
van Dieren JM, van Vuuren AJ, Kusters JG, et al. ITPA genotyping is not predictive for the development of side effects in AZA treated inflammatory bowel disease patients. Gut. 2005;54:1664.PubMedPubMedCentral
67.
Van Dieren JM, Hansen BE, Kuipers EJ, et al. Meta-analysis: Inosine triphosphate pyrophosphatase polymorphisms and thiopurine toxicity in the treatment of inflammatory bowel disease. Aliment Pharmacol Ther. 2007;26:643–52.CrossRefPubMed
68.
Kudo M, Saito Y, Sasaki T, et al. Genetic variations in the HGPRT, ITPA, IMPDH1, IMPDH2, and GMPS genes in Japanese individuals. Drug Metab Pharmacokinet. 2009;24:557–64.CrossRefPubMed
69.
Zhu Q, Cao Q. Thiopurine methyltransferase gene polymorphisms and activity in Chinese patients with inflammatory bowel disease treated with azathioprine. Chin Med J (Engl). 2012;125:3665–70.PubMed
70.
Yang SK, Hong M, Baek J, et al. A common missense variant in NUDT15 confers susceptibility to thiopurine-induced leukopenia. Nat Genet. 2014;46:1017–20.CrossRefPubMedPubMedCentral
71.
Tanaka Y, Kato M, Hasegawa D, et al. Susceptibility to 6-MP toxicity conferred by a NUDT15 variant in Japanese children with acute lymphoblastic leukaemia. Br J Haematol. 2015;171:109–15.CrossRefPubMed
72.
Kakuta Y, Naito T, Onodera M, et al. NUDT15 R139C causes thiopurine-induced early severe hair loss and leukopenia in Japanese patients with IBD. Pharmacogenomics J. 2016;16:280–5.CrossRefPubMed
73.
Asada A, Nishida A, Shioya M, 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;51:22–9.CrossRefPubMed
74.
Zhu X, Wang XD, Chao K, 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;44:967–75.CrossRefPubMed
75.
Ailing Z, Jing Y, Jingli L, et al. Further evidence that a variant of the gene NUDT15 may be an important predictor of azathioprine-induced toxicity in Chinese subjects: a case report. J Clin Pharm Ther. 2016;41:572–4.CrossRefPubMed
76.
Wong FC, Leung AW, Kwok JS, et al. NUDT15 variant and thiopurine-induced leukopenia in Hong Kong. Hong Kong Med J. 2016;22:185–7.CrossRefPubMed
77.
Liang DC, Yang CP, Liu HC, et al. NUDT15 gene polymorphism related to mercaptopurine intolerance in Taiwan Chinese children with acute lymphoblastic leukemia. Pharmacogenomics J. 2016;16:536–9.CrossRefPubMed
78.
Shah SA, Paradkar M, Desai D, et al. Nucleoside diphosphate-linked moiety X-type motif 15 C415T variant as a predictor for thiopurine-induced toxicity in Indian patients. J Gastroenterol Hepatol. 2017;32:620–4.CrossRefPubMed
79.
Chiengthong K, Ittiwut C, Muensri S, et al. NUDT15 c.415C>T increases risk of 6-mercaptopurine induced myelosuppression during maintenance therapy in children with acute lymphoblastic leukemia. Haematologica. 2016;101:e24–6.CrossRefPubMedPubMedCentral
80.
81.
82.
Sato T, Takagawa T, Kakuta Y, et al. NUDT15, FTO, and RUNX1 genetic variants and thiopurine intolerance among Japanese patients with inflammatory bowel diseases. Intest Res. 2017;15:328–37.CrossRefPubMedPubMedCentral
83.
84.
Cai JP, Ishibashi T, Takagi Y, et al. Mouse MTH2 protein which prevents mutations caused by 8-oxoguanine nucleotides. Biochem Biophys Res Commun. 2003;305:1073–7.CrossRefPubMed
85.
Carter M, Jemth AS, Hagenkort A, et al. Crystal structure, biochemical and cellular activities demonstrate separate functions of MTH1 and MTH2. Nat Commun. 2015;6:7871.CrossRefPubMedPubMedCentral
86.
Moriyama T, Nishii R, Lin TN, et al. The effects of inherited NUDT15 polymorphisms on thiopurine active metabolites in Japanese children with acute lymphoblastic leukemia. Pharmacogenet Genomics. 2017;27:236–9.CrossRefPubMed
87.
Valerie NC, Hagenkort A, Page BD, et al. NUDT15 hydrolyzes 6-Thio-DeoxyGTP to mediate the anticancer efficacy of 6-thioguanine. Cancer Res. 2016;76:5501–11.CrossRefPubMed
88.
Kim HT, Choi R, Won HH, et al. NUDT15 genotype distributions in the Korean population. Pharmacogenet Genomics. 2017;27:197–200.CrossRefPubMed
89.
Chao K, Wang X, Cao Q, et al. Combined detection of NUDT15 variants could highly predict thiopurine-induced leukopenia in Chinese patients with inflammatory bowel disease: a multicenter analysis. Inflamm Bowel Dis. 2017;23:1592–9.CrossRefPubMed
90.
Kuriyama S, Yaegashi N, Nagami F, et al. The Tohoku Medical Megabank Project: design and mission. J Epidemiol. 2016;26:493–511.CrossRefPubMed
91.
Moriyama T, Yang YL, Nishii R, et al. Novel variants in NUDT15 and thiopurine intolerance in children with acute lymphoblastic leukemia from diverse ancestry. Blood. 2017;130:1209–12.CrossRefPubMed
92.
Connell WR, Kamm MA, Ritchie JK, et al. Bone marrow toxicity caused by azathioprine in inflammatory bowel disease: 27 years of experience. Gut. 1993;34:1081–5.CrossRefPubMedPubMedCentral
Metadata
Title
Pharmacogenetics of thiopurines for inflammatory bowel disease in East Asia: prospects for clinical application of NUDT15 genotyping
Authors
Yoichi Kakuta
Yoshitaka Kinouchi
Tooru Shimosegawa
Publication date
01-02-2018
Publisher
Springer Japan
Published in
Journal of Gastroenterology / Issue 2/2018
Print ISSN: 0944-1174
Electronic ISSN: 1435-5922
DOI
https://doi.org/10.1007/s00535-017-1416-0

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