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NUDT15, FTO, and RUNX1 genetic variants and thiopurine intolerance among Japanese patients with inflammatory bowel diseases
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Toshiyuki Sato, Tetsuya Takagawa, Yoichi Kakuta, Akihiro Nishio, Mikio Kawai, Koji Kamikozuru, Yoko Yokoyama, Yuko Kita, Takako Miyazaki, Masaki Iimuro, Nobuyuki Hida, Kazutoshi Hori, Hiroki Ikeuchi, Shiro Nakamura
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Intest Res 2017;15(3):328-337. Published online June 12, 2017
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DOI: https://doi.org/10.5217/ir.2017.15.3.328
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 Abstract
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- <b>Background/Aims</b><br/>
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). MethodsOne hundred sixty thiopurine-treated patients with IBD were enrolled. Genotyping was performed using TaqMan SNP Genotyping Assays or Sanger sequencing. ResultsNone 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. ConclusionsOf 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.
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Citations
Citations to this article as recorded by  - A case of rapidly progressive hair loss due to azathioprine, and the prevalence of NUDT15 variants among Japanese patients with autoimmune blistering diseases: A single‐center retrospective observational study
Sho Katayama, Kentaro Izumi, Inkin Ujiie, Hideyuki Ujiie
The Journal of Dermatology.2025; 52(2): 363. CrossRef - Comparative study on the pathogenesis of Crohn’s disease and ulcerative colitis
Qi-Hang Yang, Chuang-Nian Zhang
World Journal of Gastroenterology.2025;[Epub] CrossRef - Real-world NUDT15 genotyping and thiopurine treatment optimization in inflammatory bowel disease: a multicenter study
Motoki Makuuchi, Yoichi Kakuta, Junji Umeno, Toshimitsu Fujii, Tetsuya Takagawa, Takashi Ibuka, Miki Miura, Yu Sasaki, Sakuma Takahashi, Hiroshi Nakase, Hiroki Kiyohara, Keiichi Tominaga, Yosuke Shimodaira, Sakiko Hiraoka, Nobuhiro Ueno, Shunichi Yanai, T
Journal of Gastroenterology.2024; 59(6): 468. CrossRef - Differences in the risk of clinical failure between thiopurine and methotrexate in bio-naïve patients with Crohn’s disease: a Korean nationwide population-based study
Yu Kyung Jun, Eunjeong Ji, Hye Ran Yang, Yonghoon Choi, Cheol Min Shin, Young Soo Park, Nayoung Kim, Dong Ho Lee, Hyuk Yoon
Therapeutic Advances in Gastroenterology.2024;[Epub] CrossRef - A systematic review of aspects of NUDT15 pharmacogenomic variants and thiopurine-induced myelosuppression
Rachel Palmer, Jaime Peters
RPS Pharmacy and Pharmacology Reports.2024;[Epub] CrossRef - m6A modification in inflammatory bowel disease provides new insights into clinical applications
Jiamin Zhang, Bimei Song, Yue Zeng, Chao Xu, Liang Gao, Yan Guo, Jingbo Liu
Biomedicine & Pharmacotherapy.2023; 159: 114298. CrossRef - Targeting FTO by Dac51 contributes to attenuating DSS-induced colitis
Chunyan Peng, Chang Zheng, Fan Zhou, Ying Xie, Lei Wang, Deyan Chen, Xiaoqi Zhang
International Immunopharmacology.2023; 116: 109789. CrossRef - Single-Nucleotide Polymorphisms, c.415C > T (Arg139Cys) and c.416G > A (Arg139His), in the NUDT15 Gene Are Associated with Thiopurine-Induced Leukopenia
Tetsuichiro Isono, Daiki Hira, Yoshito Ikeda, Masahiro Kawahara, Satoshi Noda, Atsushi Nishida, Osamu Inatomi, Noriki Fujimoto, Akira Andoh, Tomohiro Terada, Shin-ya Morita
Biological and Pharmaceutical Bulletin.2023; 46(3): 412. CrossRef - Evaluation of FTO polymorphism in 6-mercaptopurine related intolerance in children with acute lymphoblastic leukemia
Minu Singh, Divya Bhaskar, Prateek Bhatia, Rozy Thakur, Pankaj Sharma, Deepak Bansal, Richa Jain, Amita Trehan
Cancer Chemotherapy and Pharmacology.2023; 92(1): 51. CrossRef - Time to incorporate preemptive NUDT15 testing before starting thiopurines in inflammatory bowel disease in Asia and beyond: a review
Devendra Desai, Anuraag Jena, Vishal Sharma, Toshifumi Hibi
Expert Review of Clinical Pharmacology.2023; 16(7): 643. CrossRef - Safety and efficacy of personalized versus standard initial dosing of thiopurines: Systematic review and meta-analysis of randomized trials
Anuraag Jena, Chhagan L Birda, Arup Choudhury, Vishal Sharma
Expert Opinion on Drug Safety.2023; 22(12): 1253. CrossRef - Comparative assessment of anti-cancer drugs against NUDT15 variants to prevent leucopenia side effect in leukemia patients
V. Janakiraman, M. Sudhan, Khalaf F. Alsharif, Ibrahim F. Halawani, Shiek S.S.J. Ahmed, Shankargouda Patil
Journal of Genetic Engineering and Biotechnology.2023; 21(1): 82. CrossRef - A rare case of Azathioprine-induced leukopenia in an European woman
Wautier Séverine, De Koninck Xavier, Coche Jean-Charles
Acta Clinica Belgica.2022; 77(1): 163. CrossRef - NUDT15 is a key genetic factor for prediction of hematotoxicity in pediatric patients who received a standard low dosage regimen of 6-mercaptopurine
Kanyarat Khaeso, Patcharee Komvilaisak, Su-on Chainansamit, Nontaya Nakkam, Kunanya Suwannaying, Pitchayanan Kuwatjanakul, Keiko Hikino, Areerat Dornsena, Sirimas Kanjanawart, Napat Laoaroon, Suda Vannaprasaht, Takeshi Taketani, Wichittra Tassaneeyakul
Drug Metabolism and Pharmacokinetics.2022; 43: 100436. CrossRef - Nudix Hydroxylase 15 Mutations Strongly Predict Thiopurine-Induced Leukopenia Across Different Asian Ethnicities: Implications for Screening in a Diverse Population
Xin-Hui Khoo, Shin Yee Wong, Nik Razima Wan Ibrahim, Ruey Terng Ng, Kee Seang Chew, Way Seah Lee, Zhi Qin Wong, Raja Affend Raja Ali, Shahreedhan Shahrani, Alex Hwong-Ruey Leow, Ida Normiha Hilmi
Frontiers in Medicine.2022;[Epub] CrossRef - NUDT15Genotyping in Thiopurine Drug Therapy
Jong Kwon Lee, Rihwa Choi, Soo-Youn Lee
Laboratory Medicine Online.2022; 12(4): 217. CrossRef - Personalized medicine to implementation science: Thiopurines set for the leap
Vishal Sharma, Saurabh Kedia, Vineet Ahuja
JGH Open.2022; 6(10): 651. CrossRef - Pharmacogenetic determinants of thiopurines in an Indian cohort
Shaik Mohammad Naushad, Mekala Janaki Ramaiah, Vijay Kumar Kutala, Tajamul Hussain, Salman A. Alrokayan
Pharmacological Reports.2021; 73(1): 278. CrossRef - The Emerging Clinical Application of m6A RNA Modification in Inflammatory Bowel Disease and Its Associated Colorectal Cancer
Xinwei Xu, Jintu Huang, Dickson Kofi Wiredu Ocansey, Yuxuan Xia, Zihan Zhao, Zhiwei Xu, Yongmin Yan, Xu Zhang, Fei Mao
Journal of Inflammation Research.2021; Volume 14: 3289. CrossRef - Importance of NUDT15 Polymorphisms in Thiopurine Treatments
Yoichi Tanaka, Yoshiro Saito
Journal of Personalized Medicine.2021; 11(8): 778. CrossRef - Randomised clinical trial: dose optimising strategy by NUDT15 genotyping reduces leucopenia during thiopurine treatment of Crohn's disease
Kang Chao, Yibiao Huang, Xia Zhu, Jian Tang, Xueding Wang, Lang Lin, Huili Guo, Caibin Zhang, Miao Li, Qingfan Yang, Jie Huang, Lingna Ye, Pinjin Hu, Min Huang, Qian Cao, Xiang Gao
Alimentary Pharmacology & Therapeutics.2021; 54(9): 1124. CrossRef - Meta-Analysis of NUDT15 Genetic Polymorphism on Thiopurine-Induced Myelosuppression in Asian Populations
Kanyarat Khaeso, Sariya Udayachalerm, Patcharee Komvilaisak, Su-on Chainansamit, Kunanya Suwannaying, Napat Laoaroon, Pitchayanan Kuwatjanakul, Nontaya Nakkam, Chonlaphat Sukasem, Apichaya Puangpetch, Wichittra Tassaneeyakul, Nathorn Chaiyakunapruk
Frontiers in Pharmacology.2021;[Epub] CrossRef - High-resolution melt analysis enables simple genotyping of complicated polymorphisms of codon 18 rendering the NUDT15 diplotype
Yoichi Kakuta, Yasuhiro Izumiyama, Daisuke Okamoto, Takeru Nakano, Ryo Ichikawa, Takeo Naito, Rintaro Moroi, Masatake Kuroha, Yoshitake Kanazawa, Tomoya Kimura, Hisashi Shiga, Hisaaki Kudo, Naoko Minegishi, Yosuke Kawai, Katsushi Tokunaga, Masao Nagasaki,
Journal of Gastroenterology.2020; 55(1): 67. CrossRef - An intronic FTO variant rs16952570 confers protection against thiopurine-induced myelotoxicities in multiethnic Asian IBD patients
Sylvia Chen, Wei Zhi Tan, Natalia Sutiman, Cindy Lim, Sze Sing Lee, Wai Fook Leong, Madeline Tjai, Chunyan Wang, Chris San Choon Kong, Sai Wei Chuah, Brian John Schwender, Webber Chan, Hang Hock Shim, Wee Chian Lim, Chiea Chuen Khor, Khoon Lin Ling, Balra
The Pharmacogenomics Journal.2020; 20(3): 505. CrossRef - Precision therapy of 6‐mercaptopurine in Chinese children with acute lymphoblastic leukaemia
Yue Zhou, Li Wang, Xiao‐Ying Zhai, Li Wen, Fang Tang, Fan Yang, Xi‐Ting Liu, Lei Dong, Li‐Juan Zhi, Hai‐Yan Shi, Guo‐Xiang Hao, Yi Zheng, Evelyne Jacqz‐Aigrain, Tian‐You Wang, Wei Zhao
British Journal of Clinical Pharmacology.2020; 86(8): 1519. CrossRef - NUDT15 gene variants and thiopurine-induced leukopenia in patients with inflammatory bowel disease
Katsuyoshi Matsuoka
Intestinal Research.2020; 18(3): 275. CrossRef - Long‐term effect of NUDT15 R139C on hematologic indices in inflammatory bowel disease patients treated with thiopurine
Shintaro Akiyama, Katsuyoshi Matsuoka, Kyoko Fukuda, Shunsuke Hamada, Mikiko Shimizu, Kosaku Nanki, Shinta Mizuno, Hiroki Kiyohara, Mari Arai, Shinya Sugimoto, Yasushi Iwao, Haruhiko Ogata, Tadakazu Hisamatsu, Makoto Naganuma, Maiko Motobayashi, Kohei Suz
Journal of Gastroenterology and Hepatology.2019; 34(10): 1751. CrossRef - Systematic review with meta‐analysis: risk factors for thiopurine‐induced leukopenia in IBD
Sara van Gennep, Kadère Konté, Berrie Meijer, Martijn W. Heymans, Geert R. D’Haens, Mark Löwenberg, Nanne K. H. de Boer
Alimentary Pharmacology & Therapeutics.2019; 50(5): 484. CrossRef - Mycophenolate mofetil and prednisolone for cerebral sinus venous thrombosis with Behcet's disease
Shintaro Terashita, Tomomi Tanaka, Hiromichi Taneichi, Yuichi Adachi, Masaaki Mori
Pediatrics International.2019; 61(9): 920. CrossRef - Behcet's Disease With Cerebral Artery Infarction Caused by Cerebral Arteritis as an Early Symptom Only With Elevated Interleukin-8
Hao Yin, Yun Song, Meimei Zheng, Ju Han, Jiyou Tang
Frontiers in Neurology.2019;[Epub] CrossRef - Pharmacogenetics of thiopurines for inflammatory bowel disease in East Asia: prospects for clinical application of NUDT15 genotyping
Yoichi Kakuta, Yoshitaka Kinouchi, Tooru Shimosegawa
Journal of Gastroenterology.2018; 53(2): 172. CrossRef - 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, Yosuke Kawai, Daisuke Okamoto, Tetsuya Takagawa, Kentaro Ikeya, Hirotake Sakuraba, Atsushi Nishida, Shoko Nakagawa, Miki Miura, Takahiko Toyonaga, Kei Onodera, Masaru Shinozaki, Yoh Ishiguro, Shinta Mizuno, Masahiro Takahara, Shunichi Yanai
Journal of Gastroenterology.2018; 53(9): 1065. CrossRef - Severe thiopurine‐induced leukocytopenia and hair loss in Japanese patients with defective NUDT15 variant: Retrospective case–control study
Mari Kishibe, Hiroyoshi Nozaki, Mizue Fujii, Shin Iinuma, Sawa Ohtsubo, Satomi Igawa, Kyoko Kanno, Masaru Honma, Kan Kishibe, Kensaku Okamoto, Akemi Ishida‐Yamamoto
The Journal of Dermatology.2018; 45(10): 1160. CrossRef - Diagnostic accuracy of NUDT15 gene variants for thiopurine-induced leukopenia: a systematic review and meta-analysis
Sarah Cargnin, Armando A. Genazzani, Pier Luigi Canonico, Salvatore Terrazzino
Pharmacological Research.2018; 135: 102. CrossRef - A single‐center experience with methotrexate in the treatment of Chinese Crohn’s disease patients
Tian Rong Wang, Yu Qi Qiao, Duo Wu Zou, Zhi Hua Ran
Journal of Digestive Diseases.2018; 19(12): 753. CrossRef
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Propensity score-matched real-world comparative treatment outcomes of Janus kinase inhibitors for ulcerative colitis in patients with and without prior exposure to anti-tumor necrosis factor α antibody
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Maiko Ikenouchi, Hirokazu Fukui, Soichi Yagi, Akira Nogami, Koji Kaku, Toshiyuki Sato, Mikio Kawai, Koji Kamikozuru, Yoko Yokoyama, Tetsuya Takagawa, Toshihiko Tomita, Taku Kobayashi, Shinichiro Shinzaki
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Received September 22, 2024 Accepted November 20, 2024 Published online February 3, 2025
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DOI: https://doi.org/10.5217/ir.2024.00148
[Epub ahead of print]
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Abstract
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- Background/Aims
Tofacitinib (TFB), filgotinib (FIL), and upadacitinib (UPA) are Janus kinase (JAK) inhibitors approved for moderate-to-severe ulcerative colitis (UC). The appropriate positioning of each JAK inhibitor in the treatment algorithm, however, is unclear. Furthermore, real-world efficacy of JAK inhibitors for patients with UC and prior anti-tumor necrosis factor α antibody (aTNF) treatment are not fully investigated. We compared the efficacy and safety of 3 JAK inhibitors in patients with UC, considering their prior aTNF exposure.
Methods
A retrospective study was conducted in patients with UC who started TFB, FIL, or UPA at 2 academic centers. This propensity score-matched cohort study assessed the effectiveness of the 3 JAK inhibitors for UC in patients with and without prior aTNF exposure, comparing steroid-free clinical remission and response rates after 8 weeks.
Results
Among 274 patients who met the inclusion criteria, 145 experienced aTNF exposure (TFB: 59.2%, 100/169; FIL: 34.5%, 20/58; UPA: 53.2%, 25/47). Based on propensity score-matching, UPA led to a higher steroid-free clinical remission rates than TFB (adjusted odds ratio [aOR], 5.57; 95% confidence interval [CI], 1.42–21.90) or FIL (aOR, 9.00; 95% CI, 1.42–57.10) in patients exposed to aTNF. Steroid-free clinical remission and clinical response rates did not differ significantly between each group in patients non-exposed to aTNF. The incidence of adverse events was slightly higher with UPA than TFB or FIL.
Conclusions
UPA may be more effective for UC than TFB or FIL, especially in patients with previous aTNF exposure, although consideration should be given to adverse events.
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