Intestinal Research 2017; 15(3): 328-337  http://dx.doi.org/10.5217/ir.2017.15.3.328
NUDT15 , FTO , and RUNX1 genetic variants and thiopurine intolerance among Japanese patients with inflammatory bowel diseases
Toshiyuki Sato1*, Tetsuya Takagawa1,2*, Yoichi Kakuta3, Akihiro Nishio1, Mikio Kawai1, Koji Kamikozuru1, Yoko Yokoyama1, Yuko Kita1, Takako Miyazaki1, Masaki Iimuro1, Nobuyuki Hida1, Kazutoshi Hori1,2, Hiroki Ikeuchi4, Shiro Nakamura1,2
1Division of Internal Medicine, Department of Inflammatory Bowel Disease, 2Department of Intestinal Inflammation Research, Hyogo
College of Medicine, Nishinomiya, 3Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, 4Department of Inflammatory Bowel Disease Surgery, Hyogo College of Medicine, Nishinomiya, Japan
Correspondence to: Tetsuya Takagawa, Division of Internal Medicine, Department of Inflammatory Bowel Disease, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya 663-8501, Japan.  Tel: +81-798-45-6663, Fax: +81-798-45-6790, E-mail: takagawa@hyo-med.ac.jp
*These authors contributed equally to this study.
Received: December 27, 2016; Revised: February 15, 2017; Accepted: February 24, 2017; Published online: May 22, 2017.
© Korean Association for the Study of Intestinal Diseases. All rights reserved.

Abstract
Background/Aims: Recent genome-wide analyses have provided strong evidence concerning adverse events caused by thiopurine drugs such as azathioprine (AZA) and 6-mercaptopurine. The strong associations identified between NUDT15 p.Arg139Cys and thiopurine-induced leukopenia and severe hair loss have been studied and confirmed over the last 2 years. However, other coding variants, including NUDT15 p.Val18_Val19insGlyVal, NUDT15 p.Val18Ile, and FTO p.Ala134Thr, and a noncoding variation in RUNX1 (rs2834826) remain to be examined in detail in this respect. Therefore, we investigated the correlation between these adverse events and the 5 recently identified variants mentioned above among Japanese patients with inflammatory bowel diseases (IBD). Methods: One hundred sixty thiopurine-treated patients with IBD were enrolled. Genotyping was performed using TaqMan SNP Genotyping Assays or Sanger sequencing. Results: None of the 5 variants were associated with gastrointestinal intolerance to AZA. However, NUDT15 p.Arg139Cys was significantly associated with the interval between initiation and discontinuation of AZA among patients with gastrointestinal intolerance. This variant was strongly associated with early (<8 weeks) and late (≥8 weeks) leukopenia and severe hair loss. Moreover, it correlated with the interval between initiation of thiopurine therapy and leukopenia occurrence, and average thiopurine dose. NUDT15 p.Val18_Val19insGlyVal, NUDT15 p.Val18Ile, FTO p.Ala134Thr, and RUNX1 rs2834826 exhibited no significant relationship with the adverse events examined. Conclusions: Of the 5 variants investigated, NUDT15 p.Arg139Cys had the strongest impact on thiopurineinduced leukopenia and severe hair loss; therefore, its genotyping should be prioritized over that of other variants in efforts to predict these adverse events in Japanese patients with IBD. (Intest Res 2017;15:328-337)
Keywords: NUDT15 ; FTO ; Thiopurine; Leukopenia; Inflammatory bowel disease


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