{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T11:32:01Z","timestamp":1787311921903,"version":"build-2736575974"},"reference-count":32,"publisher":"Springer Science and Business Media LLC","issue":"9","license":[{"start":{"date-parts":[[2025,5,15]],"date-time":"2025-05-15T00:00:00Z","timestamp":1747267200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,5,15]],"date-time":"2025-05-15T00:00:00Z","timestamp":1747267200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100001700","name":"Ministry of Education, Culture, Sports, Science and Technology","doi-asserted-by":"publisher","award":["JP17km0105001"],"award-info":[{"award-number":["JP17km0105001"]}],"id":[{"id":"10.13039\/501100001700","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","award":["JP21tm0424601"],"award-info":[{"award-number":["JP21tm0424601"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","award":["JP21tm0124005"],"award-info":[{"award-number":["JP21tm0124005"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["J Gastroenterol"],"published-print":{"date-parts":[[2025,9]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>A method for predicting ulcerative colitis (UC) onset has not been established. Serum autoantibodies have been suggested as potential predictive biomarkers for UC onset. We aimed to validate the risks associated with serological and environmental factors and construct a model for predicting UC development.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Using the population-based cohort studies (\n                      <jats:italic>n<\/jats:italic>\n                      \u2009&gt;\u200983,000), we identified 42 individuals who were diagnosed with UC later in life and compared them with matched healthy controls. We analyzed serum anti-integrin \u03b1v\u03b26 antibody (anti-\u03b1v\u03b26) and anti-endothelial protein C receptor antibody (anti-EPCR) titers, and lifestyle and dietary habits to explore UC onset predictors. The predictive performance of the models was evaluated based on these predictors.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      The sensitivity and specificity of anti-EPCR for predicting UC onset were 51.4% and 97.8%, respectively, comparable to those of anti-\u03b1v\u03b26 (52.5% and 97.6%, respectively). The proportion of individuals with insomnia was significantly higher in the preclinical UC group (adjusted odds ratio\u2009=\u20092.14, 95% confidence interval [CI] 1.11\u20134.04,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.019). The predictive performance of anti-EPCR alone was high with an area under the curve (AUC) of 0.89 (95%CI 0.83\u20130.96), and that of anti-EPCR combined with anti-\u03b1v\u03b26 was even better with an AUC of 0.92 (95%CI 0.87\u20130.97); the lifestyle model had lower predictive accuracy (AUC\u2009=\u20090.65, 95%CI 0.55\u20130.74).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Anti-EPCR and anti-\u03b1v\u03b26 each strongly predict UC onset. The combined anti-EPCR and anti-\u03b1v\u03b26 model had stronger predictive performance than the single models.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1007\/s00535-025-02263-7","type":"journal-article","created":{"date-parts":[[2025,5,15]],"date-time":"2025-05-15T05:02:02Z","timestamp":1747285322000},"page":"1108-1117","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Autoantibodies against endothelial protein C receptor and integrin \u03b1v\u03b26 predict the development of ulcerative colitis"],"prefix":"10.1007","volume":"60","author":[{"given":"Motoi","family":"Sawahashi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7042-009X","authenticated-orcid":false,"given":"Yoichi","family":"Kakuta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takeo","family":"Naito","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Soshi","family":"Okazaki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kinuko","family":"Ohneda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masatsugu","family":"Orui","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taku","family":"Obara","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Soichi","family":"Ogishima","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazuki","family":"Kumada","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hisaaki","family":"Kudo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fuji","family":"Nagami","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Atsushi","family":"Hozawa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hideya","family":"Iwaki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroshi","family":"Nagai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yusuke","family":"Shimoyama","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rintaro","family":"Moroi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hisashi","family":"Shiga","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshitaka","family":"Kinouchi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tsuyoshi","family":"Shirai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroshi","family":"Fujii","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Atsushi","family":"Masamune","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,5,15]]},"reference":[{"key":"2263_CR1","doi-asserted-by":"publisher","first-page":"427","DOI":"10.1038\/nature06005","volume":"448","author":"RJ Xavier","year":"2007","unstructured":"Xavier RJ, Podolsky DK. Unravelling the pathogenesis of inflammatory bowel disease. Nature. 2007;448:427\u201334.","journal-title":"Nature"},{"key":"2263_CR2","doi-asserted-by":"publisher","first-page":"1061","DOI":"10.1136\/gutjnl-2016-311785","volume":"65","author":"J Torres","year":"2016","unstructured":"Torres J, Burisch J, Riddle M, et al. Preclinical disease and preventive strategies in IBD: perspectives, challenges and opportunities. Gut. 2016;65:1061\u20139.","journal-title":"Gut"},{"key":"2263_CR3","doi-asserted-by":"publisher","first-page":"86","DOI":"10.1038\/s41575-023-00854-4","volume":"21","author":"JJ Rudbaek","year":"2024","unstructured":"Rudbaek JJ, Agrawal M, Torres J, et al. Deciphering the different phases of preclinical inflammatory bowel disease. Nat Rev Gastroenterol Hepatol. 2024;21:86\u2013100.","journal-title":"Nat Rev Gastroenterol Hepatol"},{"key":"2263_CR4","doi-asserted-by":"publisher","first-page":"1232","DOI":"10.1136\/gut.2004.060228","volume":"54","author":"E Israeli","year":"2005","unstructured":"Israeli E, Grotto I, Gilburd B, et al. Anti-Saccharomyces cerevisiae and antineutrophil cytoplasmic antibodies as predictors of inflammatory bowel disease. Gut. 2005;54:1232\u20136.","journal-title":"Gut"},{"key":"2263_CR5","doi-asserted-by":"publisher","first-page":"683","DOI":"10.1136\/gutjnl-2012-302717","volume":"62","author":"FDM van Schaik","year":"2013","unstructured":"van Schaik FDM, Oldenburg B, Hart AR, et al. Serological markers predict inflammatory bowel disease years before the diagnosis. Gut. 2013;62:683\u20138.","journal-title":"Gut"},{"key":"2263_CR6","doi-asserted-by":"publisher","first-page":"96","DOI":"10.1053\/j.gastro.2020.03.007","volume":"159","author":"J Torres","year":"2020","unstructured":"Torres J, Petralia F, Sato T, et al. Serum biomarkers identify patients who will develop inflammatory bowel diseases Up to 5 Years before diagnosis. Gastroenterology. 2020;159:96\u2013104.","journal-title":"Gastroenterology"},{"key":"2263_CR7","doi-asserted-by":"publisher","first-page":"619","DOI":"10.1053\/j.gastro.2022.12.042","volume":"164","author":"AE Livanos","year":"2023","unstructured":"Livanos AE, Dunn A, Fischer J, et al. Anti-integrin \u03b1v\u03b26 autoantibodies are a novel biomarker that antedate ulcerative colitis. Gastroenterology. 2023;164:619\u201329.","journal-title":"Gastroenterology"},{"key":"2263_CR8","doi-asserted-by":"publisher","first-page":"2383","DOI":"10.1053\/j.gastro.2021.02.019","volume":"160","author":"T Kuwada","year":"2021","unstructured":"Kuwada T, Shiokawa M, Kodama Y, et al. Identification of an anti-integrin \u03b1v\u03b26 autoantibody in patients with ulcerative colitis. Gastroenterology. 2021;160:2383-2394.e21.","journal-title":"Gastroenterology"},{"key":"2263_CR9","doi-asserted-by":"publisher","first-page":"1253","DOI":"10.1038\/s41467-020-15088-0","volume":"11","author":"T Mutoh","year":"2020","unstructured":"Mutoh T, Shirai T, Ishii T, et al. Identification of two major autoantigens negatively regulating endothelial activation in Takayasu arteritis. Nat Commun. 2020;11:1253.","journal-title":"Nat Commun"},{"key":"2263_CR10","first-page":"265","volume":"6","author":"T Shirai","year":"2023","unstructured":"Shirai T. Common autoantibody among Takayasu arteritis and ulcerative colitis: a possible pathophysiology that includes gut-vessel connection in vascular inflammation. JMA J. 2023;6:265\u201373.","journal-title":"JMA J"},{"key":"2263_CR11","doi-asserted-by":"publisher","first-page":"844","DOI":"10.1016\/j.cgh.2021.12.035","volume":"21","author":"Y Kakuta","year":"2023","unstructured":"Kakuta Y, Shirai T, McGovern DPB, et al. Novel diagnostic autoantibodies against endothelial protein C receptor in patients with ulcerative colitis. Clin Gastroenterol Hepatol. 2023;21:844\u20136.","journal-title":"Clin Gastroenterol Hepatol"},{"key":"2263_CR12","doi-asserted-by":"publisher","first-page":"205","DOI":"10.1038\/nrgastro.2015.34","volume":"12","author":"AN Ananthakrishnan","year":"2015","unstructured":"Ananthakrishnan AN. Epidemiology and risk factors for IBD. Nat Rev Gastroenterol Hepatol. 2015;12:205\u201317.","journal-title":"Nat Rev Gastroenterol Hepatol"},{"key":"2263_CR13","doi-asserted-by":"publisher","first-page":"511","DOI":"10.14309\/ajg.0000000000002180","volume":"118","author":"Y Sun","year":"2023","unstructured":"Sun Y, Yuan S, Chen X, et al. The contribution of genetic risk and lifestyle factors in the development of adult-onset inflammatory bowel disease: a prospective cohort study. Am J Gastroenterol. 2023;118:511\u201322.","journal-title":"Am J Gastroenterol"},{"key":"2263_CR14","doi-asserted-by":"publisher","first-page":"1093","DOI":"10.1136\/gutjnl-2022-328174","volume":"72","author":"EW Lopes","year":"2022","unstructured":"Lopes EW, Chan SSM, Song M, Lochhead P, et al. Lifestyle factors for the prevention of inflammatory bowel disease. Gut. 2022;72:1093\u2013100.","journal-title":"Gut."},{"key":"2263_CR15","doi-asserted-by":"publisher","first-page":"493","DOI":"10.2188\/jea.JE20150268","volume":"26","author":"S Kuriyama","year":"2016","unstructured":"Kuriyama S, Yaegashi N, Nagami F, et al. The Tohoku Medical Megabank Project: design and mission. J Epidemiol. 2016;26:493\u2013511.","journal-title":"J Epidemiol"},{"key":"2263_CR16","doi-asserted-by":"publisher","first-page":"65","DOI":"10.2188\/jea.JE20190271","volume":"31","author":"A Hozawa","year":"2021","unstructured":"Hozawa A, Tanno K, Nakaya N, et al. Study profile of the Tohoku Medical Megabank Community-based Cohort study. J Epidemiol. 2021;31:65\u201376.","journal-title":"J Epidemiol"},{"key":"2263_CR17","doi-asserted-by":"publisher","first-page":"18","DOI":"10.1093\/ije\/dyz169","volume":"49","author":"S Kuriyama","year":"2020","unstructured":"Kuriyama S, Metoki H, Kikuya M, et al. Cohort profile: Tohoku Medical Megabank Project Birth and Three-Generation Cohort Study (TMM BirThree Cohort Study): rationale, progress and perspective. Int J Epidemiol. 2020;49:18\u201319m.","journal-title":"Int J Epidemiol"},{"key":"2263_CR18","unstructured":"Ministry of Health, Labour and Welfare, Grant-in-Aid for Scientific Research on Intractable Diseases, \u201cResearch on Intractable Inflammatory Bowel Disorders\u201d (Hisamatsu Group), 2024, Diagnostic Criteria and Treatment Guidelines for Ulcerative Colitis and Crohn\u2019s Disease (revised version). http:\/\/www.ibdjapan.org\/. Accessed 17 Dec 2024."},{"key":"2263_CR19","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1080\/00365521.1984.12199901","volume":"95","author":"J Myren","year":"1984","unstructured":"Myren J, Bouchier IA, Watkinson G, et al. The O.M.G.E. Multinational inflammatory Bowel Disease Survey 1976\u20131982 A further report on 2,657 cases. Scand J Gastroenterol. 1984;95:1\u201327.","journal-title":"Scand J Gastroenterol"},{"key":"2263_CR20","doi-asserted-by":"publisher","first-page":"555","DOI":"10.1016\/S0022-3999(00)00095-7","volume":"48","author":"CR Soldatos","year":"2000","unstructured":"Soldatos CR, Dikeos DG, Paparrigopoulos TJ. Athens insomnia scale: validation of an instrument based on ICD-10 criteria. J Psychosom Res. 2000;48:555\u201360.","journal-title":"J Psychosom Res"},{"key":"2263_CR21","doi-asserted-by":"publisher","first-page":"385","DOI":"10.1177\/014662167700100306","volume":"1","author":"LS Radloff","year":"1977","unstructured":"Radloff LS. The CES-D Scale: a self-report depression scale for research in the general population. Appl Psychol Meas. 1977;1:385\u2013401.","journal-title":"Appl Psychol Meas"},{"key":"2263_CR22","doi-asserted-by":"publisher","first-page":"959","DOI":"10.1017\/S0033291702006074","volume":"32","author":"RC Kessler","year":"2002","unstructured":"Kessler RC, Andrews G, Colpe LJ, et al. Short screening scales to monitor population prevalences and trends in non-specific psychological distress. Psychol Med. 2002;32:959\u201376.","journal-title":"Psychol Med"},{"key":"2263_CR23","doi-asserted-by":"publisher","first-page":"S51","DOI":"10.2188\/jea.13.1sup_51","volume":"13","author":"S Tsugane","year":"2003","unstructured":"Tsugane S, Kobayashi M, Sasaki S. JPHC. Validity of the self-administered food frequency questionnaire used in the 5-year follow-up survey of the JPHC Study Cohort I: comparison with dietary records for main nutrients. J Epidemiol. 2003;13:S51\u20136.","journal-title":"J Epidemiol."},{"key":"2263_CR24","doi-asserted-by":"publisher","first-page":"154","DOI":"10.1097\/00054725-200502000-00009","volume":"11","author":"N Sakamoto","year":"2005","unstructured":"Sakamoto N, Kono S, Wakai K, et al. Dietary risk factors for inflammatory bowel disease: a multicenter case-control study in Japan. Inflamm Bowel Dis. 2005;11:154\u201363.","journal-title":"Inflamm Bowel Dis"},{"key":"2263_CR25","doi-asserted-by":"publisher","DOI":"10.1007\/s00535-024-02169-w","author":"M Yasuda","year":"2024","unstructured":"Yasuda M, Shiokawa M, Kuwada T, et al. Anti-integrin \u03b1v\u03b26 autoantibody in primary sclerosing cholangitis: a Japanese nationwide study. J Gastroenterol. 2024. https:\/\/doi.org\/10.1007\/s00535-024-02169-w.","journal-title":"J Gastroenterol"},{"key":"2263_CR26","doi-asserted-by":"publisher","first-page":"1951","DOI":"10.1172\/JCI31027","volume":"117","author":"F Scaldaferri","year":"2007","unstructured":"Scaldaferri F, Sans M, Vetrano S, et al. Crucial role of the protein C pathway in governing microvascular inflammation in inflammatory bowel disease. J Clin Invest. 2007;117:1951\u201360.","journal-title":"J Clin Invest"},{"key":"2263_CR27","doi-asserted-by":"publisher","first-page":"20569","DOI":"10.1038\/s41598-020-77502-3","volume":"10","author":"V Kondreddy","year":"2020","unstructured":"Kondreddy V, Keshava S, Esmon CT, et al. A critical role of endothelial cell protein C receptor in the intestinal homeostasis in experimental colitis. Sci Rep. 2020;10:20569.","journal-title":"Sci Rep"},{"key":"2263_CR28","doi-asserted-by":"publisher","first-page":"19830","DOI":"10.1073\/pnas.1107140108","volume":"108","author":"S Vetrano","year":"2011","unstructured":"Vetrano S, Ploplis VA, Sala E, et al. Unexpected role of anticoagulant protein C in controlling epithelial barrier integrity and intestinal inflammation. Proc Natl Acad Sci U S A. 2011;108:19830\u20135.","journal-title":"Proc Natl Acad Sci U S A"},{"key":"2263_CR29","doi-asserted-by":"publisher","DOI":"10.1093\/ecco-jcc\/jjae116","author":"H Oyama","year":"2025","unstructured":"Oyama H, Moroi R, Sakuma A, et al. Chronic poor sleep is associated with increased disease activity in patients with ulcerative colitis: prospective observational study in japan. J Crohns Colitis. 2025. https:\/\/doi.org\/10.1093\/ecco-jcc\/jjae116.","journal-title":"J Crohns Colitis."},{"key":"2263_CR30","doi-asserted-by":"publisher","first-page":"1879","DOI":"10.1016\/j.cgh.2014.04.021","volume":"12","author":"AN Ananthakrishnan","year":"2014","unstructured":"Ananthakrishnan AN, Khalili H, Konijeti GG, et al. Sleep duration affects risk for ulcerative colitis: a prospective cohort study. Clin Gastroenterol Hepatol. 2014;12:1879\u201386.","journal-title":"Clin Gastroenterol Hepatol"},{"key":"2263_CR31","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0082291","volume":"8","author":"J Axelsson","year":"2013","unstructured":"Axelsson J, Rehman J-U, Akerstedt T, et al. Effects of sustained sleep restriction on mitogen-stimulated cytokines, chemokines and T helper 1\/ T helper 2 balance in humans. PLoS ONE. 2013;8: e82291.","journal-title":"PLoS ONE"},{"key":"2263_CR32","doi-asserted-by":"publisher","first-page":"727","DOI":"10.1126\/science.1243884","volume":"342","author":"X Yu","year":"2013","unstructured":"Yu X, Rollins D, Ruhn KA, et al. TH17 cell differentiation is regulated by the circadian clock. Science. 2013;342:727\u201330.","journal-title":"Science"}],"container-title":["Journal of Gastroenterology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00535-025-02263-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s00535-025-02263-7","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00535-025-02263-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T09:21:07Z","timestamp":1786612867000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s00535-025-02263-7"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,5,15]]},"references-count":32,"journal-issue":{"issue":"9","published-print":{"date-parts":[[2025,9]]}},"alternative-id":["2263"],"URL":"https:\/\/doi.org\/10.1007\/s00535-025-02263-7","relation":{},"ISSN":["0944-1174","1435-5922"],"issn-type":[{"value":"0944-1174","type":"print"},{"value":"1435-5922","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,5,15]]},"assertion":[{"value":"9 March 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"1 May 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"15 May 2025","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"A license fee was granted to Y Kakuta, T Naito, and Y Kinouchi for a patent unrelated to this study by Medical & Biological Laboratories Co., Ltd (MBL) and research funding unrelated to this study was granted to Y Kakuta by MBL. The other authors have no conflicts of interest to declare.","order":1,"name":"Ethics","label":"Conflict of interest","group":{"name":"EthicsHeading","label":"Declarations"}}]}}