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Multicenter Study
. 2018 Sep;53(9):1065-1078.
doi: 10.1007/s00535-018-1486-7. Epub 2018 Jun 19.

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

Yoichi Kakuta  1 , Yosuke Kawai  2   3 , Daisuke Okamoto  4 , Tetsuya Takagawa  5 , Kentaro Ikeya  6 , Hirotake Sakuraba  7 , Atsushi Nishida  8 , Shoko Nakagawa  9 , Miki Miura  10 , Takahiko Toyonaga  11 , Kei Onodera  12 , Masaru Shinozaki  13 , Yoh Ishiguro  14 , Shinta Mizuno  15 , Masahiro Takahara  16 , Shunichi Yanai  17 , Ryota Hokari  18 , Tomoo Nakagawa  19 , Hiroshi Araki  20 , Satoshi Motoya  21 , Takeo Naito  4 , Rintaro Moroi  4 , Hisashi Shiga  4 , Katsuya Endo  4 , Taku Kobayashi  11 , Makoto Naganuma  15 , Sakiko Hiraoka  16 , Takayuki Matsumoto  17 , Shiro Nakamura  5 , Hiroshi Nakase  12 , Tadakazu Hisamatsu  10 , Makoto Sasaki  9 , Hiroyuki Hanai  6 , Akira Andoh  8 , Masao Nagasaki  2 , Yoshitaka Kinouchi  22 , Tooru Shimosegawa  4 , Atsushi Masamune  4 , Yasuo Suzuki  23 ; MENDEL study group
Affiliations
Multicenter Study

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

Yoichi Kakuta et al. J Gastroenterol. 2018 Sep.

Abstract

Background: Despite NUDT15 variants showing significant association with thiopurine-induced adverse events (AEs) in Asians, it remains unclear which variants of NUDT15 or whether additional genetic variants should be tested to predict AEs. To clarify the best pharmacogenetic test to be used clinically, we performed association studies of NUDT15 variants and haplotypes with AEs, genome-wide association study (GWAS) to discover additional variants, and ROC analysis to select the model to predict severe AEs.

Methods: Overall, 2630 patients with inflammatory bowel disease (IBD) were enrolled and genotyped for NUDT15 codon 139; 1291 patients were treated with thiopurines. diplotypes were analyzed in 970 patients, and GWASs of AEs were performed with 1221 patients using population-optimized genotyping array and imputation.

Results: We confirmed the association of NUDT15 p.Arg139Cys with leukopenia and alopecia (p = 2.20E-63, 1.32E-69, OR = 6.59, 12.1, respectively), and found a novel association with digestive symptoms (p = 6.39E-04, OR = 1.89). Time to leukopenia was significantly shorter, and when leukopenia was diagnosed, thiopurine doses were significantly lower in Arg/Cys and Cys/Cys than in Arg/Arg. In GWASs, no additional variants were found to be associated with thiopurine-induced AEs. Despite strong correlation of leukopenia frequency with estimated enzyme activities based on the diplotypes (r2 = 0.926, p = 0.0087), there were no significant differences in the AUCs of diplotypes from those of codon 139 to predict severe AEs (AUC = 0.916, 0.921, for acute severe leukopenia, AUC = 0.990, 0.991, for severe alopecia, respectively).

Conclusions: Genotyping of NUDT15 codon 139 was sufficient to predict acute severe leukopenia and alopecia in Japanese patients with IBD.

Keywords: GWAS; Inflammatory bowel disease; NUDT15; Pharmacogenetics; Thiopurine.

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Conflict of interest statement

Ryota Hokari received commercial research funding from EA pharma Co. Ltd and Chugai pharma Co. Ltd; Taku Kobayashi received lecture fees from Mitsubishi Tanabe Pharma Corporation, AbbVie Inc., Takeda Pharmaceutical Co. Ltd, and Janssen Pharmaceutical K.K.; Makoto Naganuma received commercial research funding from Mochida Pharmaceuticals Co. Ltd; Masaru Shinozaki received research grants from Mitsubishi Tanabe Pharma Co., Ltd; Shiro Nakamura received a commercial research funding from AbbVie Inc., Kyorin Pharmaceutical Co. Ltd, Mitsubishi Tanabe Pharma Corporation, Astellas Pharma Inc., Asahi Kasei Medical Co. Ltd, Ajinomoto Pharmaceuticals Co. Ltd, Eisai Co. Ltd, JIMRO Co. Ltd, Otsuka Pharmaceutical Co. Ltd, Otsuka Pharmaceutical Factory Inc., UCB Japan Co. Ltd, and Zeria Pharmaceutical Co. Ltd; Hiroshi Nakase received lecture fees from Mitsubishi Tanabe Pharma Corporation, Mochida Pharmaceuticals Co. Ltd, and Janssen Pharmaceutical K.K., and received commercial research funding from Hoya group Pentax Medical, Boehringer Ingelheim GmbH, and Daiichi-Sankyo Co. Ltd; Tadakazu Hisamatsu received lecture fees from EA pharma Co. Ltd, AbbVie GK, Celgene K.K., Janssen Pharmaceutical K.K., Pfizer Inc., Mitsubishi Tanabe Pharma Corporation, Kyorin Pharmaceutical Co. Ltd, JIMRO Co. Mochida Pharmaceutical Co., Ltd Nichi-Iko Pharmaceutical Co., Ltd, and received commercial research funding from Mitsubishi Tanabe Pharma Corporation, EA pharma Co. Ltd, AbbVie GK, Daiichi-Sankyo, Kyorin Pharmaceutical Co. Ltd, Takeda Pharmaceutical Co. Ltd, Pfizer Inc., Mochida Pharmaceutical Co., Ltd; Masao Nagasaki held the concurrent post at Department of Cohort Genome Information Analysis endowed by Toshiba Corporation until March 2017, and received a research funding from Toshiba Corporation until March 2017; Yasuo Suzuki received lecture fees from AbbVie Inc., Kyorin Pharmaceutical Co. Ltd, Mitsubishi Tanabe Pharma Corporation, EA Pharma Co. Ltd, Mochida Pharmaceuticals Co. Ltd, and Zeria Pharmaceutical Co. Ltd; and received commercial research funding from AbbVie Inc., Mitsubishi Tanabe Pharma Corporation, EA Pharma Co. Ltd, JIMRO Co. Ltd, Mochida Pharmaceuticals Co. Ltd, and NIPPON KAYAKU Co. Ltd.

Figures

Fig. 1
Fig. 1
Flow of the analysis in this study. In total, 2630 patients with IBD were enrolled. All the patients were genotyped for NUDT15 codon 139. The number of patients exposed to thiopurines was 1291; additional genetic analyses were performed on 995 of these 1291 patients. This study consisted of five analyses: (analysis 1) association study of NUDT15 p.Arg139Cys with adverse events of other IBD drugs; (analysis 2) association analysis of NUDT15 codon 139 with thiopurine-induced adverse events; (analysis 3) diplotype-based association study of NUDT15 with thiopurines; (analysis 4) GWAS of thiopurine-induced adverse events; (analysis 5) ROC analysis to investigate the best model to predict thiopurine-induced severe AEs in Japanese patients with IBD
Fig. 2
Fig. 2
Time to leukopenia and the doses of AZA according to the genotype of NUDT15 codon 139. a Time to leukopenia after starting treatment with thiopurines is plotted in terms of the genotype. Average time to leukopenia in patients with the Cys/Cys and Arg/Cys genotypes was significantly shorter than that for those with the Arg/Arg genotype. b Doses of thiopurines at the time when severe leukopenia was diagnosed were plotted. The 6-MP dose was adjusted to AZA equivalents by multiplying by 2.08. The dose of the patients carrying the p.Arg139Cys allele was significantly lower than that of the patients with Arg/Arg. *p < 0.05, **p < 0.005
Fig. 3
Fig. 3
Manhattan plots for results of the discovery and conditional GWASs for thiopurine-induced leukopenia and alopecia in Japanese individuals. Single-nucleotide polymorphisms are plotted according to chromosomal location, with the − log10(P) from the results of GWASs. The red line indicates the threshold for genome-wide significance (p = 1E−8). The blue line indicates the threshold for nominal significance (p = 1E−6). a GWAS for thiopurine-induced leukopenia, b conditional GWAS for leukopenia on rs116855232 (p.Arg139Cys), c GWAS for alopecia, and d conditional GWAS for alopecia on rs116855232. All significant associations disappeared in the conditional GWASs
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