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

for the MENDEL study group

Research output: Contribution to journalArticle

12 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1-14
Number of pages14
JournalJournal of Gastroenterology
DOIs
Publication statusAccepted/In press - Jun 19 2018

Fingerprint

Pharmacogenetics
Leukopenia
Inflammatory Bowel Diseases
Codon
Multicenter Studies
Alopecia
Area Under Curve
Genome-Wide Association Study
ROC Curve
Haplotypes
Enzymes
Population

Keywords

  • GWAS
  • Inflammatory bowel disease
  • NUDT15
  • Pharmacogenetics
  • Thiopurine

ASJC Scopus subject areas

  • Gastroenterology

Cite this

@article{88ec055151f049bf86eff1368d596930,
title = "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",
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",
author = "{for the MENDEL study group} and Yoichi Kakuta and Yosuke Kawai and Daisuke Okamoto and Tetsuya Takagawa and Kentaro Ikeya and Hirotake Sakuraba and Atsushi Nishida and Shoko Nakagawa and Miki Miura and Takahiko Toyonaga and Kei Onodera and Masaru Shinozaki and Yoh Ishiguro and Shinta Mizuno and Masahiro Takahara and Shunichi Yanai and Ryota Hokari and Tomoo Nakagawa and Hiroshi Araki and Satoshi Motoya and Takeo Naito and Rintaro Moroi and Hisashi Shiga and Katsuya Endo and Taku Kobayashi and Makoto Naganuma and Sakiko Hiraoka and Takayuki Matsumoto and Shiro Nakamura and Hiroshi Nakase and Tadakazu Hisamatsu and Makoto Sasaki and Hiroyuki Hanai and Akira Andoh and Masao Nagasaki and Yoshitaka Kinouchi and Tooru Shimosegawa and Atsushi Masamune and Yasuo Suzuki",
year = "2018",
month = "6",
day = "19",
doi = "10.1007/s00535-018-1486-7",
language = "English",
pages = "1--14",
journal = "Journal of Gastroenterology",
issn = "0944-1174",
publisher = "Springer Japan",

}

TY - JOUR

T1 - NUDT15 codon 139 is the best pharmacogenetic marker for predicting thiopurine-induced severe adverse events in Japanese patients with inflammatory bowel disease

T2 - a multicenter study

AU - for the MENDEL study group

AU - Kakuta, Yoichi

AU - Kawai, Yosuke

AU - Okamoto, Daisuke

AU - Takagawa, Tetsuya

AU - Ikeya, Kentaro

AU - Sakuraba, Hirotake

AU - Nishida, Atsushi

AU - Nakagawa, Shoko

AU - Miura, Miki

AU - Toyonaga, Takahiko

AU - Onodera, Kei

AU - Shinozaki, Masaru

AU - Ishiguro, Yoh

AU - Mizuno, Shinta

AU - Takahara, Masahiro

AU - Yanai, Shunichi

AU - Hokari, Ryota

AU - Nakagawa, Tomoo

AU - Araki, Hiroshi

AU - Motoya, Satoshi

AU - Naito, Takeo

AU - Moroi, Rintaro

AU - Shiga, Hisashi

AU - Endo, Katsuya

AU - Kobayashi, Taku

AU - Naganuma, Makoto

AU - Hiraoka, Sakiko

AU - Matsumoto, Takayuki

AU - Nakamura, Shiro

AU - Nakase, Hiroshi

AU - Hisamatsu, Tadakazu

AU - Sasaki, Makoto

AU - Hanai, Hiroyuki

AU - Andoh, Akira

AU - Nagasaki, Masao

AU - Kinouchi, Yoshitaka

AU - Shimosegawa, Tooru

AU - Masamune, Atsushi

AU - Suzuki, Yasuo

PY - 2018/6/19

Y1 - 2018/6/19

N2 - 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.

AB - 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.

KW - GWAS

KW - Inflammatory bowel disease

KW - NUDT15

KW - Pharmacogenetics

KW - Thiopurine

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U2 - 10.1007/s00535-018-1486-7

DO - 10.1007/s00535-018-1486-7

M3 - Article

SP - 1

EP - 14

JO - Journal of Gastroenterology

JF - Journal of Gastroenterology

SN - 0944-1174

ER -