{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,1]],"date-time":"2026-08-01T02:37:38Z","timestamp":1785551858821,"version":"3.56.0"},"reference-count":25,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2021,8,8]],"date-time":"2021-08-08T00:00:00Z","timestamp":1628380800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Liver International"],"published-print":{"date-parts":[[2021,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background &amp; Aims<\/jats:title><jats:p>Tolvaptan, vasopressin V2\u2010receptor antagonist, has been used for patients with difficult\u2010to\u2010treat ascites in Japan. In this study, we conducted a genome\u2010wide association study (GWAS) in the Japanese population to identify genetic variants associated with tolvaptan's efficacy for patients with hepatic ascites.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>From 2014 through 2018, genomic DNA samples were obtained from 550 patients who were treated with tolvaptan. Of those, 80 cases (non\u2010responder; increase of body weight [BW]) and 333 controls (responder; &gt;1.5\u00a0kg decrease of BW) were included in the GWAS and replication study.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Genome\u2010wide association study showed 5 candidate SNPs around the <jats:italic>miR818, KIAA1109<\/jats:italic>, and <jats:italic>SVEP1<\/jats:italic> genes. After validation and performing a replication study, an SNP (rs2991364) located in the <jats:italic>SVEP1<\/jats:italic> gene was found to have a significant genome\u2010wide association (OR\u00a0=\u00a03.55, <jats:italic>P<\/jats:italic>\u00a0=\u00a02.01\u00a0\u00d7\u00a010<jats:sup>\u20108<\/jats:sup>). Multivariate analyses showed that serum sodium (Na), blood urea nitrogen (BUN) and <jats:italic>SVEP1<\/jats:italic> SNP were significantly associated with the response (OR\u00a0=\u00a00.92, <jats:italic>P<\/jats:italic>\u00a0=\u00a0.003; OR\u00a0=\u00a01.02, <jats:italic>P<\/jats:italic>\u00a0=\u00a0.02 and OR\u00a0=\u00a03.98, <jats:italic>P<\/jats:italic>\u00a0=\u00a0.000008, respectively). Based on a prediction model of logistic regression analysis in a population with the rs2991364 risk allele, the failure probability (=exp (score: 22.234\u00a0+\u00a0BUN*0.077\u00a0+\u00a0Na*\u20100.179) (1\u00a0+\u00a0exp (score)) was determined for the detection of non\u2010responders. Assuming a cutoff of failure probability at 38.6%, sensitivity was 84.4%, specificity was 70% and AUC was 0.774.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p><jats:italic>SVEP1<\/jats:italic> rs2991364 was identified as the specific SNP for the tolvaptan response. The prediction score (&gt;38.6%) can identify tolvaptan non\u2010responders and help to avoid a lengthy period of futile treatment.<\/jats:p><\/jats:sec>","DOI":"10.1111\/liv.15022","type":"journal-article","created":{"date-parts":[[2021,7,26]],"date-time":"2021-07-26T09:11:01Z","timestamp":1627290661000},"page":"2944-2953","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["A genome\u2010wide association study identifying <i>SVEP1<\/i> variant as a predictor of response to tolvaptan for cirrhotic ascites"],"prefix":"10.1111","volume":"41","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4361-0592","authenticated-orcid":false,"given":"Hideto","family":"Kawaratani","sequence":"first","affiliation":[{"name":"Department of Gastroenterology Nara Medical University Nara Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiromi","family":"Sawai","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Graduate School of Medicine The University of Tokyo Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masaya","family":"Onishi","sequence":"additional","affiliation":[{"name":"Department of Virology and Liver Unit Nagoya City University Graduate School of Medical Sciences Nagoya Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomomi","family":"Kogiso","sequence":"additional","affiliation":[{"name":"Institute of Gastroenterology, Department of Internal Medicine Tokyo Women's Medical University Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Noritomo","family":"Shimada","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology Ootakanomori Hospital Kashiwa Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1719-1352","authenticated-orcid":false,"given":"Haruki","family":"Uojima","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Internal Medicine Kitasato University School of Medicine Sagamihara Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomoaki","family":"Nakajima","sequence":"additional","affiliation":[{"name":"Department of Hepatology Sapporo Kosei General Hospital Hokkaido Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naoki","family":"Matsumoto","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology, Department of Medicine Nihon University School of Medicine Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenichi","family":"Ikejima","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology Juntendo University Graduate School of Medicine Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Toru","family":"Ishikawa","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology Saiseikai Niigata Hospital Niigata Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuji","family":"Terai","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology Niigata University Graduate School of Medical and Dental Sciences Niigata Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroyuki","family":"Motoyama","sequence":"additional","affiliation":[{"name":"Department of Hepatology, Graduate School of Medicine Osaka City University Osaka Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Atsumasa","family":"Komori","sequence":"additional","affiliation":[{"name":"Clinical Research Center Nagasaki Medical Center Nagasaki Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Noboru","family":"Hirashima","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, National Hospital Organization Nagoya Medical Center Nagoya Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Satoru","family":"Saito","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology Yokohama City University Graduate School of Medicine Yokohama Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuichiro","family":"Eguchi","sequence":"additional","affiliation":[{"name":"Liver Center Saga University Saga Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masanori","family":"Nojima","sequence":"additional","affiliation":[{"name":"Center for Translational Research, The Institute of Medical Science the University of Tokyo Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yosuke","family":"Kawai","sequence":"additional","affiliation":[{"name":"Genome Medical Science Project (Toyama) National Center for Global Health and Medicine Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masakuni","family":"Tateyama","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology Kumamoto University Kumamoto Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hitoshi","family":"Yoshiji","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology Nara Medical University Nara Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2473-6966","authenticated-orcid":false,"given":"Yasuhito","family":"Tanaka","sequence":"additional","affiliation":[{"name":"Department of Virology and Liver Unit Nagoya City University Graduate School of Medical Sciences Nagoya Japan"},{"name":"Department of Gastroenterology and Hepatology Kumamoto University Kumamoto Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2021,8,8]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2018.03.024"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00535-010-0240-6"},{"key":"e_1_2_10_4_1","first-page":"860","article-title":"OPC\u201041061, a highly potent human vasopressin V2\u2010receptor antagonist: pharmacological profile and aquaretic effect by single and multiple oral dosing in rats","volume":"287","author":"Yamamura Y","year":"1998","journal-title":"J Pharmocol Exp There"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00535-016-1216-y"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa065181"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00535-020-01691-x"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00535-017-1366-6"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40261-018-0714-5"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1111\/hepr.13566"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00535-015-1143-3"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.449"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1262110"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3547"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.116.308825"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1042\/bj3520049"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1507652"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1111\/hepr.12822"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1111\/hepr.12988"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0174649"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.3748\/wjg.v23.i29.5379"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.1097\/MEG.0000000000001985"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00535-020-01721-8"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI80465"},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-4419-1599-3_5"},{"key":"e_1_2_10_26_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrc3539"}],"container-title":["Liver International"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/liv.15022","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/liv.15022","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/liv.15022","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,8,24]],"date-time":"2023-08-24T04:09:42Z","timestamp":1692850182000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/liv.15022"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,8,8]]},"references-count":25,"journal-issue":{"issue":"12","published-print":{"date-parts":[[2021,12]]}},"alternative-id":["10.1111\/liv.15022"],"URL":"https:\/\/doi.org\/10.1111\/liv.15022","archive":["Portico"],"relation":{},"ISSN":["1478-3223","1478-3231"],"issn-type":[{"value":"1478-3223","type":"print"},{"value":"1478-3231","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,8,8]]},"assertion":[{"value":"2021-06-02","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2021-07-15","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2021-08-08","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}