Long-term effect of NUDT15 R139C on hematologic indices in inflammatory bowel disease patients treated with thiopurine.

Adult Anti-Inflammatory Agents / adverse effects Azathioprine / adverse effects Colitis, Ulcerative / diagnosis Crohn Disease / diagnosis Erythrocyte Indices Female Gastrointestinal Agents / adverse effects Genetic Predisposition to Disease Heterozygote Humans Leukocyte Count Leukopenia / blood Male Mercaptopurine / adverse effects Middle Aged Mutation, Missense Pyrophosphatases / genetics Retrospective Studies Risk Factors Time Factors Tokyo Treatment Outcome Young Adult

NUDT15 inflammatory bowel disease leukopenia long-term thiopurine administration mean corpuscular volume

Journal

Journal of gastroenterology and hepatology

ISSN: 1440-1746

Titre abrégé: J Gastroenterol Hepatol

Pays: Australia

ID NLM: 8607909

Informations de publication

Date de publication:
Oct 2019

Historique:

received: 23 10 2018

revised: 08 04 2019

accepted: 20 04 2019

pubmed: 3 5 2019

medline: 6 5 2020

entrez: 3 5 2019

Statut: ppublish

Résumé

A missense variant of the nucleoside diphosphate-linked moiety X-type motif 15 (NUDT15) gene (R139C) predisposes Asian patients with inflammatory bowel disease (IBD) to thiopurine-induced leukopenia. This study evaluates the long-term effect of NUDT15 R139C heterozygosity on hematological parameters during thiopurine administration. We enrolled 83 Japanese IBD patients who were on anti-tumor necrosis factor-α agents and had used thiopurine. NUDT15 R139C was genotyped by polymerase chain reaction. We retrospectively reviewed patient clinical charts to collect data on white blood cell (WBC) count, mean corpuscular volume (MCV), hemoglobin, and platelet count during the 24 months following thiopurine initiation. The included patients had either Crohn's disease (54; 65.1%) or ulcerative colitis (29; 34.9%). Genotyping of NUDT15 R139C identified 62 patients (74.7%) of genotype C/C and 21 (25.3%) of genotype C/T. The median dose of thiopurine was lower in the C/T group than in the C/C group after starting thiopurine. At 6 months, the mean WBC count of the C/T group became significantly lower than that of the C/C group (P = 0.008) and remained lower through the 24 months. The C/T group developed grade 2-4 leukopenia by 6 months, which persisted through 12-24 months. The mean MCV in the C/T group became higher than that of the C/C group after 3 months. NUDT15 R139C heterozygosity affected the WBC count and MCV for 24 months after thiopurine administration. Our results indicate that careful monitoring of leukopenia and dose adjustment are necessary throughout treatment in IBD patients heterozygous for the NUDT15 R139C.

Sections du résumé

BACKGROUND AND AIM OBJECTIVE

METHODS METHODS

We enrolled 83 Japanese IBD patients who were on anti-tumor necrosis factor-α agents and had used thiopurine. NUDT15 R139C was genotyped by polymerase chain reaction. We retrospectively reviewed patient clinical charts to collect data on white blood cell (WBC) count, mean corpuscular volume (MCV), hemoglobin, and platelet count during the 24 months following thiopurine initiation.

RESULTS RESULTS

The included patients had either Crohn's disease (54; 65.1%) or ulcerative colitis (29; 34.9%). Genotyping of NUDT15 R139C identified 62 patients (74.7%) of genotype C/C and 21 (25.3%) of genotype C/T. The median dose of thiopurine was lower in the C/T group than in the C/C group after starting thiopurine. At 6 months, the mean WBC count of the C/T group became significantly lower than that of the C/C group (P = 0.008) and remained lower through the 24 months. The C/T group developed grade 2-4 leukopenia by 6 months, which persisted through 12-24 months. The mean MCV in the C/T group became higher than that of the C/C group after 3 months.

CONCLUSIONS CONCLUSIONS

NUDT15 R139C heterozygosity affected the WBC count and MCV for 24 months after thiopurine administration. Our results indicate that careful monitoring of leukopenia and dose adjustment are necessary throughout treatment in IBD patients heterozygous for the NUDT15 R139C.

Identifiants

DOI: 10.1111/jgh.14693 PMID: 31045285

pubmed: 31045285

doi: 10.1111/jgh.14693

doi:

Substances chimiques

Anti-Inflammatory Agents 0

Gastrointestinal Agents 0

Mercaptopurine E7WED276I5

NUDT15 protein, human EC 2.6.1.-

Pyrophosphatases EC 3.6.1.-

Azathioprine MRK240IY2L

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

Pagination

1751-1757

Informations de copyright

Références

Nielsen OH, Vainer B, Rask-Madsen J. Review article: the treatment of inflammatory bowel disease with 6-mercaptopurine or azathioprine. Aliment. Pharmacol. Ther. 2001; 15: 1699-1708.

Gisbert JP, Gomollon F. Thiopurine-induced myelotoxicity in patients with inflammatory bowel disease: a review. Am. J. Gastroenterol. 2008; 103: 1783-1800.

de la Spire-Vayron MC, Debuysere H, Mastain B et al. Genotypic and phenotypic analysis of the polymorphic thiopurine S-methyltransferase gene (TPMT) in a European population. Br. J. Pharmacol. 1998; 125: 879-887.

Collie-Duguid ES, Pritchard SC, Powrie RH et al. The frequency and distribution of thiopurine methyltransferase alleles in Caucasian and Asian populations. Pharmacogenetics 1999; 9: 37-42.

Hon YY, Fessing MY, Pui CH, Relling MV, Krynetski EY, Evans WE. Polymorphism of the thiopurine S-methyltransferase gene in African-Americans. Hum. Mol. Genet. 1999; 8: 371-376.

Kumagai K, Hiyama K, Ishioka S et al. Allelotype frequency of the thiopurine methyltransferase (TPMT) gene in Japanese. Pharmacogenetics 2001; 11: 275-278.

Kubota T, Chiba K. Frequencies of thiopurine S-methyltransferase mutant alleles (TPMT*2, *3A, *3B and *3C) in 151 healthy Japanese subjects and the inheritance of TPMT*3C in the family of a propositus. Br. J. Clin. Pharmacol. 2001; 51: 475-477.

Cao Q, Zhu Q, Shang Y, Gao M, Si J. Thiopurine methyltransferase gene polymorphisms in Chinese patients with inflammatory bowel disease. Digestion 2009; 79: 58-63.

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: 1258-1264.

Kim JH, Cheon JH, Hong SS et al. Influences of thiopurine methyltransferase genotype and activity on thiopurine-induced leukopenia in Korean patients with inflammatory bowel disease: a retrospective cohort study. J. Clin. Gastroenterol. 2010; 44: e242-e248.

Iyer SN, Tilak AV, Mukherjee MS, Singhal RS. Genotype frequencies of drug-metabolizing enzymes responsible for purine and pyrimidine antagonists in a healthy Asian-Indian population. Biochem. Genet. 2012; 50: 684-693.

Yang SK, Hong M, Baek J et al. A common missense variant in NUDT15 confers susceptibility to thiopurine-induced leukopenia. Nat. Genet. 2014; 46: 1017-1020.

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; 28: 475-478.

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: 328-337.

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: 22-29.

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: 280-285.

Matsuoka K, Hamada S, Shimizu M et al. Factors predicting the therapeutic response to infliximab during maintenance therapy in Japanese patients with Crohn's disease. PLoS ONE 2018; 13: e0204632.

Bernstein CN, Artinian L, Anton PA, Shanahan F. Low-dose 6-mercaptopurine in inflammatory bowel disease is associated with minimal hematologic toxicity. Dig. Dis. Sci. 1994; 39: 1638-1641.

Thomas CW Jr, Lowry PW, Franklin CL et al. Erythrocyte mean corpuscular volume as a surrogate marker for 6-thioguanine nucleotide concentration monitoring in patients with inflammatory bowel disease treated with azathioprine or 6-mercaptopurine. Inflamm. Bowel Dis. 2003; 9: 237-245.

Kopylov U, Battat R, Benmassaoud A, Paradis-Surprenant L, Seidman EG. Hematologic indices as surrogate markers for monitoring thiopurine therapy in IBD. Dig. Dis. Sci. 2015; 60: 478-484.

Heerasing NM, Ng JF, Dowling D. Does lymphopenia or macrocytosis reflect 6-thioguanine levels in patients with inflammatory bowel disease treated with azathioprine or 6-mercaptopurine? Intern. Med. J. 2016; 46: 465-469.

Kakuta Y, Kawai Y, Okamoto D et al. NUDT15 codon 139 is the best pharmacogenetic marker for predicting thiopurine-induced severe adverse events in Japanese patients with inflammatory bowel disease: a multicenter study. J. Gastroenterol. 2018.

Kojima Y, Hirotsu Y, Omata W et al. Influence of NUDT15 variants on hematological pictures of patients with inflammatory bowel disease treated with thiopurines. World J. Gastroenterol. 2018; 24: 511-518.

Sutiman N, Chen S, Ling KL et al. Predictive role of NUDT15 variants on thiopurine-induced myelotoxicity in Asian inflammatory bowel disease patients. Pharmacogenomics 2018; 19: 31-43.

Soman S, Ashok D, Connolly SA, Cordell SJ, Taylor CJ, Campbell DI. Change in hematologic indices over time in pediatric inflammatory bowel disease treated with azathioprine. Drugs R D 2010; 10: 213-217.

Wickramasinghe SN, Dodsworth H, Rault RM, Hulme B. Observations on the incidence and cause of macrocytosis in patients on azathioprine therapy following renal transplantation. Transplantation 1974; 18: 443-446.

Uchiyama K, Nakamura M, Kubota T, Yamane T, Fujise K, Tajiri H. 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.

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: 44-49.

Krishnamurthy P, Schwab M, Takenaka K et al. Transporter-mediated protection against thiopurine-induced hematopoietic toxicity. Cancer Res. 2008; 68: 4983-4989.

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: 1014-1021.