{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,8]],"date-time":"2026-05-08T05:33:09Z","timestamp":1778218389280,"version":"3.51.4"},"reference-count":50,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,5,31]],"date-time":"2023-05-31T00:00:00Z","timestamp":1685491200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","award":["JP22fk0210111, 20K08370"],"award-info":[{"award-number":["JP22fk0210111, 20K08370"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["20590800, 23591006, 26293181"],"award-info":[{"award-number":["20590800, 23591006, 26293181"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>Primary biliary cholangitis (PBC) is a rare autoimmune disease with a clear predisposition for human leukocyte antigen <jats:italic>(HLA)-DR\/DQ<\/jats:italic>-associated loss of immune tolerance for the E2 component of the pyruvate dehydrogenase complex. Three-field-resolution <jats:italic>HLA<\/jats:italic> imputation of 1,670 Japanese PBC patients and 2,328 healthy controls was conducted using Japanese population-specific <jats:italic>HLA<\/jats:italic> reference panels. Eighteen previously reported Japanese PBC-associated <jats:italic>HLA<\/jats:italic> alleles were confirmed and extended to 3-field-resolution, including <jats:italic>HLA-DRB1*08:03<\/jats:italic> to <jats:italic>HLA-DRB1*08:03:02<\/jats:italic>, <jats:italic>HLA-DQB1*03:01<\/jats:italic> to <jats:italic>HLA-DQB1*03:01:01<\/jats:italic>, <jats:italic>HLA-DQB1*04:01<\/jats:italic> to <jats:italic>HLA-DQB1*04:01:01<\/jats:italic> and <jats:italic>HLA-DQB1*06:04<\/jats:italic> to <jats:italic>HLA-DQB1*06:04:01<\/jats:italic>. In addition, additional significant novel <jats:italic>HLA<\/jats:italic> alleles were identified, including 3 novel susceptible <jats:italic>HLA-DQA1<\/jats:italic> alleles: <jats:italic>HLA-DQA1*03:03:01<\/jats:italic>, <jats:italic>HLA-DQA1*04:01:01<\/jats:italic>, <jats:italic>HLA-DQA1*01:04:01<\/jats:italic> and 1 novel protective <jats:italic>HLA-DQA1<\/jats:italic> allele, <jats:italic>HLA-DQA1*05:05:01<\/jats:italic>. In addition, PBC patients carrying <jats:italic>HLA-DRB1*15:01:01<\/jats:italic> and <jats:italic>HLA-DQA1*03:03:01<\/jats:italic> would have a higher predisposition toward developing concomitant autoimmune hepatitis (AIH). Further, late-stage and symptomatic PBC shared the same susceptible <jats:italic>HLA<\/jats:italic> alleles of <jats:italic>HLA-A*26:01:01<\/jats:italic>, <jats:italic>HLA-DRB1*09:01:02<\/jats:italic> and <jats:italic>HLA-DQB1*03:03:02<\/jats:italic>. Lastly, <jats:italic>HLA-DPB1*05:01:01<\/jats:italic> was identified as a potential risk <jats:italic>HLA<\/jats:italic> allele for development of hepatocellular carcinoma (HCC) in PBC patients. In conclusion, we have extended the current knowledge of <jats:italic>HLA<\/jats:italic> allele associations to 3-field resolution and identified novel <jats:italic>HLA<\/jats:italic> allele associations with predisposition risk, staging, symptomatic state, and AIH and HCC events for Japanese PBC patients.<\/jats:p>","DOI":"10.3389\/fimmu.2023.1151502","type":"journal-article","created":{"date-parts":[[2023,5,31]],"date-time":"2023-05-31T05:21:30Z","timestamp":1685510490000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":13,"title":["Novel HLA allele associations with susceptibility, staging, symptomatic state, autoimmune hepatitis and hepatocellular carcinoma events for primary biliary cholangitis in the Japanese population"],"prefix":"10.3389","volume":"14","author":[{"given":"Seik-Soon","family":"Khor","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kazuko","family":"Ueno","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nao","family":"Nishida","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Minae","family":"Kawashima","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yosuke","family":"Kawai","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yoshihiro","family":"Aiba","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuki","family":"Hitomi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Masao","family":"Nagasaki","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Minoru","family":"Nakamura","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Katsushi","family":"Tokunaga","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2023,5,31]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2009.11.027","article-title":"Primary biliary cirrhosis: a 2010 update","volume":"52","author":"Poupon","year":"2010","journal-title":"J Hepatol"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(20)31607-X","article-title":"Primary biliary cholangitis","volume":"396","author":"Lleo","year":"2020","journal-title":"Lancet"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1111\/j.1572-0241.2000.01857.x","article-title":"Impact of fatigue on the quality of life of patients with primary biliary cirrhosis","volume":"95","author":"Huet","year":"2000","journal-title":"Am J Gastroenterol"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(10)61965-4","article-title":"Primary biliary cirrhosis","volume":"377","author":"Selmi","year":"2011","journal-title":"Lancet"},{"key":"B5","volume-title":"Diseases of the liver and biliary system","author":"Sherlock","year":"2008"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.3748\/wjg.v21.i25.7683","article-title":"Primary biliary cirrhosis: clinical and laboratory criteria for its diagnosis","volume":"21","author":"Reshetnyak","year":"2015","journal-title":"World J Gastroenterol"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1016\/j.dld.2010.02.014","article-title":"Update on primary biliary cirrhosis","volume":"42","author":"Invernizzi","year":"2010","journal-title":"Dig Liver Dis"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2021.04.055","article-title":"An international genome-wide meta-analysis of primary biliary cholangitis: novel risk loci and candidate drugs","volume":"75","author":"Cordell","year":"2021","journal-title":"J Hepatol"},{"key":"B9","doi-asserted-by":"publisher","first-page":"489","DOI":"10.1016\/j.jhep.2021.11.015","article-title":"Corrigendum to 'An international genome-wide meta-analysis of primary biliary cholangitis: novel risk loci and candidate drugs' [J hepatol 2021;75(3):572-581]","volume":"76","author":"Cordell","year":"2022","journal-title":"J Hepatol"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1016\/s0168-8278(05)80617-8","article-title":"DNA Typing of HLA class II genes; 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