{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T16:53:20Z","timestamp":1790009600109,"version":"4.0.1"},"reference-count":50,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"2","license":[{"start":{"date-parts":[[2018,1,2]],"date-time":"2018-01-02T00:00:00Z","timestamp":1514851200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2018,1,2]],"date-time":"2018-01-02T00:00:00Z","timestamp":1514851200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["Hepatology"],"published-print":{"date-parts":[[2018,2]]},"abstract":"<jats:p>Cholangiopathies are a diverse group of progressive diseases whose primary cell targets are cholangiocytes. To identify shared pathogenesis and molecular connectivity among the three main human cholangiopathies (biliary atresia [BA], primary biliary cholangitis [PBC], and primary sclerosing cholangitis [PSC]), we built a comprehensive platform of published data on gene variants, gene expression, and functional studies and applied network\u2010based analytics in the search for shared molecular circuits. Mining the data platform with largest connected component and interactome analyses, we validated previously reported associations and identified essential and hub genes. In addition to disease\u2010specific modules, we found a substantial overlap of disease neighborhoods and uncovered a group of 34 core genes that are enriched for immune processes and abnormal intestine\/hepatobiliary mouse phenotypes. Within this core, we identified a gene subcore containing <jats:italic toggle=\"yes\">signal transduction and activator of transcription 3<\/jats:italic>, <jats:italic toggle=\"yes\">interleukin\u20106<\/jats:italic>, <jats:italic toggle=\"yes\">tumor necrosis factor<\/jats:italic>, and <jats:italic toggle=\"yes\">forkhead box P3<\/jats:italic> prominently placed in a regulatory connectome of genes related to cellular immunity and fibrosis. We also found substantial gene enrichment in the advanced glycation endproduct\/receptor for advanced glycation endproducts (RAGE) pathway and showed that RAGE activation induced cholangiocyte proliferation. <jats:italic toggle=\"yes\">Conclusion:<\/jats:italic> Human cholangiopathies share pathways enriched by immunity genes and a molecular connectome that links different pathogenic features of BA, PBC, and PSC. (H<jats:sc>epatology<\/jats:sc> 2018;67:676\u2010689).<\/jats:p>","DOI":"10.1002\/hep.29504","type":"journal-article","created":{"date-parts":[[2017,9,2]],"date-time":"2017-09-02T15:46:50Z","timestamp":1504367210000},"page":"676-689","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":19,"title":["Gene\u2010disease associations identify a connectome with shared molecular pathways in human cholangiopathies"],"prefix":"10.1097","volume":"67","author":[{"given":"Zhenhua","family":"Luo","sequence":"first","affiliation":[{"name":"The Liver Care Center and Divisions of Gastroenterology,Hepatology and Nutrition,Cincinnati,OH"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anil G.","family":"Jegga","sequence":"additional","affiliation":[{"name":"Biomedical Informatics of Cincinnati Children's Hospital Medical Center and the Department of Pediatrics of the University Of Cincinnati College of Medicine,Cincinnati,OH"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jorge A.","family":"Bezerra","sequence":"additional","affiliation":[{"name":"The Liver Care Center and Divisions of Gastroenterology,Hepatology and Nutrition,Cincinnati,OH"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","published-online":{"date-parts":[[2018,1,2]]},"reference":[{"key":"hep29504-bib-0001-20241017","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1097\/01.mog.0000218965.78558.bc","article-title":"Cholangiocyte biology","volume":"22","year":"2006","journal-title":"Curr Opin Gastroenterol"},{"key":"hep29504-bib-0002-20241017","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1055\/s-2002-34501","article-title":"Functional heterogeneity of cholangiocytes","volume":"22","year":"2002","journal-title":"Semin Liver Dis"},{"key":"hep29504-bib-0003-20241017","doi-asserted-by":"crossref","first-page":"G1077","DOI":"10.1152\/ajpgi.00227.2012","article-title":"Advances in cholangiocyte immunobiology","volume":"303","year":"2012","journal-title":"Am J Physiol Gastrointest Liver Physiol"},{"key":"hep29504-bib-0004-20241017","doi-asserted-by":"crossref","first-page":"934","DOI":"10.1016\/j.jhep.2014.11.027","article-title":"Autophagy and senescence in fibrosing cholangiopathies","volume":"62","year":"2015","journal-title":"J Hepatol"},{"key":"hep29504-bib-0005-20241017","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1016\/j.jhep.2012.10.011","article-title":"The dynamic biliary epithelia: molecules, pathways, and disease","volume":"58","year":"2013","journal-title":"J Hepatol"},{"key":"hep29504-bib-0006-20241017","doi-asserted-by":"crossref","first-page":"791","DOI":"10.1016\/j.mayocp.2015.03.017","article-title":"The cholangiopathies","volume":"90","year":"2015","journal-title":"Mayo Clin Proc"},{"key":"hep29504-bib-0007-20241017","doi-asserted-by":"crossref","first-page":"342","DOI":"10.1038\/nrgastro.2015.74","article-title":"Pathogenesis of biliary atresia: defining biology to understand clinical phenotypes","volume":"12","year":"2015","journal-title":"Nat Rev Gastroenterol Hepatol"},{"key":"hep29504-bib-0008-20241017","doi-asserted-by":"crossref","first-page":"1181","DOI":"10.1016\/j.jhep.2011.10.025","article-title":"Epidemiology of primary sclerosing cholangitis and primary biliary cirrhosis: a systematic review","volume":"56","year":"2012","journal-title":"J Hepatol"},{"key":"hep29504-bib-0009-20241017","doi-asserted-by":"crossref","first-page":"1653","DOI":"10.1016\/S0140-6736(02)11603-5","article-title":"Genetic induction of proinflammatory immunity in children with biliary atresia","volume":"360","year":"2002","journal-title":"Lancet"},{"key":"hep29504-bib-0010-20241017","doi-asserted-by":"crossref","first-page":"565","DOI":"10.1136\/gut.49.4.565","article-title":"Identification of novel molecules and pathogenic pathways in primary biliary cirrhosis: cDNA array analysis of intrahepatic differential gene expression","volume":"49","year":"2001","journal-title":"Gut"},{"key":"hep29504-bib-0011-20241017","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1016\/j.jaut.2015.08.016","article-title":"Using GWAS to identify genetic predisposition in hepatic autoimmunity","volume":"66","year":"2016","journal-title":"J Autoimmun"},{"key":"hep29504-bib-0012-20241017","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1007\/s00439-013-1368-2","article-title":"Replication of a GWAS signal in a Caucasian population implicates ADD3 in susceptibility to biliary atresia","volume":"133","year":"2014","journal-title":"Hum Genet"},{"key":"hep29504-bib-0013-20241017","doi-asserted-by":"crossref","first-page":"670","DOI":"10.1038\/ng.2616","article-title":"Dense genotyping of immune\u2010related disease regions identifies nine new risk loci for primary sclerosing cholangitis","volume":"45","year":"2013","journal-title":"Nat Genet"},{"key":"hep29504-bib-0014-20241017","doi-asserted-by":"crossref","first-page":"bav028","DOI":"10.1093\/database\/bav028","article-title":"DisGeNET: a discovery platform for the dynamical exploration of human diseases and their genes","volume":"2015","year":"2015","journal-title":"Database (Oxford)"},{"key":"hep29504-bib-0015-20241017","doi-asserted-by":"crossref","first-page":"W305","DOI":"10.1093\/nar\/gkp427","article-title":"ToppGene Suite for gene list enrichment analysis and candidate gene prioritization","volume":"37","year":"2009","journal-title":"Nucleic Acids Res"},{"key":"hep29504-bib-0016-20241017","first-page":"G1060","article-title":"Regulation of intracellular pH by immortalized human intrahepatic biliary epithelial cell lines","volume":"266","year":"1994","journal-title":"Am J Physiol"},{"key":"hep29504-bib-0017-20241017","doi-asserted-by":"crossref","first-page":"1257601","DOI":"10.1126\/science.1257601","article-title":"Disease networks. Uncovering disease\u2010disease relationships through the incomplete interactome","volume":"347","year":"2015","journal-title":"Science"},{"key":"hep29504-bib-0018-20241017","doi-asserted-by":"crossref","first-page":"8685","DOI":"10.1073\/pnas.0701361104","article-title":"The human disease network","volume":"104","year":"2007","journal-title":"Proc Natl Acad Sci USA"},{"key":"hep29504-bib-0019-20241017","doi-asserted-by":"crossref","first-page":"755","DOI":"10.1016\/j.ajhg.2011.05.006","article-title":"The orphan disease networks","volume":"88","year":"2011","journal-title":"Am J Hum Genet"},{"key":"hep29504-bib-0020-20241017","doi-asserted-by":"crossref","first-page":"508","DOI":"10.1038\/nature19356","article-title":"High\u2010throughput discovery of novel developmental phenotypes","volume":"537","year":"2016","journal-title":"Nature"},{"key":"hep29504-bib-0021-20241017","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1006\/jaut.2002.0622","article-title":"Autoantibodies to the transcriptional factor SOX13 in primary biliary cirrhosis compared with other diseases","volume":"19","year":"2002","journal-title":"J Autoimmun"},{"key":"hep29504-bib-0022-20241017","doi-asserted-by":"crossref","first-page":"1074","DOI":"10.1002\/hep.25977","article-title":"Genome\u2010wide association analysis in primary sclerosing cholangitis and ulcerative colitis identifies risk loci at GPR35 and TCF4","volume":"58","year":"2013","journal-title":"Hepatology"},{"key":"hep29504-bib-0023-20241017","doi-asserted-by":"crossref","first-page":"1688","DOI":"10.3390\/jcm4091688","article-title":"MicroRNAs in the cholangiopathies: pathogenesis, diagnosis, and treatment","volume":"4","year":"2015","journal-title":"J Clin Med"},{"key":"hep29504-bib-0024-20241017","doi-asserted-by":"crossref","first-page":"6189","DOI":"10.3748\/wjg.v18.i43.6189","article-title":"MicroRNAs in biliary diseases","volume":"18","year":"2012","journal-title":"World J Gastroenterol"},{"key":"hep29504-bib-0025-20241017","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1186\/1752-0509-7-104","article-title":"Integrative genomics identifies candidate microRNAs for pathogenesis of experimental biliary atresia","volume":"7","year":"2013","journal-title":"BMC Syst Biol"},{"key":"hep29504-bib-0026-20241017","doi-asserted-by":"crossref","first-page":"450","DOI":"10.1038\/nrg2102","article-title":"Network motifs: theory and experimental approaches","volume":"8","year":"2007","journal-title":"Nat Rev Genet"},{"key":"hep29504-bib-0027-20241017","doi-asserted-by":"crossref","first-page":"e131","DOI":"10.1371\/journal.pcbi.0030131","article-title":"Global and local architecture of the mammalian microRNA\u2010transcription factor regulatory network","volume":"3","year":"2007","journal-title":"PLoS Comput Biol"},{"key":"hep29504-bib-0028-20241017","first-page":"89","article-title":"Increased expression of interleukin\u20106 and tumor necrosis factor\u2010alpha in pathologic biliary epithelial cells: in situ and culture study","volume":"78","year":"1998","journal-title":"Lab Invest"},{"key":"hep29504-bib-0029-20241017","doi-asserted-by":"crossref","first-page":"1037","DOI":"10.1002\/hep.510290423","article-title":"Lipopolysaccharide induces cholangiocyte proliferation via an interleukin\u20106\u2010mediated activation of p44\/p42 mitogen\u2010activated protein kinase","volume":"29","year":"1999","journal-title":"Hepatology"},{"key":"hep29504-bib-0030-20241017","doi-asserted-by":"crossref","first-page":"1245","DOI":"10.1136\/gut.34.9.1245","article-title":"Intercellular adhesion molecule\u20101 and MHC antigens on human intrahepatic bile duct cells: effect of pro\u2010inflammatory cytokines","volume":"34","year":"1993","journal-title":"Gut"},{"key":"hep29504-bib-0031-20241017","doi-asserted-by":"crossref","first-page":"1567","DOI":"10.1002\/hep.22229","article-title":"Temporal\u2010spatial activation of apoptosis and epithelial injury in murine experimental biliary atresia","volume":"47","year":"2008","journal-title":"Hepatology"},{"key":"hep29504-bib-0032-20241017","first-page":"E3246","article-title":"Inflammation negatively regulates FOXP3 and regulatory T\u2010cell function via DBC1","volume":"112","year":"2015","journal-title":"Proc Natl Acad Sci USA"},{"key":"hep29504-bib-0033-20241017","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1002\/iub.1349","article-title":"Regulatory T cells: Mechanisms of suppression and impairment in autoimmune liver disease","volume":"67","year":"2015","journal-title":"IUBMB Life"},{"key":"hep29504-bib-0034-20241017","doi-asserted-by":"crossref","first-page":"718","DOI":"10.1016\/j.jhep.2009.12.027","article-title":"Post\u2010natal paucity of regulatory T cells and control of NK cell activation in experimental biliary atresia","volume":"52","year":"2010","journal-title":"J Hepatol"},{"key":"hep29504-bib-0035-20241017","doi-asserted-by":"crossref","first-page":"1102","DOI":"10.1136\/jcp.2006.044776","article-title":"Naturally\u2010occurring regulatory T cells are increased in inflamed portal tracts with cholangiopathy in primary biliary cirrhosis","volume":"60","year":"2007","journal-title":"J Clin Pathol"},{"key":"hep29504-bib-0036-20241017","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1111\/j.1365-2249.2009.03898.x","article-title":"Imbalance between T helper type 17 and T regulatory cells in patients with primary biliary cirrhosis: the serum cytokine profile and peripheral cell population","volume":"156","year":"2009","journal-title":"Clin Exp Immunol"},{"key":"hep29504-bib-0037-20241017","doi-asserted-by":"crossref","first-page":"422","DOI":"10.1023\/A:1020511002025","article-title":"Cytokine profile in the liver of primary biliary cirrhosis","volume":"19","year":"1999","journal-title":"J Clin Immunol"},{"key":"hep29504-bib-0038-20241017","doi-asserted-by":"crossref","first-page":"889","DOI":"10.1016\/j.jhep.2014.10.033","article-title":"Dysregulated miR\u2010124 and miR\u2010200 expression contribute to cholangiocyte proliferation in the cholestatic liver by targeting IL\u20106\/STAT3 signalling","volume":"62","year":"2015","journal-title":"J Hepatol"},{"key":"hep29504-bib-0039-20241017","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1002\/hep.23664","article-title":"Deletion of interleukin\u20106 in mice with the dominant negative form of transforming growth factor beta receptor II improves colitis but exacerbates autoimmune cholangitis","volume":"52","year":"2010","journal-title":"Hepatology"},{"key":"hep29504-bib-0040-20241017","doi-asserted-by":"crossref","first-page":"2499","DOI":"10.1053\/j.gastro.2010.02.049","article-title":"Signal transducer and activator of transcription 3 protects from liver injury and fibrosis in a mouse model of sclerosing cholangitis","volume":"138","year":"2010","journal-title":"Gastroenterology"},{"key":"hep29504-bib-0041-20241017","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1089\/vim.2006.0088","article-title":"Progressive biliary destruction is independent of a functional tumor necrosis factor\u2010alpha pathway in a rhesus rotavirus\u2010induced murine model of biliary atresia","volume":"20","year":"2007","journal-title":"Viral Immunol"},{"key":"hep29504-bib-0042-20241017","first-page":"e88747","article-title":"Preferential TNF\u03b1 signaling via TNFR2 regulates epithelial injury and duct obstruction in experimental biliary atresia","volume":"2","year":"2017","journal-title":"JCI Insight"},{"key":"hep29504-bib-0043-20241017","doi-asserted-by":"crossref","first-page":"617","DOI":"10.1007\/s12041-013-0272-9","article-title":"Tumour necrosis factor alpha (TNF\u2010alpha) genetic polymorphisms and the risk of autoimmune liver disease: a meta\u2010analysis","volume":"92","year":"2013","journal-title":"J Genet"},{"key":"hep29504-bib-0044-20241017","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1136\/gut.49.1.131","article-title":"Tumour necrosis factor alpha impairs function of liver derived T lymphocytes and natural killer cells in patients with primary sclerosing cholangitis","volume":"49","year":"2001","journal-title":"Gut"},{"key":"hep29504-bib-0045-20241017","doi-asserted-by":"crossref","first-page":"790","DOI":"10.1016\/j.jhep.2013.05.010","article-title":"Regulatory T cells inhibit Th1 cell\u2010mediated bile duct injury in murine biliary atresia","volume":"59","year":"2013","journal-title":"J Hepatol"},{"key":"hep29504-bib-0046-20241017","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1002\/hep.25662","article-title":"Regulatory T cells control the CD8 adaptive immune response at the time of ductal obstruction in experimental biliary atresia","volume":"56","year":"2012","journal-title":"Hepatology"},{"key":"hep29504-bib-0047-20241017","doi-asserted-by":"crossref","first-page":"1010","DOI":"10.1016\/j.jhep.2013.12.027","article-title":"Reduced FOXP3(+) regulatory T cells in patients with primary sclerosing cholangitis are associated with IL2RA gene polymorphisms","volume":"60","year":"2014","journal-title":"J Hepatol"},{"key":"hep29504-bib-0048-20241017","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1136\/jcp.2005.032391","article-title":"Hepatic expression of galectin\u20103 and receptor for advanced glycation end products in patients with liver disease","volume":"60","year":"2007","journal-title":"J Clin Pathol"},{"key":"hep29504-bib-0049-20241017","doi-asserted-by":"crossref","first-page":"5789","DOI":"10.3748\/wjg.15.5789","article-title":"Role of the receptor for advanced glycation end products in hepatic fibrosis","volume":"15","year":"2009","journal-title":"World J Gastroenterol"},{"key":"hep29504-bib-0050-20241017","doi-asserted-by":"crossref","first-page":"102","DOI":"10.1016\/j.ejphar.2016.03.017","article-title":"Therapeutic effects of antigen affinity\u2010purified polyclonal anti\u2010receptor of advanced glycation end\u2010product (RAGE) antibodies on cholestasis\u2010induced liver injury in rats","volume":"779","year":"2016","journal-title":"Eur J Pharmacol"}],"container-title":["Hepatology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fhep.29504","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/hep.29504","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/hep.29504","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.lww.com\/01515467-201802000-00024","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,10,17]],"date-time":"2024-10-17T23:30:07Z","timestamp":1729207807000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.lww.com\/01515467-201802000-00024"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,1,2]]},"references-count":50,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2018]]}},"URL":"https:\/\/doi.org\/10.1002\/hep.29504","relation":{},"ISSN":["0270-9139","1527-3350"],"issn-type":[{"value":"0270-9139","type":"print"},{"value":"1527-3350","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,1,2]]},"assertion":[{"value":"2017-04-12","name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2017-08-29","name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}}]}}