PMID- 29923122
OWN - NLM
STAT- MEDLINE
DCOM- 20190711
LR  - 20210212
IS  - 1435-5922 (Electronic)
IS  - 0944-1174 (Print)
IS  - 0944-1174 (Linking)
VI  - 53
IP  - 9
DP  - 2018 Sep
TI  - 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.
PG  - 1065-1078
LID - 10.1007/s00535-018-1486-7 [doi]
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 (r(2) = 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.
FAU - Kakuta, Yoichi
AU  - Kakuta Y
AUID- ORCID: 0000-0002-7042-009X
AD  - Division of Gastroenterology, Tohoku University Graduate School of Medicine, 1-1 
      Seiryo, Aoba, Sendai, 980-8574, Japan. ykakuta@med.tohoku.ac.jp.
FAU - Kawai, Yosuke
AU  - Kawai Y
AD  - Department of Integrative Genomics, Tohoku Medical Megabank Organization, Tohoku 
      University, Sendai, Japan.
AD  - Department of Human Genetics, Graduate School of Medicine, University of Tokyo, 
      Tokyo, Japan.
FAU - Okamoto, Daisuke
AU  - Okamoto D
AD  - Division of Gastroenterology, Tohoku University Graduate School of Medicine, 1-1 
      Seiryo, Aoba, Sendai, 980-8574, Japan.
FAU - Takagawa, Tetsuya
AU  - Takagawa T
AD  - Division of Internal Medicine, Department of Inflammatory Bowel Disease, Hyogo 
      College of Medicine, Nishinomiya, Japan.
FAU - Ikeya, Kentaro
AU  - Ikeya K
AD  - Centre for Gastroenterology and Inflammatory Bowel Disease Research, Hamamatsu 
      South Hospital, Hamamatsu, Japan.
FAU - Sakuraba, Hirotake
AU  - Sakuraba H
AD  - Department of Gastroenterology and Hematology, Hirosaki University Graduate 
      School of Medicine, Hirosaki, Japan.
FAU - Nishida, Atsushi
AU  - Nishida A
AD  - Department of Gastroenterology, Shiga University of Medical Science, Otsu, Japan.
FAU - Nakagawa, Shoko
AU  - Nakagawa S
AD  - Division of Gastroenterology, Department of Internal Medicine, Aichi Medical 
      University School of Medicine, Nagakute, Japan.
FAU - Miura, Miki
AU  - Miura M
AD  - The Third Department of Internal Medicine, Kyorin University School of Medicine, 
      Mitaka, Japan.
FAU - Toyonaga, Takahiko
AU  - Toyonaga T
AD  - Center for Advanced IBD Research and Treatment, Kitasato University Kitasato 
      Institute Hospital, Tokyo, Japan.
FAU - Onodera, Kei
AU  - Onodera K
AD  - Department of Gastroenterology and Hepatology, Sapporo Medical University School 
      of Medicine, Sapporo, Japan.
FAU - Shinozaki, Masaru
AU  - Shinozaki M
AD  - Department of Surgery, IMSUT Hospital, The Institute of Medical Science, The 
      University of Tokyo, Tokyo, Japan.
FAU - Ishiguro, Yoh
AU  - Ishiguro Y
AD  - Department of Gastroenterology and Hematology, Hirosaki National Hospital, 
      Hirosaki, Japan.
FAU - Mizuno, Shinta
AU  - Mizuno S
AD  - Division of Gastroenterology and Hepatology, Department of Internal Medicine, 
      Keio University School of Medicine, Tokyo, Japan.
FAU - Takahara, Masahiro
AU  - Takahara M
AD  - Department of Gastroenterology and Hepatology, Okayama University Graduate School 
      of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan.
FAU - Yanai, Shunichi
AU  - Yanai S
AD  - Division of Gastroenterology, Department of Internal Medicine, School of 
      Medicine, Iwate Medical University, Morioka, Japan.
FAU - Hokari, Ryota
AU  - Hokari R
AD  - Division of Gastroenterology and Hepatology, Department of Internal Medicine, 
      National Defense Medical College, Tokorozawa, Japan.
FAU - Nakagawa, Tomoo
AU  - Nakagawa T
AD  - Department of Gastroenterology, Graduate School of Medicine, Chiba University, 
      Chiba, Japan.
FAU - Araki, Hiroshi
AU  - Araki H
AD  - Division of Endscopy, Gifu University Hospital, Gifu, Japan.
FAU - Motoya, Satoshi
AU  - Motoya S
AD  - IBD Center, Sapporo-Kosei General Hospital, Sapporo, Japan.
FAU - Naito, Takeo
AU  - Naito T
AD  - Division of Gastroenterology, Tohoku University Graduate School of Medicine, 1-1 
      Seiryo, Aoba, Sendai, 980-8574, Japan.
FAU - Moroi, Rintaro
AU  - Moroi R
AD  - Division of Gastroenterology, Tohoku University Graduate School of Medicine, 1-1 
      Seiryo, Aoba, Sendai, 980-8574, Japan.
FAU - Shiga, Hisashi
AU  - Shiga H
AD  - Division of Gastroenterology, Tohoku University Graduate School of Medicine, 1-1 
      Seiryo, Aoba, Sendai, 980-8574, Japan.
FAU - Endo, Katsuya
AU  - Endo K
AD  - Division of Gastroenterology, Tohoku University Graduate School of Medicine, 1-1 
      Seiryo, Aoba, Sendai, 980-8574, Japan.
FAU - Kobayashi, Taku
AU  - Kobayashi T
AD  - Center for Advanced IBD Research and Treatment, Kitasato University Kitasato 
      Institute Hospital, Tokyo, Japan.
FAU - Naganuma, Makoto
AU  - Naganuma M
AD  - Division of Gastroenterology and Hepatology, Department of Internal Medicine, 
      Keio University School of Medicine, Tokyo, Japan.
FAU - Hiraoka, Sakiko
AU  - Hiraoka S
AD  - Department of Gastroenterology and Hepatology, Okayama University Graduate School 
      of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan.
FAU - Matsumoto, Takayuki
AU  - Matsumoto T
AD  - Division of Gastroenterology, Department of Internal Medicine, School of 
      Medicine, Iwate Medical University, Morioka, Japan.
FAU - Nakamura, Shiro
AU  - Nakamura S
AD  - Division of Internal Medicine, Department of Inflammatory Bowel Disease, Hyogo 
      College of Medicine, Nishinomiya, Japan.
FAU - Nakase, Hiroshi
AU  - Nakase H
AD  - Department of Gastroenterology and Hepatology, Sapporo Medical University School 
      of Medicine, Sapporo, Japan.
FAU - Hisamatsu, Tadakazu
AU  - Hisamatsu T
AD  - The Third Department of Internal Medicine, Kyorin University School of Medicine, 
      Mitaka, Japan.
FAU - Sasaki, Makoto
AU  - Sasaki M
AD  - Division of Gastroenterology, Department of Internal Medicine, Aichi Medical 
      University School of Medicine, Nagakute, Japan.
FAU - Hanai, Hiroyuki
AU  - Hanai H
AD  - Centre for Gastroenterology and Inflammatory Bowel Disease Research, Hamamatsu 
      South Hospital, Hamamatsu, Japan.
FAU - Andoh, Akira
AU  - Andoh A
AD  - Department of Gastroenterology, Shiga University of Medical Science, Otsu, Japan.
FAU - Nagasaki, Masao
AU  - Nagasaki M
AD  - Department of Integrative Genomics, Tohoku Medical Megabank Organization, Tohoku 
      University, Sendai, Japan.
FAU - Kinouchi, Yoshitaka
AU  - Kinouchi Y
AD  - Health Administration Center, Center for the Advancement of Higher Education, 
      Tohoku University, Sendai, Japan.
FAU - Shimosegawa, Tooru
AU  - Shimosegawa T
AD  - Division of Gastroenterology, Tohoku University Graduate School of Medicine, 1-1 
      Seiryo, Aoba, Sendai, 980-8574, Japan.
FAU - Masamune, Atsushi
AU  - Masamune A
AD  - Division of Gastroenterology, Tohoku University Graduate School of Medicine, 1-1 
      Seiryo, Aoba, Sendai, 980-8574, Japan.
FAU - Suzuki, Yasuo
AU  - Suzuki Y
AD  - Department of Internal Medicine, Toho University Sakura Medical Center, Sakura, 
      Japan.
CN  - MENDEL study group
LA  - eng
GR  - 18kk0305002/Japan Agency for Medical Research and Development/
GR  - 16km0405205h0101/Japan Agency for Medical Research and Development/
PT  - Journal Article
PT  - Multicenter Study
DEP - 20180619
PL  - Japan
TA  - J Gastroenterol
JT  - Journal of gastroenterology
JID - 9430794
RN  - 0 (Antibodies, Monoclonal)
RN  - 0 (Biomarkers, Pharmacological)
RN  - 0 (Immunosuppressive Agents)
RN  - 3XC8GUZ6CB (Sulfasalazine)
RN  - 4Q81I59GXC (Mesalamine)
RN  - E7WED276I5 (Mercaptopurine)
RN  - EC 2.6.1.- (NUDT15 protein, human)
RN  - EC 3.6.1.- (Pyrophosphatases)
RN  - MRK240IY2L (Azathioprine)
SB  - IM
MH  - Alopecia/chemically induced
MH  - Antibodies, Monoclonal/adverse effects/therapeutic use
MH  - Azathioprine/*adverse effects/*therapeutic use
MH  - *Biomarkers, Pharmacological
MH  - Genetic Predisposition to Disease
MH  - Genome-Wide Association Study
MH  - Genomic Structural Variation
MH  - Haplotypes
MH  - Humans
MH  - Immunosuppressive Agents/*adverse effects/*therapeutic use
MH  - Inflammatory Bowel Diseases/*drug therapy
MH  - Japan
MH  - Leukopenia/chemically induced
MH  - Logistic Models
MH  - Mercaptopurine/*adverse effects/*therapeutic use
MH  - Mesalamine/adverse effects/therapeutic use
MH  - Pharmacogenetics
MH  - Pyrophosphatases/*genetics
MH  - ROC Curve
MH  - Retrospective Studies
MH  - Risk
MH  - Sulfasalazine/adverse effects/therapeutic use
PMC - PMC6132901
OTO - NOTNLM
OT  - GWAS
OT  - Inflammatory bowel disease
OT  - NUDT15
OT  - Pharmacogenetics
OT  - Thiopurine
COIS- 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.
EDAT- 2018/06/21 06:00
MHDA- 2019/07/12 06:00
PMCR- 2018/06/19
CRDT- 2018/06/21 06:00
PHST- 2018/06/12 00:00 [received]
PHST- 2018/06/13 00:00 [accepted]
PHST- 2018/06/21 06:00 [pubmed]
PHST- 2019/07/12 06:00 [medline]
PHST- 2018/06/21 06:00 [entrez]
PHST- 2018/06/19 00:00 [pmc-release]
AID - 10.1007/s00535-018-1486-7 [pii]
AID - 1486 [pii]
AID - 10.1007/s00535-018-1486-7 [doi]
PST - ppublish
SO  - J Gastroenterol. 2018 Sep;53(9):1065-1078. doi: 10.1007/s00535-018-1486-7. Epub 
      2018 Jun 19.