Observational Study
Copyright ©The Author(s) 2018. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Jan 28, 2018; 24(4): 511-518
Published online Jan 28, 2018. doi: 10.3748/wjg.v24.i4.511
Influence of NUDT15 variants on hematological pictures of patients with inflammatory bowel disease treated with thiopurines
Yuichiro Kojima, Yosuke Hirotsu, Wataru Omata, Makoto Sugimori, Shinya Takaoka, Hiroshi Ashizawa, Keiko Nakagomi, Dai Yoshimura, Kenji Hosoda, Yoji Suzuki, Hitoshi Mochizuki, Masao Omata
Yuichiro Kojima, Shinya Takaoka, Hiroshi Ashizawa, Keiko Nakagomi, Dai Yoshimura, Kenji Hosoda, Yoji Suzuki, Department of Gastroenterology, Yamanashi Prefectural Central Hospital, Yamanashi 400-8506, Japan
Yosuke Hirotsu, Genome Analysis Center, Yamanashi Prefectural Central Hospital, Yamanashi 400-8506, Japan
Wataru Omata, Department of Dermatologic Oncology, National Cancer Institute, Tokyo 104-0045, Japan
Makoto Sugimori, Division of Gastroenterology, Department of Medicine, Yokohama City University, Graduate School of Medicine, Kanagawa 236-0004, Japan
Hitoshi Mochizuki, Masao Omata, Department of Gastroenterology, Genome Analysis Center, Yamanashi Prefectural Central Hospital, Yamanashi 400-8506, Japan
Author contributions: Kojima Y contributed to writing a paper and data acquisition and most of the patients were in his charge; Hirotsu Y, Omata W, Sugimori M and Takaoka S performed genome analysis; Ashizawa H, Nakagomi K, Yoshimura D, Hosoda K and Suzuki Y contributed to the treatment of patients; Mochizuki H contributed to the data analysis; Omata M contributed to the study conception, design, reviewing and final approval of the article.
Institutional review board statement: The protocol was approved by the Institutional Review Board of Yamanashi Prefectural Central Hospital.
Informed consent statement: Written informed consent to conduct genetic analysis of NUDT15 and TPMT was obtained by all 96 patients.
Conflict-of-interest statement: The authors have no conflict of interest to declare.
Data sharing statement: Technical appendix, statistical code, and dataset available from the corresponding author.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Yuichiro Kojima, MD, PhD, Chief Doctor, Department of Gastroenterology, Yamanashi Prefectural Central Hospital, 1-1-1 Fujimi, Kofu, Yamanashi 400-8506, Japan. y-kojima@ych.pref.yamanashi.jp
Telephone: +81-55-2537111 Fax: +81-55-2538011
Received: October 16, 2017
Peer-review started: October 17, 2017
First decision: November 8, 2017
Revised: December 2, 2017
Accepted: December 5, 2017
Article in press: December 4, 2017
Published online: January 28, 2018
Processing time: 101 Days and 11.2 Hours
Abstract
AIM

The single nucleotide polymorphism (SNP) c.415C>T in exon 3 of NUDT15 affects thiopurine-induced leukopenia in Asian patients with Crohn’s disease. Meanwhile, three additional genetic variants of NUDT15 were reported in patients with acute lymphoblastic leukemia. We evaluated the effects of these additional genetic variants of NUDT15 in patients with inflammatory bowel disease (IBD) treated with thiopurines.

METHODS

Ninety-six Japanese patients with IBD were enrolled. Genotyping for the NUDT15 and TPMT genes was performed using Custom TaqMan SNP genotyping assays or Sanger sequencing. The changes in white blood cell (WBC) count, mean corpuscular volume (MCV), platelet count, hemoglobin, CRP, amylase, albumin, AST, ALT, and ESR were evaluated.

RESULTS

Genetic variants of exon 1 and exon 3 of NUDT15 were identified in 24 of 96 patients (25.0%). C.52G > A and c.36_37insGGAGTC in exon 1 were found in three patients each. All three patients with c.36_37insGGAGTC in exon 1 were heterozygotes of p.Arg139Cys in exon 3. Eighteen patients had p.Arg139Cys in exon 3 alone. The WBC count gradually decreased after initiation of thiopurine treatment in the mutated cases (n = 24), and was significantly lower at 6, 8, 10, and 16 wk (P = 0.0271, 0.0037, 0.0051, and 0.0185, respectively). The WBC counts were also evaluated in patients with and without prednisolone treatment. In the patients with prednisolone treatment, the WBC count tended to show a greater decrease in the mutated cases, with significant differences at 8 and 10 wk (P = 0.012 and 0.029, respectively). In the patients without prednisolone treatment, the WBC count was significantly lower at 2, 4, 8, and 14 wk in mutated cases (P = 0.0196, 0.0182, 0.0237 and 0.0241, respectively). MCV increased after starting thiopurine treatment in the mutated cases, and was significantly higher at 10 wk (P = 0.0085). Platelet count, hemoglobin, CRP, amylase, albumin, AST, ALT and ESR did not differ significantly between the wild-type and mutated cases. TPMT mutations were not found in any of the patients.

CONCLUSION

Mutations in exon 1 of NUDT15 also affect thiopurine-induced leukopenia in patients with IBD. To discuss thiopurine-induced leukopenia in more detail, investigation of SNPs in both exon 1 and exon 3 of NUDT15 is needed.

Keywords: Inflammatory bowel disease; NUDT15; Leukopenia; Mean corpuscular volume; Japanese

Core tip: Single nucleotide polymorphism (SNP) in NUDT15 c.415C>T in exon 3 affects thiopurine-induced leukopenia in Asian Crohn’s disease patients. Meanwhile, there is a report of additional three genetic variants of NUDT15 in patients with acute lymphoblastic leukemia. We evaluated the effect of these additional genetic variants of NUDT15 on inflammatory bowel disease (IBD) treated with thiopurines. The increase rate of mean corpuscular volume was higher in the variants than the wild, Mutations of NUDT15 in exon 1 also affects thiopurine-induced leukopenia in patients with IBD. To discuss thiopurine-induced leukopenia, investigating SNPs both exons 1 and exon 3 of NUDT15 is needed.