{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T08:16:05Z","timestamp":1788336965343,"version":"build-2803163510"},"reference-count":42,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2016,7,11]],"date-time":"2016-07-11T00:00:00Z","timestamp":1468195200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2016,7,11]],"date-time":"2016-07-11T00:00:00Z","timestamp":1468195200000},"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":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Autoimmune hepatitis (AIH) and primary biliary cholangitis (PBC) are liver-specific autoimmune conditions that are characterized by chronic hepatic damage and often lead to cirrhosis and hepatic failure. Specifically, the <jats:italic>protein tyrosine phosphatase N22<\/jats:italic> (<jats:italic>PTPN22<\/jats:italic>) gene encodes the lymphoid protein tyrosine phosphatase, which acts as a negative regulator of T-cell receptor signaling. A missense single nucleotide polymorphism (SNP) (rs2476601) in <jats:italic>PTPN22<\/jats:italic> has been linked to numerous autoimmune diseases in Caucasians. In the present series, nine SNPs in the <jats:italic>PTPN22<\/jats:italic> gene were analyzed in 166 patients with AIH, 262 patients with PBC, and 322 healthy controls in the Japanese population using TaqMan assays. Although the functional rs3996649 and rs2476601 were non-polymorphic in all subject groups, the frequencies of the minor alleles at rs1217412, rs1217388, rs1217407, and rs2488458 were significantly decreased in AIH patients as compared with controls (all <jats:italic>Pc<\/jats:italic>\u2009&lt;\u20090.05). There were no significant relationships with PTPN22 SNPs in PBC patients. Interestingly, the AAGTCCC haplotype was significantly associated with resistance to both AIH (odds ratio [OR]\u2009=\u20090.58, <jats:italic>P<\/jats:italic>\u2009=\u20090.0067) and PBC (OR\u2009=\u20090.58, <jats:italic>P<\/jats:italic>\u2009=\u20090.0048). SNPs in the <jats:italic>PTPN22<\/jats:italic> gene may therefore play key roles in the genetic resistance to autoimmune liver disease in the Japanese.<\/jats:p>","DOI":"10.1038\/srep29770","type":"journal-article","created":{"date-parts":[[2016,7,13]],"date-time":"2016-07-13T07:12:37Z","timestamp":1468393957000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":29,"title":["Genetic Association of PTPN22 Polymorphisms with Autoimmune Hepatitis and Primary Biliary Cholangitis in Japan"],"prefix":"10.1038","volume":"6","author":[{"given":"Takeji","family":"Umemura","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Satoru","family":"Joshita","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomoo","family":"Yamazaki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michiharu","family":"Komatsu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshihiko","family":"Katsuyama","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaname","family":"Yoshizawa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eiji","family":"Tanaka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masao","family":"Ota","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2016,7,11]]},"reference":[{"key":"BFsrep29770_CR1","doi-asserted-by":"publisher","first-page":"54","DOI":"10.1056\/NEJMra050408","volume":"354","author":"EL Krawitt","year":"2006","unstructured":"Krawitt, E. L. Autoimmune hepatitis. N Engl J Med. 354, 54\u201366 (2006).","journal-title":"N Engl J Med."},{"key":"BFsrep29770_CR2","doi-asserted-by":"publisher","first-page":"1433","DOI":"10.1016\/S0140-6736(12)62163-1","volume":"382","author":"MA Heneghan","year":"2013","unstructured":"Heneghan, M. A., Yeoman, A. D., Verma, S., Smith, A. D. & Longhi, M. S. Autoimmune hepatitis. Lancet. 382, 1433\u20131444 (2013).","journal-title":"Lancet."},{"key":"BFsrep29770_CR3","doi-asserted-by":"publisher","first-page":"1261","DOI":"10.1056\/NEJMra043898","volume":"353","author":"MM Kaplan","year":"2005","unstructured":"Kaplan, M. M. & Gershwin, M. E. Primary biliary cirrhosis. N Engl J Med. 353, 1261\u20131273 (2005).","journal-title":"N Engl J Med."},{"key":"BFsrep29770_CR4","doi-asserted-by":"publisher","first-page":"1565","DOI":"10.1016\/S0140-6736(15)00154-3","volume":"386","author":"EJ Carey","year":"2015","unstructured":"Carey, E. J., Ali, A. H. & Lindor, K. D. Primary biliary cirrhosis. Lancet. 386, 1565\u20131575 (2015).","journal-title":"Lancet."},{"key":"BFsrep29770_CR5","doi-asserted-by":"publisher","first-page":"1041","DOI":"10.1016\/0016-5085(92)90041-V","volume":"103","author":"T Seki","year":"1992","unstructured":"Seki, T. et al. HLA class II molecules and autoimmune hepatitis susceptibility in Japanese patients. Gastroenterology. 103, 1041\u20131047 (1992).","journal-title":"Gastroenterology."},{"key":"BFsrep29770_CR6","doi-asserted-by":"publisher","first-page":"e100565","DOI":"10.1371\/journal.pone.0100565","volume":"9","author":"T Umemura","year":"2014","unstructured":"Umemura, T. et al. Human leukocyte antigen class II haplotypes affect clinical characteristics and progression of type 1 autoimmune hepatitis in Japan. PLoS One. 9, e100565 (2014).","journal-title":"PLoS One."},{"key":"BFsrep29770_CR7","doi-asserted-by":"publisher","first-page":"506","DOI":"10.1002\/hep.24705","volume":"55","author":"T Umemura","year":"2012","unstructured":"Umemura, T. et al. Human leukocyte antigen class II molecules confer both susceptibility and progression in Japanese patients with primary biliary cirrhosis. Hepatology. 55, 506\u2013511 (2012).","journal-title":"Hepatology."},{"key":"BFsrep29770_CR8","doi-asserted-by":"publisher","first-page":"537","DOI":"10.1016\/j.jhep.2010.03.017","volume":"53","author":"S Joshita","year":"2010","unstructured":"Joshita, S. et al. Association analysis of cytotoxic T-lymphocyte antigen 4 gene polymorphisms with primary biliary cirrhosis in Japanese patients. J Hepatol. 53, 537\u2013541 (2010).","journal-title":"J Hepatol."},{"key":"BFsrep29770_CR9","doi-asserted-by":"publisher","first-page":"689","DOI":"10.1111\/j.1872-034X.2008.00337.x","volume":"38","author":"T Umemura","year":"2008","unstructured":"Umemura, T. et al. Association of cytotoxic T-lymphocyte antigen 4 gene polymorphisms with type 1 autoimmune hepatitis in Japanese. Hepatol Res. 38, 689\u2013695 (2008).","journal-title":"Hepatol Res."},{"key":"BFsrep29770_CR10","doi-asserted-by":"publisher","first-page":"655","DOI":"10.1038\/ng.631","volume":"42","author":"GM Hirschfield","year":"2010","unstructured":"Hirschfield, G. M. et al. Variants at IRF5-TNPO3, 17q12-21 and MMEL1 are associated with primary biliary cirrhosis. Nat Genet. 42, 655\u2013657 (2010).","journal-title":"Nat Genet."},{"key":"BFsrep29770_CR11","doi-asserted-by":"publisher","first-page":"658","DOI":"10.1038\/ng.627","volume":"42","author":"X Liu","year":"2010","unstructured":"Liu, X. et al. Genome-wide meta-analyses identify three loci associated with primary biliary cirrhosis. Nat Genet. 42, 658\u2013660 (2010).","journal-title":"Nat Genet."},{"key":"BFsrep29770_CR12","doi-asserted-by":"publisher","first-page":"329","DOI":"10.1038\/ng.789","volume":"43","author":"GF Mells","year":"2011","unstructured":"Mells, G. F. et al. Genome-wide association study identifies 12 new susceptibility loci for primary biliary cirrhosis. Nat Genet. 43, 329\u2013332 (2011).","journal-title":"Nat Genet."},{"key":"BFsrep29770_CR13","doi-asserted-by":"publisher","first-page":"443","DOI":"10.1053\/j.gastro.2014.04.022","volume":"147","author":"YS de Boer","year":"2014","unstructured":"de Boer, Y. S. et al. Genome-wide association study identifies variants associated with autoimmune hepatitis type 1. Gastroenterology. 147, 443\u2013452 e445 (2014).","journal-title":"Gastroenterology."},{"key":"BFsrep29770_CR14","doi-asserted-by":"publisher","first-page":"337","DOI":"10.1038\/ng1323","volume":"36","author":"N Bottini","year":"2004","unstructured":"Bottini, N. et al. A functional variant of lymphoid tyrosine phosphatase is associated with type I diabetes. Nat Genet. 36, 337\u2013338 (2004).","journal-title":"Nat Genet."},{"key":"BFsrep29770_CR15","doi-asserted-by":"publisher","first-page":"330","DOI":"10.1086\/422827","volume":"75","author":"AB Begovich","year":"2004","unstructured":"Begovich, A. B. et al. A missense single-nucleotide polymorphism in a gene encoding a protein tyrosine phosphatase (PTPN22) is associated with rheumatoid arthritis. Am J Hum Genet. 75, 330\u2013337 (2004).","journal-title":"Am J Hum Genet."},{"key":"BFsrep29770_CR16","doi-asserted-by":"publisher","first-page":"60","DOI":"10.1016\/j.humimm.2004.09.016","volume":"66","author":"MB Ladner","year":"2005","unstructured":"Ladner, M. B., Bottini, N., Valdes, A. M. & Noble, J. A. Association of the single nucleotide polymorphism C1858T of the PTPN22 gene with type 1 diabetes. Hum Immunol. 66, 60\u201364 (2005).","journal-title":"Hum Immunol."},{"key":"BFsrep29770_CR17","doi-asserted-by":"publisher","first-page":"1694","DOI":"10.1002\/art.21049","volume":"52","author":"A Hinks","year":"2005","unstructured":"Hinks, A. et al. Association between the PTPN22 gene and rheumatoid arthritis and juvenile idiopathic arthritis in a UK population: further support that PTPN22 is an autoimmunity gene. Arthritis Rheum. 52, 1694\u20131699 (2005).","journal-title":"Arthritis Rheum."},{"key":"BFsrep29770_CR18","doi-asserted-by":"publisher","first-page":"219","DOI":"10.1002\/art.20771","volume":"52","author":"G Orozco","year":"2005","unstructured":"Orozco, G. et al. Association of a functional single-nucleotide polymorphism of PTPN22, encoding lymphoid protein phosphatase, with rheumatoid arthritis and systemic lupus erythematosus. Arthritis Rheum. 52, 219\u2013224 (2005).","journal-title":"Arthritis Rheum."},{"key":"BFsrep29770_CR19","doi-asserted-by":"publisher","first-page":"264","DOI":"10.1007\/s10038-005-0246-8","volume":"50","author":"M Mori","year":"2005","unstructured":"Mori, M., Yamada, R., Kobayashi, K., Kawaida, R. & Yamamoto, K. Ethnic differences in allele frequency of autoimmune-disease-associated SNPs. J Hum Genet. 50, 264\u2013266 (2005).","journal-title":"J Hum Genet."},{"key":"BFsrep29770_CR20","doi-asserted-by":"publisher","first-page":"1115","DOI":"10.1089\/thy.2005.15.1115","volume":"15","author":"Y Ban","year":"2005","unstructured":"Ban, Y., Tozaki, T., Taniyama, M., Tomita, M. & Ban, Y. The codon 620 single nucleotide polymorphism of the protein tyrosine phosphatase-22 gene does not contribute to autoimmune thyroid disease susceptibility in the Japanese. Thyroid. 15, 1115\u20131118 (2005).","journal-title":"Thyroid."},{"key":"BFsrep29770_CR21","doi-asserted-by":"publisher","first-page":"586","DOI":"10.1002\/ajmg.a.31124","volume":"140","author":"E Kawasaki","year":"2006","unstructured":"Kawasaki, E. et al. Systematic search for single nucleotide polymorphisms in a lymphoid tyrosine phosphatase gene (PTPN22): association between a promoter polymorphism and type 1 diabetes in Asian populations. Am J Med Genet A. 140, 586\u2013593 (2006).","journal-title":"Am J Med Genet A."},{"key":"BFsrep29770_CR22","doi-asserted-by":"publisher","first-page":"1345","DOI":"10.1093\/rheumatology\/kel169","volume":"45","author":"K Ikari","year":"2006","unstructured":"Ikari, K. et al. Haplotype analysis revealed no association between the PTPN22 gene and RA in a Japanese population. Rheumatology (Oxford). 45, 1345\u20131348 (2006).","journal-title":"Rheumatology (Oxford)."},{"key":"BFsrep29770_CR23","doi-asserted-by":"publisher","first-page":"1431","DOI":"10.1038\/ng.2007.32","volume":"39","author":"W Thomson","year":"2007","unstructured":"Thomson, W. et al. Rheumatoid arthritis association at 6q23. Nat Genet. 39, 1431\u20131433 (2007).","journal-title":"Nat Genet."},{"key":"BFsrep29770_CR24","doi-asserted-by":"publisher","first-page":"703","DOI":"10.1038\/ng.381","volume":"41","author":"JC Barrett","year":"2009","unstructured":"Barrett, J. C. et al. Genome-wide association study and meta-analysis find that over 40 loci affect risk of type 1 diabetes. Nat Genet. 41, 703\u2013707 (2009).","journal-title":"Nat Genet."},{"key":"BFsrep29770_CR25","doi-asserted-by":"publisher","first-page":"32","DOI":"10.1016\/j.jaut.2015.03.006","volume":"60","author":"Y Tomer","year":"2015","unstructured":"Tomer, Y. et al. Genome wide identification of new genes and pathways in patients with both autoimmune thyroiditis and type 1 diabetes. J Autoimmun. 60, 32\u201339 (2015).","journal-title":"J Autoimmun."},{"key":"BFsrep29770_CR26","doi-asserted-by":"publisher","first-page":"569","DOI":"10.1093\/hmg\/ddn363","volume":"18","author":"V Orru","year":"2009","unstructured":"Orru, V. et al. A loss-of-function variant of PTPN22 is associated with reduced risk of systemic lupus erythematosus. Hum Mol Genet. 18, 569\u2013579 (2009).","journal-title":"Hum Mol Genet."},{"key":"BFsrep29770_CR27","doi-asserted-by":"publisher","first-page":"26506","DOI":"10.1074\/jbc.M110.111104","volume":"285","author":"E Fiorillo","year":"2010","unstructured":"Fiorillo, E. et al. Autoimmune-associated PTPN22 R620W variation reduces phosphorylation of lymphoid phosphatase on an inhibitory tyrosine residue. J Biol Chem. 285, 26506\u201326518 (2010).","journal-title":"J Biol Chem."},{"key":"BFsrep29770_CR28","doi-asserted-by":"publisher","first-page":"297","DOI":"10.1111\/j.1399-0039.2010.01521.x","volume":"76","author":"X Feng","year":"2010","unstructured":"Feng, X. et al. Association of the PTPN22 gene (-1123G &gt; C) polymorphism with rheumatoid arthritis in Chinese patients. Tissue Antigens. 76, 297\u2013300 (2010).","journal-title":"Tissue Antigens."},{"key":"BFsrep29770_CR29","doi-asserted-by":"publisher","first-page":"767","DOI":"10.1007\/s00296-010-1705-x","volume":"32","author":"JJ Huang","year":"2012","unstructured":"Huang, J. J. et al. A PTPN22 promoter polymorphism -1123G&gt;C is associated with RA pathogenesis in Chinese. Rheumatol Int. 32, 767\u2013771 (2012).","journal-title":"Rheumatol Int."},{"key":"BFsrep29770_CR30","doi-asserted-by":"publisher","first-page":"683","DOI":"10.1007\/s00296-013-2894-x","volume":"34","author":"CH Huang","year":"2014","unstructured":"Huang, C. H. et al. Associations of the PTPN22 and CTLA-4 genetic polymorphisms with Taiwanese ankylosing spondylitis. Rheumatol Int. 34, 683\u2013691 (2014).","journal-title":"Rheumatol Int."},{"key":"BFsrep29770_CR31","doi-asserted-by":"publisher","first-page":"641","DOI":"10.1038\/gene.2012.46","volume":"13","author":"J Zheng","year":"2012","unstructured":"Zheng, J., Ibrahim, S., Petersen, F. & Yu, X. Meta-analysis reveals an association of PTPN22 C1858T with autoimmune diseases, which depends on the localization of the affected tissue. Genes Immun. 13, 641\u2013652 (2012).","journal-title":"Genes Immun."},{"key":"BFsrep29770_CR32","doi-asserted-by":"publisher","first-page":"434","DOI":"10.1111\/j.1399-0039.2006.00594.x","volume":"67","author":"P Milkiewicz","year":"2006","unstructured":"Milkiewicz, P. et al. The PTPN22 1858T variant is not associated with primary biliary cirrhosis. Tissue Antigens. 67, 434\u2013437 (2006).","journal-title":"Tissue Antigens."},{"key":"BFsrep29770_CR33","doi-asserted-by":"publisher","first-page":"721","DOI":"10.1016\/j.ajhg.2012.08.010","volume":"91","author":"M Nakamura","year":"2012","unstructured":"Nakamura, M. et al. Genome-wide association study identifies TNFSF15 and POU2AF1 as susceptibility loci for primary biliary cirrhosis in the Japanese population. Am J Hum Genet. 91, 721\u2013728 (2012).","journal-title":"Am J Hum Genet."},{"key":"BFsrep29770_CR34","doi-asserted-by":"publisher","first-page":"8019","DOI":"10.1038\/ncomms9019","volume":"6","author":"HJ Cordell","year":"2015","unstructured":"Cordell, H. J. et al. International genome-wide meta-analysis identifies new primary biliary cirrhosis risk loci and targetable pathogenic pathways. Nat Commun. 6, 8019 (2015).","journal-title":"Nat Commun."},{"key":"BFsrep29770_CR35","doi-asserted-by":"publisher","first-page":"271","DOI":"10.1038\/sj.gene.6364178","volume":"6","author":"MK Viken","year":"2005","unstructured":"Viken, M. K. et al. Association analysis of the 1858C&gt;T polymorphism in the PTPN22 gene in juvenile idiopathic arthritis and other autoimmune diseases. Genes Immun. 6, 271\u2013273 (2005).","journal-title":"Genes Immun."},{"key":"BFsrep29770_CR36","doi-asserted-by":"publisher","first-page":"929","DOI":"10.1016\/S0168-8278(99)80297-9","volume":"31","author":"F Alvarez","year":"1999","unstructured":"Alvarez, F. et al. International Autoimmune Hepatitis Group Report: review of criteria for diagnosis of autoimmune hepatitis. J Hepatol. 31, 929\u2013938 (1999).","journal-title":"J Hepatol."},{"key":"BFsrep29770_CR37","doi-asserted-by":"publisher","first-page":"291","DOI":"10.1002\/hep.22906","volume":"50","author":"KD Lindor","year":"2009","unstructured":"Lindor, K. D. et al. Primary biliary cirrhosis. Hepatology. 50, 291\u2013308 (2009).","journal-title":"Hepatology."},{"key":"BFsrep29770_CR38","doi-asserted-by":"publisher","first-page":"463","DOI":"10.1002\/hep.21700","volume":"46","author":"T Umemura","year":"2007","unstructured":"Umemura, T. et al. Immunoglobin G4-hepatopathy: association of immunoglobin G4-bearing plasma cells in liver with autoimmune pancreatitis. Hepatology. 46, 463\u2013471 (2007).","journal-title":"Hepatology."},{"key":"BFsrep29770_CR39","doi-asserted-by":"publisher","first-page":"857","DOI":"10.1038\/ajg.2015.118","volume":"110","author":"T Umemura","year":"2015","unstructured":"Umemura, T. et al. Serum Wisteria floribunda Agglutinin-Positive Mac-2-Binding Protein Level Predicts Liver Fibrosis and Prognosis in Primary Biliary Cirrhosis. Am J Gastroenterol. 110, 857\u2013864 (2015).","journal-title":"Am J Gastroenterol."},{"key":"BFsrep29770_CR40","doi-asserted-by":"publisher","first-page":"1928","DOI":"10.1093\/bioinformatics\/btl268","volume":"22","author":"X Sole","year":"2006","unstructured":"Sole, X., Guino, E., Valls, J., Iniesta, R. & Moreno, V. SNPStats: a web tool for the analysis of association studies. Bioinformatics. 22, 1928\u20131929 (2006).","journal-title":"Bioinformatics."},{"key":"BFsrep29770_CR41","doi-asserted-by":"publisher","first-page":"263","DOI":"10.1093\/bioinformatics\/bth457","volume":"21","author":"JC Barrett","year":"2005","unstructured":"Barrett, J. C., Fry, B., Maller, J. & Daly, M. J. Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics. 21, 263\u2013265 (2005).","journal-title":"Bioinformatics."},{"key":"BFsrep29770_CR42","doi-asserted-by":"publisher","first-page":"716","DOI":"10.1109\/TAC.1974.1100705","volume":"19","author":"H Akaike","year":"1974","unstructured":"Akaike, H. A new look at the statistical model iddentification. IEEE Transactions on Automatic Control. 19, 716\u2013723 (1974).","journal-title":"IEEE Transactions on Automatic Control."}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/srep29770.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/srep29770","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/srep29770.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,1,5]],"date-time":"2023-01-05T06:45:35Z","timestamp":1672901135000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/srep29770"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,7,11]]},"references-count":42,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2016,7,28]]}},"alternative-id":["BFsrep29770"],"URL":"https:\/\/doi.org\/10.1038\/srep29770","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2016,7,11]]},"assertion":[{"value":"8 April 2016","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"23 June 2016","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"11 July 2016","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing financial interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"29770"}}