Intest Res.  2017 Jul;15(3):328-337. 10.5217/ir.2017.15.3.328.

NUDT15, FTO, and RUNX1 genetic variants and thiopurine intolerance among Japanese patients with inflammatory bowel diseases

• Sato T
• Takagawa T
• Kakuta Y
• Nishio A
• Kawai M
• Kamikozuru K
• Yokoyama Y
• Kita Y
• Miyazaki T
• Iimuro M
• Hida N
• Hori K
• Ikeuchi H
• Nakamura S

• KMID: 2382376
• DOI: http://doi.org/10.5217/ir.2017.15.3.328

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 thiopurine-induced 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.

Keyword

NUDT15; FTO; Thiopurine; Leukopenia; Inflammatory bowel disease

MeSH Terms

6-Mercaptopurine
Asian Continental Ancestry Group*
Azathioprine
Clinical Coding
Hair
Humans
Inflammatory Bowel Diseases*
Leukopenia
6-Mercaptopurine
Azathioprine

Figure

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  Fig. 1 Interval from initiation to discontinuation of azathioprine among patients with gastrointestinal intolerance.

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  Fig. 2 (A) Interval from initiation of thiopurine treatment to leukopenia development according to NUDT15 p.Arg139Cys genotype. (B) Association between NUDT15 p.Arg139Cys genotype and thiopurine dose tolerated.

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