{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,16]],"date-time":"2026-01-16T11:19:32Z","timestamp":1768562372986,"version":"3.49.0"},"reference-count":37,"publisher":"Springer Science and Business Media LLC","issue":"6","license":[{"start":{"date-parts":[[2024,11,23]],"date-time":"2024-11-23T00:00:00Z","timestamp":1732320000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.springernature.com\/gp\/researchers\/text-and-data-mining"},{"start":{"date-parts":[[2024,11,23]],"date-time":"2024-11-23T00:00:00Z","timestamp":1732320000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.springernature.com\/gp\/researchers\/text-and-data-mining"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Pharmacogenomics J"],"published-print":{"date-parts":[[2024,12]]},"DOI":"10.1038\/s41397-024-00358-7","type":"journal-article","created":{"date-parts":[[2024,11,23]],"date-time":"2024-11-23T13:04:02Z","timestamp":1732367042000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Genetic association analysis and frequency of NUDT15*3 with thiopurine-induced myelosuppression in patients with inflammatory bowel disease in a large Dutch cohort"],"prefix":"10.1038","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4389-6420","authenticated-orcid":false,"given":"Maarten J.","family":"Deenen","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anouk J.","family":"van Noordenburg","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jo\u00eblle","family":"Bouwens-Bijsterveld","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maarten A.","family":"van Dijk","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Janneke M.","family":"Stapelbroek","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Luc J. J.","family":"Derijks","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lennard P. L.","family":"Gilissen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9579-7555","authenticated-orcid":false,"given":"Birgit A. L. M.","family":"Deiman","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2024,11,23]]},"reference":[{"key":"358_CR1","doi-asserted-by":"publisher","first-page":"715","DOI":"10.1111\/j.1365-2036.2006.02980.x","volume":"24","author":"LJJ Derijks","year":"2006","unstructured":"Derijks LJJ, Gilissen LPL, Hooymans PM, Hommes DW. Review article: thiopurines in inflammatory bowel disease. Aliment Pharmacol Ther. 2006;24:715\u201329.","journal-title":"Aliment Pharmacol Ther"},{"key":"358_CR2","doi-asserted-by":"publisher","first-page":"485 LP","DOI":"10.1136\/gut.50.4.485","volume":"50","author":"AG Fraser","year":"2002","unstructured":"Fraser AG, Orchard TR, Jewell DP. The efficacy of azathioprine for the treatment of inflammatory bowel disease: a 30 year review. Gut. 2002;50:485 LP\u2013489.","journal-title":"Gut"},{"key":"358_CR3","doi-asserted-by":"crossref","unstructured":"Gisbert JP, Gomoll\u00f3n F. Thiopurine-induced myelotoxicity in patients with inflammatory bowel disease: a review. Am J Gastroenterol. 2008;103:1783\u2013800.","DOI":"10.1111\/j.1572-0241.2008.01848.x"},{"key":"358_CR4","doi-asserted-by":"publisher","first-page":"1592","DOI":"10.1097\/MIB.0000000000001148","volume":"23","author":"K Chao","year":"2017","unstructured":"Chao K, Wang X, Cao Q, Qian J, Wu K, Zhu X, et al. Combined detection of NUDT15 variants could highly predict thiopurine-induced leukopenia in Chinese patients with inflammatory bowel disease: a multicenter analysis. Inflamm Bowel Dis. 2017;23:1592\u20139.","journal-title":"Inflamm Bowel Dis"},{"key":"358_CR5","doi-asserted-by":"publisher","first-page":"367","DOI":"10.1038\/ng.3508","volume":"48","author":"T Moriyama","year":"2016","unstructured":"Moriyama T, Nishii R, Perez-Andreu V, Yang W, Klussmann FA, Zhao X, et al. NUDT15 polymorphisms alter thiopurine metabolism and hematopoietic toxicity. Nat Genet. 2016;48:367\u201373.","journal-title":"Nat Genet"},{"key":"358_CR6","doi-asserted-by":"publisher","first-page":"967","DOI":"10.1111\/apt.13796","volume":"44","author":"X Zhu","year":"2016","unstructured":"Zhu X, Wang XD, Chao K, Zhi M, Zheng H, Ruan HL, et al. NUDT15 polymorphisms are better than thiopurine S-methyltransferase as predictor of risk for thiopurine-induced leukopenia in Chinese patients with Crohn\u2019s disease. Aliment Pharmacol Ther. 2016;44:967\u201375.","journal-title":"Aliment Pharmacol Ther"},{"key":"358_CR7","doi-asserted-by":"publisher","first-page":"22","DOI":"10.1007\/s00535-015-1142-4","volume":"51","author":"A Asada","year":"2016","unstructured":"Asada A, Nishida A, Shioya M, Imaeda H, Inatomi O, Bamba S, et al. NUDT15 R139C-related thiopurine leukocytopenia is mediated by 6-thioguanine nucleotide-independent mechanism in Japanese patients with inflammatory bowel disease. J Gastroenterol. 2016;51:22\u20139.","journal-title":"J Gastroenterol"},{"key":"358_CR8","doi-asserted-by":"publisher","first-page":"1404","DOI":"10.1097\/MIB.0b013e318281f28f","volume":"19","author":"M Chaparro","year":"2013","unstructured":"Chaparro M, Ord\u00e1s I, Cabr\u00e9 E, Garcia-Sanchez V, Bastida G, Pe\u00f1alva M, et al. Safety of thiopurine therapy in inflammatory bowel disease: long-term follow-up study of 3931 patients. Inflamm Bowel Dis. 2013;19:1404\u201310.","journal-title":"Inflamm Bowel Dis"},{"key":"358_CR9","doi-asserted-by":"crossref","unstructured":"Lee YJ, Hwang EH, Park JH, Shin JH, Kang B, Kim SY. NUDT15 variant is the most common variant associated with thiopurine-induced early leukopenia and alopecia in Korean pediatric patients with Crohn\u2019s disease. Eur J Gastroenterol Hepatol. 2016;28:475\u20138.","DOI":"10.1097\/MEG.0000000000000564"},{"key":"358_CR10","doi-asserted-by":"publisher","first-page":"563","DOI":"10.1002\/pds.926","volume":"13","author":"RB Gearry","year":"2004","unstructured":"Gearry RB, Barclay ML, Burt MJ, Collett JA, Chapman BA. Thiopurine drug adverse effects in a population of New Zealand patients with inflammatory bowel disease. Pharmacoepidemiol Drug Saf. 2004;13:563\u20137.","journal-title":"Pharmacoepidemiol Drug Saf"},{"key":"358_CR11","doi-asserted-by":"publisher","first-page":"753","DOI":"10.1001\/jama.2019.0709","volume":"321","author":"GJ Walker","year":"2019","unstructured":"Walker GJ, Harrison JW, Heap GA, Voskuil MD, Andersen V, Anderson CA, et al. Association of genetic variants in NUDT15 with thiopurine-induced myelosuppression in patients with inflammatory bowel disease. JAMA J Am Med Assoc. 2019;321:753\u201361.","journal-title":"JAMA J Am Med Assoc"},{"key":"358_CR12","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.clinbiochem.2021.02.007","volume":"92","author":"AM Moyer","year":"2021","unstructured":"Moyer AM. NUDT15: a bench to bedside success story. Clin Biochem. 2021;92:1\u20138.","journal-title":"Clin Biochem"},{"key":"358_CR13","unstructured":"Zaza G, Meyling C, Krynetskaia N, Thorn C, Stocco G, Hebert JM, et al. Thiopurine Pathway [Internet]. Pharmacogenetics and genomics. 2010 [cited 2022 Sep 23]. Available from: https:\/\/www.pharmgkb.org\/pathway\/PA2040"},{"key":"358_CR14","doi-asserted-by":"publisher","first-page":"275","DOI":"10.5217\/ir.2020.00002","volume":"18","author":"K Matsuoka","year":"2020","unstructured":"Matsuoka K. NUDT15 gene variants and thiopurine-induced leukopenia in patients with inflammatory bowel disease. Intest Res. 2020;18:275\u201381.","journal-title":"Intest Res"},{"key":"358_CR15","unstructured":"KNMP. Algemene achtergrondtekst Farmacogenetica - NUDT15 [Internet]. 2018 [cited 2022 Sep 19]. Available from: https:\/\/www.knmp.nl\/downloads\/g-standaard\/farmacogenetica\/achtergrondtekst-Farmacogenetica-CYP2D6-feb2020.pdf\/view"},{"key":"358_CR16","doi-asserted-by":"publisher","first-page":"1075","DOI":"10.1007\/s40262-018-0639-4","volume":"57","author":"LJJ Derijks","year":"2018","unstructured":"Derijks LJJ, Wong DR, Hommes DW, van Bodegraven AA. Clinical pharmacokinetic and pharmacodynamic considerations in the treatment of inflammatory bowel disease. Clin Pharmacokinet. 2018;57:1075\u2013106.","journal-title":"Clin Pharmacokinet"},{"key":"358_CR17","doi-asserted-by":"publisher","first-page":"1065","DOI":"10.1007\/s00535-018-1486-7","volume":"53","author":"Y Kakuta","year":"2018","unstructured":"Kakuta Y, Kawai Y, Okamoto D, Takagawa T, Ikeya K, Sakuraba H, et al. 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. J Gastroenterol. 2018;53:1065\u201378.","journal-title":"J Gastroenterol"},{"key":"358_CR18","unstructured":"Dean L. Azathioprine therapy and TPMT and NUDT15 genotype [Internet]. Med Genet Summaries. 2012. Available from: https:\/\/www.ncbi.nlm.nih.gov\/books\/"},{"key":"358_CR19","doi-asserted-by":"crossref","unstructured":"Tanaka Y, Saito Y. Importance of NUDT15 Polymorphisms in Thiopurine Treatments. J Pers Med. 2021;11:778.","DOI":"10.3390\/jpm11080778"},{"key":"358_CR20","doi-asserted-by":"publisher","first-page":"1017","DOI":"10.1038\/ng.3060","volume":"46","author":"SK Yang","year":"2014","unstructured":"Yang SK, Hong M, Baek J, Choi H, Zhao W, Jung Y, et al. A common missense variant in NUDT15 confers susceptibility to thiopurine-induced leukopenia. Nat Genet. 2014;46:1017\u201320.","journal-title":"Nat Genet"},{"key":"358_CR21","doi-asserted-by":"publisher","first-page":"13575","DOI":"10.18632\/oncotarget.14594","volume":"8","author":"D Yin","year":"2017","unstructured":"Yin D, Xia X, Zhang J, Zhang S, Liao F, Zhang G, et al. Impact of NUDT15 polymorphisms on thiopurines-induced myelotoxicity and thiopurines tolerance dose. Oncotarget. 2017;8:13575\u201385.","journal-title":"Oncotarget"},{"key":"358_CR22","doi-asserted-by":"publisher","first-page":"280","DOI":"10.1038\/tpj.2015.43","volume":"16","author":"Y Kakuta","year":"2016","unstructured":"Kakuta Y, Naito T, Onodera M, Kuroha M, Kimura T, Shiga H, et al. NUDT15 R139C causes thiopurine-induced early severe hair loss and leukopenia in Japanese patients with IBD. Pharmacogenomics J. 2016;16:280\u20135.","journal-title":"Pharmacogenomics J"},{"key":"358_CR23","doi-asserted-by":"crossref","unstructured":"Khaeso K, Udayachalerm S, Komvilaisak P, Chainansamit SO, Suwannaying K, Laoaroon N, et al. Meta-Analysis of NUDT15 Genetic Polymorphism on Thiopurine-Induced Myelosuppression in Asian Populations. Front Pharmacol. 2021;12:784712.","DOI":"10.3389\/fphar.2021.784712"},{"key":"358_CR24","unstructured":"PHARMGKB. rs116855232 [Internet]. [cited 2023 Jan 19]. Available from: https:\/\/www.pharmgkb.org\/variant\/PA166154759\/overview."},{"key":"358_CR25","doi-asserted-by":"publisher","first-page":"285","DOI":"10.1038\/nature19057","volume":"536","author":"M Lek","year":"2016","unstructured":"Lek M, Karczewski KJ, Minikel EV, Samocha KE, Banks E, Fennell T, et al. Analysis of protein-coding genetic variation in 60,706 humans. Nature. 2016;536:285\u201391.","journal-title":"Nature"},{"key":"358_CR26","unstructured":"Common Terminology Criteria for Adverse Events v3.0 (CTCAE). Blood\/bone marrow [Internet]. 2006 [cited 2022 Sep 19]. Available from: http:\/\/ctep.cancer.gov\/protocolDevelopment\/electronic_applications\/docs\/ctcaev3.pdf."},{"key":"358_CR27","doi-asserted-by":"publisher","first-page":"1235","DOI":"10.1200\/JCO.2014.59.4671","volume":"33","author":"JJ Yang","year":"2015","unstructured":"Yang JJ, Landier W, Yang W, Liu C, Hageman L, Cheng C, et al. Inherited NUDT15 variant is a genetic determinant of mercaptopurine intolerance in children with acute lymphoblastic leukemia. J Clin Oncol. 2015;33:1235\u201342.","journal-title":"J Clin Oncol"},{"key":"358_CR28","doi-asserted-by":"publisher","first-page":"1","DOI":"10.3389\/fphar.2019.00346","volume":"10","author":"X Fan","year":"2019","unstructured":"Fan X, Yin D, Men R, Xu H, Yang L. NUDT15 polymorphism confer increased susceptibility to thiopurine-induced leukopenia in patients with autoimmune hepatitis and related cirrhosis. Front Pharmacol. 2019;10:1\u20138.","journal-title":"Front Pharmacol"},{"key":"358_CR29","doi-asserted-by":"publisher","first-page":"8309","DOI":"10.2147\/OTT.S177007","volume":"11","author":"Y Liu","year":"2018","unstructured":"Liu Y, Meng Y, Wang L, Liu Z, Li J, Dong W. Associations between the NUDT15 R139C polymorphism and susceptibility to thiopurine-induced leukopenia in Asians: a meta-analysis. Onco Targets Ther. 2018;11:8309\u201317.","journal-title":"Onco Targets Ther"},{"key":"358_CR30","doi-asserted-by":"publisher","first-page":"145","DOI":"10.1007\/s11845-017-1608-x","volume":"187","author":"AL Zhang","year":"2018","unstructured":"Zhang AL, Yang J, Wang H, Lu JL, Tang S, Zhang XJ. Association of NUDT15 c.415C>T allele and thiopurine-induced leukocytopenia in Asians: a systematic review and meta-analysis. Ir J Med Sci. 2018;187:145\u201353.","journal-title":"Ir J Med Sci"},{"key":"358_CR31","doi-asserted-by":"publisher","first-page":"161","DOI":"10.1097\/FPC.0000000000000503","volume":"33","author":"C von Muhlenbrock","year":"2023","unstructured":"von Muhlenbrock C, Estay C, Covarrubias N, Miranda J, Venegas M. The c.415C>T polymorphism in NUDT15 is more frequent than the polymorphisms in TPMT in Chilean patients who use thiopurine drugs. Pharmacogenet Genomics. 2023;33:161\u20133.","journal-title":"Pharmacogenet Genomics"},{"key":"358_CR32","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopha.2023.115706","volume":"168","author":"X D\u00edaz-Villamar\u00edn","year":"2023","unstructured":"D\u00edaz-Villamar\u00edn X, Fern\u00e1ndez-Var\u00f3n E, Rojas Romero MC, Callejas-Rubio JL, Cabeza-Barrera J, Rodr\u00edguez-Nogales A, et al. Azathioprine dose tailoring based on pharmacogenetic information: insights of clinical implementation. Biomed Pharmacother. 2023;168:115706.","journal-title":"Biomed Pharmacother"},{"key":"358_CR33","doi-asserted-by":"publisher","first-page":"2145","DOI":"10.1038\/s41436-019-0448-7","volume":"21","author":"E Schaeffeler","year":"2019","unstructured":"Schaeffeler E, Jaeger SU, Klumpp V, Yang JJ, Igel S, Hinze L, et al. Impact of NUDT15 genetics on severe thiopurine-related hematotoxicity in patients with European ancestry. Genet Med. 2019;21:2145\u201350.","journal-title":"Genet Med"},{"key":"358_CR34","doi-asserted-by":"publisher","first-page":"1751","DOI":"10.1111\/jgh.14693","volume":"34","author":"S Akiyama","year":"2019","unstructured":"Akiyama S, Matsuoka K, Fukuda K, Hamada S, Shimizu M, Nanki K, et al. Long-term effect of NUDT15 R139C on hematologic indices in inflammatory bowel disease patients treated with thiopurine. J Gastroenterol Hepatol. 2019;34:1751\u20137.","journal-title":"J Gastroenterol Hepatol"},{"key":"358_CR35","doi-asserted-by":"publisher","first-page":"1920","DOI":"10.1093\/ecco-jcc\/jjad107","volume":"17","author":"N Yu","year":"2023","unstructured":"Yu N, Sriranganathan D, Walker GJ, Sazonovs A, Wilding H, Roberts C, et al. Prevalence of NUDT15 genetic variants and incidence of thiopurine-induced leukopenia in inflammatory bowel disease: a systematic review and meta-analysis. J Crohns Colitis. 2023;17:1920\u201330.","journal-title":"J Crohns Colitis"},{"key":"358_CR36","doi-asserted-by":"publisher","DOI":"10.1016\/j.jpba.2022.114813","volume":"217","author":"J Han","year":"2022","unstructured":"Han J, Xu J, Sun N, Jin S, Mei D, Wang X, et al. Analysis of mono-, di-, and triphosphates of thioguanosine and methylthioinosine in children with acute lymphoblastic leukemia by LC-MS\/MS. J Pharm Biomed Anal. 2022;217:114813.","journal-title":"J Pharm Biomed Anal"},{"key":"358_CR37","doi-asserted-by":"publisher","first-page":"e0155218","DOI":"10.1371\/journal.pone.0155218","volume":"11","author":"M V\u00f6gelin","year":"2016","unstructured":"V\u00f6gelin M, Biedermann L, Frei P, Vavricka SR, Scharl S, Zeitz J, et al. The impact of azathioprine-associated lymphopenia on the onset of opportunistic infections in patients with inflammatory bowel disease. PLoS ONE. 2016;11:e0155218.","journal-title":"PLoS ONE"}],"container-title":["The Pharmacogenomics Journal"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41397-024-00358-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41397-024-00358-7","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41397-024-00358-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,12,19]],"date-time":"2024-12-19T11:07:25Z","timestamp":1734606445000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41397-024-00358-7"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,11,23]]},"references-count":37,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2024,12]]}},"alternative-id":["358"],"URL":"https:\/\/doi.org\/10.1038\/s41397-024-00358-7","relation":{},"ISSN":["1470-269X","1473-1150"],"issn-type":[{"value":"1470-269X","type":"print"},{"value":"1473-1150","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,11,23]]},"assertion":[{"value":"25 January 2024","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"29 October 2024","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"13 November 2024","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"23 November 2024","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"39"}}