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Erschienen in: Journal of Gastroenterology 1/2016

01.01.2016 | ORIGINAL ARTICLE—ALIMENTARY TRACT

NUDT15 R139C-related thiopurine leukocytopenia is mediated by 6-thioguanine nucleotide-independent mechanism in Japanese patients with inflammatory bowel disease

verfasst von: Ayumi Asada, Atsushi Nishida, Makoto Shioya, Hirotsugu Imaeda, Osamu Inatomi, Shigeki Bamba, Katsuyuki Kito, Mitsushige Sugimoto, Akira Andoh

Erschienen in: Journal of Gastroenterology | Ausgabe 1/2016

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Abstract

Background

NUDT15 R139C (rs116855232) is a recently identified genetic factor responsible for thiopurine-induced leukocytopenia and hair loss. In this study, we investigated the association of NUDT15 R139C with 6-thioguanine nucleotide (6-TGN) levels and thiopurine-induced leukocytopenia in Japanese patients with inflammatory bowel disease (IBD).

Methods

Two hundred and sixty-four subjects (103 healthy volunteers and 161 IBD patients treated with thiopurines) were enrolled. Genotyping for NUDT15 R139C was performed using Custom TaqMan® SNP genotyping assays.

Results

The NUDT15 C/C, C/T, and T/T genotypes were 80.7, 18.2, and 1.1 %, respectively. The allelic frequency was 10.2 %. Among 161 IBD patients, there was no significant difference in 6-TGN levels among the NUDT15 genotypes. Forty-five patients (27.9 %) developed leukocytopenia (WBC <3000/μl), and the C/T and T/T genotypes were significantly associated with the development of leukocytopenia (P = 1.7 × 10−5). In these patients, 6-TGN levels were not significantly different between NUDT15 genotypes. NUDT15 R139C was significantly associated with early (<8 weeks) (P = 1.03 × 10−4) and late (>8 weeks) leukocytopenia (P = 4.3 × 10−4). The decrease in WBC count at 2 and 4 weeks was significantly higher in patients with the C/T or T/T genotypes as compared to the patients with the C/C genotype. All patients with the T/T genotype (n = 2) developed early severe hair loss and severe leukocytopenia (<1000/μl). The logistic regression analysis revealed that NUDT15 R139C was the sole genetic factor responsible for the thiopurine-induced leukocytopenia (P = 0.001).

Conclusions

These results suggest that NUDT15 R139C-related thiopurine-induced leukocytopenia is mediated by a 6-TGN-independent mechanism.
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Literatur
1.
Zurück zum Zitat Amin J, Huang B, Yoon J, et al. Update 2014: advances to optimize 6-mercaptopurine and azathioprine to reduce toxicity and improve efficacy in the management of IBD. Inflamm Bowel Dis. 2015;21:445–52.PubMedCrossRef Amin J, Huang B, Yoon J, et al. Update 2014: advances to optimize 6-mercaptopurine and azathioprine to reduce toxicity and improve efficacy in the management of IBD. Inflamm Bowel Dis. 2015;21:445–52.PubMedCrossRef
2.
Zurück zum Zitat Lee MN, Kang B, Choi SY, et al. Relationship between azathioprine dosage, 6-thioguanine nucleotide levels, and therapeutic response in pediatric patients with IBD treated with azathioprine. Inflamm Bowel Dis. 2015;21:1054–62.PubMedCrossRef Lee MN, Kang B, Choi SY, et al. Relationship between azathioprine dosage, 6-thioguanine nucleotide levels, and therapeutic response in pediatric patients with IBD treated with azathioprine. Inflamm Bowel Dis. 2015;21:1054–62.PubMedCrossRef
3.
Zurück zum Zitat Timmer A, McDonald JW, Tsoulis DJ, et al. Azathioprine and 6-mercaptopurine for maintenance of remission in ulcerative colitis. Cochrane Database Syst Rev. 2012;9:CD000478.PubMed Timmer A, McDonald JW, Tsoulis DJ, et al. Azathioprine and 6-mercaptopurine for maintenance of remission in ulcerative colitis. Cochrane Database Syst Rev. 2012;9:CD000478.PubMed
4.
Zurück zum Zitat 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.PubMedCrossRef 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.PubMedCrossRef
5.
Zurück zum Zitat 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.PubMedCrossRef 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.PubMedCrossRef
6.
Zurück zum Zitat Gisbert JP, Gomollon F. Thiopurine-induced myelotoxicity in patients with inflammatory bowel disease: a review. Am J Gastroenterol. 2008;103:1783–800.PubMedCrossRef Gisbert JP, Gomollon F. Thiopurine-induced myelotoxicity in patients with inflammatory bowel disease: a review. Am J Gastroenterol. 2008;103:1783–800.PubMedCrossRef
7.
Zurück zum Zitat 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.PubMedCrossRef 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.PubMedCrossRef
8.
Zurück zum Zitat Lees CW, Maan AK, Hansoti B, et al. Tolerability and safety of mercaptopurine in azathioprine-intolerant patients with inflammatory bowel disease. Aliment Pharmacol Ther. 2008;27:220–7.PubMedCrossRef Lees CW, Maan AK, Hansoti B, et al. Tolerability and safety of mercaptopurine in azathioprine-intolerant patients with inflammatory bowel disease. Aliment Pharmacol Ther. 2008;27:220–7.PubMedCrossRef
9.
Zurück zum Zitat 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.PubMedCrossRef 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.PubMedCrossRef
10.
Zurück zum Zitat 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.PubMedCrossRef 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.PubMedCrossRef
11.
Zurück zum Zitat 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. 2007;65(1):69–77.PubMedPubMedCentralCrossRef 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. 2007;65(1):69–77.PubMedPubMedCentralCrossRef
12.
Zurück zum Zitat Hiratsuka M, Inoue T, Omori F, et al. Genetic analysis of thiopurine methyltransferase polymorphism in a Japanese population. Mutat Res. 2000;448:91–5.PubMedCrossRef Hiratsuka M, Inoue T, Omori F, et al. Genetic analysis of thiopurine methyltransferase polymorphism in a Japanese population. Mutat Res. 2000;448:91–5.PubMedCrossRef
13.
Zurück zum Zitat 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.PubMedCrossRef 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.PubMedCrossRef
14.
Zurück zum Zitat Kurzawski M, Dziewanowski K, Lener A, et al. TPMT but not ITPA gene polymorphism influences the risk of azathioprine intolerance in renal transplant recipients. Eur J Clin Pharmacol. 2009;65:533–40.PubMedCrossRef Kurzawski M, Dziewanowski K, Lener A, et al. TPMT but not ITPA gene polymorphism influences the risk of azathioprine intolerance in renal transplant recipients. Eur J Clin Pharmacol. 2009;65:533–40.PubMedCrossRef
15.
Zurück zum Zitat Allorge D, Hamdan R, Broly F, et al. ITPA genotyping test does not improve detection of Crohn’s disease patients at risk of azathioprine/6-mercaptopurine induced myelosuppression. Gut. 2005;54:565.PubMedPubMedCentralCrossRef Allorge D, Hamdan R, Broly F, et al. ITPA genotyping test does not improve detection of Crohn’s disease patients at risk of azathioprine/6-mercaptopurine induced myelosuppression. Gut. 2005;54:565.PubMedPubMedCentralCrossRef
16.
Zurück zum Zitat 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.PubMedCrossRef 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.PubMedCrossRef
17.
Zurück zum Zitat Zelinkova Z, Derijks LJ, Stokkers PC, et al. Inosine triphosphate pyrophosphatase and thiopurine s-methyltransferase genotypes relationship to azathioprine-induced myelosuppression. Clin Gastroenterol Hepatol. 2006;4:44–9.PubMedCrossRef Zelinkova Z, Derijks LJ, Stokkers PC, et al. Inosine triphosphate pyrophosphatase and thiopurine s-methyltransferase genotypes relationship to azathioprine-induced myelosuppression. Clin Gastroenterol Hepatol. 2006;4:44–9.PubMedCrossRef
18.
Zurück zum Zitat Krishnamurthy P, Schwab M, Takenaka K, et al. Transporter-mediated protection against thiopurine-induced hematopoietic toxicity. Cancer Res. 2008;68:4983–9.PubMedPubMedCentralCrossRef Krishnamurthy P, Schwab M, Takenaka K, et al. Transporter-mediated protection against thiopurine-induced hematopoietic toxicity. Cancer Res. 2008;68:4983–9.PubMedPubMedCentralCrossRef
19.
Zurück zum Zitat 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.PubMedCrossRef 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.PubMedCrossRef
20.
Zurück zum Zitat 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.PubMedCrossRef 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.PubMedCrossRef
21.
Zurück zum Zitat Kakuta Y, Naito T, Onodera M, et al. NUDT15 R139C causes thiopurine-induced early severe hair loss and leukopenia in Japanese patients with IBD. The pharmacogenomics journal. 2015;. doi:10.1038/tpj.2015.43.PubMed Kakuta Y, Naito T, Onodera M, et al. NUDT15 R139C causes thiopurine-induced early severe hair loss and leukopenia in Japanese patients with IBD. The pharmacogenomics journal. 2015;. doi:10.​1038/​tpj.​2015.​43.PubMed
22.
Zurück zum Zitat Sandborn W, Sutherland L, Pearson D, et al. Azathioprine or 6-mercaptopurine for inducing remission of Crohn’s disease. Cochrane Database Syst Rev. 2000;(2):CD000545. Sandborn W, Sutherland L, Pearson D, et al. Azathioprine or 6-mercaptopurine for inducing remission of Crohn’s disease. Cochrane Database Syst Rev. 2000;(2):CD000545.
23.
Zurück zum Zitat NCI N. National Cancer Institute, common terminology criteria for adverse events v4. NIH publication, Bethesda, MD. 2009;# 09-7473. NCI N. National Cancer Institute, common terminology criteria for adverse events v4. NIH publication, Bethesda, MD. 2009;# 09-7473.
24.
Zurück zum Zitat Pike MG, Franklin CL, Mays DC, et al. Improved methods for determining the concentration of 6-thioguanine nucleotides and 6-methylmercaptopurine nucleotides in blood. J Chromatogr B Biomed Sci Appl. 2001;757:1–9.PubMedCrossRef Pike MG, Franklin CL, Mays DC, et al. Improved methods for determining the concentration of 6-thioguanine nucleotides and 6-methylmercaptopurine nucleotides in blood. J Chromatogr B Biomed Sci Appl. 2001;757:1–9.PubMedCrossRef
25.
Zurück zum Zitat 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.PubMedCrossRef 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.PubMedCrossRef
26.
Zurück zum Zitat Yang JJ, Landier W, Yang W, et al. Inherited NUDT15 variant is a genetic determinant of mercaptopurine intolerance in children with acute lymphoblastic leukemia. J Clin Oncol: Off J Am Soc Clin Oncol. 2015;33:1235–42.CrossRef Yang JJ, Landier W, Yang W, et al. Inherited NUDT15 variant is a genetic determinant of mercaptopurine intolerance in children with acute lymphoblastic leukemia. J Clin Oncol: Off J Am Soc Clin Oncol. 2015;33:1235–42.CrossRef
27.
Zurück zum Zitat Booth RA, Ansari MT, Loit E, et al. Assessment of thiopurine S-methyltransferase activity in patients prescribed thiopurines: a systematic review. Ann Intern Med. 2011;154:814–23 (W-295-818).PubMedCrossRef Booth RA, Ansari MT, Loit E, et al. Assessment of thiopurine S-methyltransferase activity in patients prescribed thiopurines: a systematic review. Ann Intern Med. 2011;154:814–23 (W-295-818).PubMedCrossRef
28.
Zurück zum Zitat Takagi Y, Setoyama D, Ito R, et al. Human MTH3 (NUDT18) protein hydrolyzes oxidized forms of guanosine and deoxyguanosine diphosphates: comparison with MTH1 and MTH2. J Biol Chem. 2012;287:21541–9.PubMedPubMedCentralCrossRef Takagi Y, Setoyama D, Ito R, et al. Human MTH3 (NUDT18) protein hydrolyzes oxidized forms of guanosine and deoxyguanosine diphosphates: comparison with MTH1 and MTH2. J Biol Chem. 2012;287:21541–9.PubMedPubMedCentralCrossRef
29.
Zurück zum Zitat Valko M, Leibfritz D, Moncol J, et al. Free radicals and antioxidants in normal physiological functions and human disease. Int J Biochem Cell Biol. 2007;39:44–84.PubMedCrossRef Valko M, Leibfritz D, Moncol J, et al. Free radicals and antioxidants in normal physiological functions and human disease. Int J Biochem Cell Biol. 2007;39:44–84.PubMedCrossRef
30.
31.
Zurück zum Zitat Ito K, Hirao A, Arai F, et al. Reactive oxygen species act through p38 MAPK to limit the lifespan of hematopoietic stem cells. Nat Med. 2006;12:446–51.PubMedCrossRef Ito K, Hirao A, Arai F, et al. Reactive oxygen species act through p38 MAPK to limit the lifespan of hematopoietic stem cells. Nat Med. 2006;12:446–51.PubMedCrossRef
32.
Zurück zum Zitat Ito K, Hirao A, Arai F, et al. Regulation of oxidative stress by ATM is required for self-renewal of haematopoietic stem cells. Nature. 2004;431:997–1002.PubMedCrossRef Ito K, Hirao A, Arai F, et al. Regulation of oxidative stress by ATM is required for self-renewal of haematopoietic stem cells. Nature. 2004;431:997–1002.PubMedCrossRef
33.
Zurück zum Zitat Zhao J, Li H, Zhou R, et al. Foxp1 Regulates the proliferation of hair follicle stem cells in response to oxidative stress during hair cycling. PLoS One. 2015;10:e0131674.PubMedPubMedCentralCrossRef Zhao J, Li H, Zhou R, et al. Foxp1 Regulates the proliferation of hair follicle stem cells in response to oxidative stress during hair cycling. PLoS One. 2015;10:e0131674.PubMedPubMedCentralCrossRef
Metadaten
Titel
NUDT15 R139C-related thiopurine leukocytopenia is mediated by 6-thioguanine nucleotide-independent mechanism in Japanese patients with inflammatory bowel disease
verfasst von
Ayumi Asada
Atsushi Nishida
Makoto Shioya
Hirotsugu Imaeda
Osamu Inatomi
Shigeki Bamba
Katsuyuki Kito
Mitsushige Sugimoto
Akira Andoh
Publikationsdatum
01.01.2016
Verlag
Springer Japan
Erschienen in
Journal of Gastroenterology / Ausgabe 1/2016
Print ISSN: 0944-1174
Elektronische ISSN: 1435-5922
DOI
https://doi.org/10.1007/s00535-015-1142-4

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