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
ARTICLE HIGHLIGHTS
Research background

Previous study demonstrated that single nucleotide polymorphism (SNP) in NUDT15 c.415C>T (encoding p.Arg139Cys) in exon 3 affects thiopurine-induced leukopenia in Asian patients with inflammatory bowel disease (IBD). In acute lymphoblastic leukemia (ALL), there are other variants of NUDT15 in exon 1 and exon 3. We demonstrated the variants of c.36_37insGGAGTC (encoding p.Val18_Val19insGlyVal) and c.52G > A (encoding p.Val18Ile) in exon 1 also affect the thiopurine-induced leukopenia. To present thiopurine-induced leukopenia and other side effects, checking both exons 1 and exon 3 of NUDT15 is definitely needed.

Research motivations

It is well known that leukopenia is one of the most important adverse effects of thiopurines. To distinguish the high risk group of the adverse effects is clinically very important. Thus we investigated other NUDT15 variants than NUDT15 c.415 C > T in exon 3.

Research objectives

The main of this paper is to investigate other NUDT15 variants than c.415 > T have an effect on hematological pictures including WBC count.

Research methods

We enrolled 96 Japanese patients with IBD. Genotyping for NUDT15 and TPMT genes was performed using Custom TaqMan SNP genotyping assays or Sanger sequencing. The changes of white blood cell (WBC) count, mean corpuscular volume (MCV), platelet count, hemoglobin, CRP, amylase, albumin, AST, ALT and ESR were analyzed.

Research results

In 24 out of 96 patients (25.0%), genetic variants of exons 1 and 3 were identified. C.52G > A and c.36_37insGGAGTC in exon 1 was found in 3 cases each. All 3 cases of c.36_37insGGAGTC in exon 1 had heterozygote of p.Arg139Cys in exon 3. Eighteen patients showed p.Arg139Cys in exon 3 alone. WBC count gradually decreased after thiopurine was started in the mutant (n = 24). The WBC count of the mutant was statistically significantly lower at 6, 8, 10 and 16 wk (P = 0.0271, 0.0037, 0.0051 and 0.0185, respectively). We also analyzed WBC count in the cases with and without prednisolone. In the cases with prednisolone, WBC count tended to decrease more in the mutant cases and was significantly lower at 8 and 10 wk (P = 0.012 and 0.029, respectively). In the cases without prednisolone, WBC count was significantly lower at 2, 4, 8 and 14 wk in the mutant than the wild cases (P = 0.0196, 0.0182, 0.0237 and 0.0241, respectively). MCV increased after starting thiopurine in the mutant. MCV was significantly higher at 10 wk in the mutant than the wild cases (P = 0.0085). Platelet count, hemoglobin, CRP, amylase, albumin, AST, ALT, and ESR was not different between the wild and the mutant cases. TPMT mutation was not found in any of our Japanese patients.

Research conclusions

We reported NUDT15 variant in exon 1 also affect thiopurine-induced leukopenia in patients with IBD. Before starting the treatment with thiopurines for patients with IBD, NUDT15 variant in exon 1 and 3 will be routinely performed for preventing adverse events of thiopurines in the near future.

Research perspectives

There are other NUDT15 variants which are reported in patients with ALL and near future their role on IBD patients will be investigated.