TY - JOUR
T1 - Gene-disease associations identify a connectome with shared molecular pathways in human cholangiopathies
AU - Luo, Zhenhua
AU - Jegga, Anil G.
AU - Bezerra, Jorge A.
N1 - Funding Information:
Received April 12, 2017; accepted August 29, 2017. Additional Supporting Information may be found at onlinelibrary.wiley.com/doi/10.1002/hep.29504/suppinfo. Supported by the NIH grants DK-64008 and DK-83781 (to J.A.B.) and by the Gene Analysis Cores of the Digestive Health Center (DK-78392).
Publisher Copyright:
© 2017 by the American Association for the Study of Liver Diseases.
PY - 2018/2
Y1 - 2018/2
N2 - 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-based 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-specific 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 signal transduction and activator of transcription 3, interleukin-6, tumor necrosis factor, and forkhead box P3 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. Conclusion: Human cholangiopathies share pathways enriched by immunity genes and a molecular connectome that links different pathogenic features of BA, PBC, and PSC. (Hepatology 2018;67:676-689).
AB - 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-based 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-specific 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 signal transduction and activator of transcription 3, interleukin-6, tumor necrosis factor, and forkhead box P3 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. Conclusion: Human cholangiopathies share pathways enriched by immunity genes and a molecular connectome that links different pathogenic features of BA, PBC, and PSC. (Hepatology 2018;67:676-689).
UR - http://www.scopus.com/inward/record.url?scp=85039775782&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85039775782&partnerID=8YFLogxK
U2 - 10.1002/hep.29504
DO - 10.1002/hep.29504
M3 - Article
C2 - 28865156
AN - SCOPUS:85039775782
SN - 0270-9139
VL - 67
SP - 676
EP - 689
JO - Hepatology
JF - Hepatology
IS - 2
ER -