{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T16:13:02Z","timestamp":1791475982396,"version":"4.3.4"},"reference-count":22,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2023,7,15]],"date-time":"2023-07-15T00:00:00Z","timestamp":1689379200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2023,7,15]],"date-time":"2023-07-15T00:00:00Z","timestamp":1689379200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["BMC Gastroenterol"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Thiopurines continue to play an important role in the treatment of inflammatory bowel disease (IBD). It is well known that thiopurines can cause several adverse reactions. Especially, hematopoietic toxicity may lead to severe agranulocytosis. In a previous prospective study, we investigated the relationship between inosine triphosphate pyrophosphatase (\n                      <jats:italic>ITPA<\/jats:italic>\n                      ) c.94c\u2009&gt;\u2009a polymorphism, 6-thioguanine nucleotide (6-TGN) concentration and toxicity.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      To clarify the cause of thiopurine toxicity, we analysed nucleoside disphosphate-linked moiety X-type motif 15 (\n                      <jats:italic>NUDT15<\/jats:italic>\n                      ) gene polymorphisms, i.e., R139C, V18I, and V19_V19insGV, and measured 6-mercaptopurines and 6-methylmercaptopurines (6-MMP) using the archived blood samples collected from 49 IBD patients for our previous study.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      The\n                      <jats:italic>ITPA<\/jats:italic>\n                      c.94c\u2009&gt;\u2009a polymorphism was detected in 19 patients (38.7%, all heterozygous). The R139C polymorphism was found in 10 patients (20.4%, 1 homozygous, 9 heterozygous), V18_V19insGV in 7 patients (14.3%, all heterozygous), and V18I in 2 patients (4.08%, all heterozygous). Although R139C was more strongly associated with leukopenia than c.94c\u2009&gt;\u2009a, there were no significant correlations with 6-TGN and 6-MMP levels, as for c.94c\u2009&gt;\u2009a. The leukopenia incidence rates for each gene polymorphism were 0% in those with all wild-type genes, 21.4% for c.94c\u2009&gt;\u2009a only, 42.9% for\n                      <jats:italic>NUDT15<\/jats:italic>\n                      polymorphism (s) only, and 80.0% for both polymorphisms.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      All cases of leukopenia were associated with\n                      <jats:italic>ITPA<\/jats:italic>\n                      c.94c\u2009&gt;\u2009a and\/or polymorphism of\n                      <jats:italic>NUDT15<\/jats:italic>\n                      and the risk of developing leukopenia was synergistically increased by\n                      <jats:italic>ITPA<\/jats:italic>\n                      and\n                      <jats:italic>NUDT15<\/jats:italic>\n                      gene polymorphism. However, there was no association between the level of azathioprine metabolites and these polymorphisms.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s12876-023-02881-6","type":"journal-article","created":{"date-parts":[[2023,7,15]],"date-time":"2023-07-15T13:01:40Z","timestamp":1689426100000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Analysis of the NUDT15 gene and metabolites of azathioprine in Japanese patients with inflammatory bowel disease"],"prefix":"10.1186","volume":"23","author":[{"given":"Shizuka","family":"Suzuki","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kan","family":"Uchiyama","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yutaro","family":"Motoi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuuki","family":"Yoshii","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yukari","family":"Inoue","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takahiro","family":"Kubota","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shunichi","family":"Odahara","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuichiro","family":"Ohtaki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shinichiro","family":"Takami","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zensho","family":"Ito","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nobuhiro","family":"Sato","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Toshifumi","family":"Ohkusa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shigeo","family":"Koido","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masayuki","family":"Saruta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2023,7,15]]},"reference":[{"key":"2881_CR1","doi-asserted-by":"publisher","first-page":"197","DOI":"10.1007\/s00535-008-2307-1","volume":"44","author":"K Uchiyama","year":"2009","unstructured":"Uchiyama K, Nakamura M, Kubota T, Yamane T, Fujise K, Tajiri H. 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This study was approved by the Jikei University Hospital ethics committee (27\u2013323) on April 11th 2016.All patients who participated in the previous prospective study gave written informed consent in advance for the use of their data and the possibility of additional genetic analyses. If the participant was under the age of 18, informed consent has been obtained from the participant and their parents\/guardians. Informed consent was obtained via an opt-out option on a website for this study.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"239"}}