{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T14:43:55Z","timestamp":1786977835601,"version":"build-2736575974"},"reference-count":29,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"3","license":[{"start":{"date-parts":[[2021,2,28]],"date-time":"2021-02-28T00:00:00Z","timestamp":1614470400000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["Hepatology"],"published-print":{"date-parts":[[2021,3]]},"abstract":"<jats:sec>\n                    <jats:title>Background and Aims<\/jats:title>\n                    <jats:p>Primary sclerosing cholangitis (PSC) is a heterogeneous cholangiopathy characterized by progressive biliary fibrosis. RNA sequencing of liver tissue from patients with PSC (n\u00a0=\u00a074) enrolled in a 96\u2010week clinical trial was performed to identify associations between biological pathways that were independent of fibrosis and clinical events.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Approach and Results<\/jats:title>\n                    <jats:p>\n                      The effect of fibrosis was subtracted from gene expression using a computational approach. The fibrosis\u2010adjusted gene expression patterns were associated with time to first PSC\u2010related clinical event (e.g., cholangitis, hepatic decompensation), and differential expression based on risk groups and Ingenuity Pathway Analysis were performed. Baseline demographic data were representative of PSC: median age 48\u00a0years, 71% male, 49% with inflammatory bowel disease, and 44% with bridging fibrosis or cirrhosis. The first principle component (PC1) of RNA\u2010sequencing data accounted for 18% of variance and correlated with fibrosis stage (\n                      <jats:italic toggle=\"yes\">\u03c1<\/jats:italic>\n                      \u00a0=\u00a0\u22120.80;\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      \u00a0&lt;\u00a00.001). After removing the effect of fibrosis\u2010related genes, the first principle component was not associated with fibrosis (\n                      <jats:italic toggle=\"yes\">\u03c1<\/jats:italic>\n                      \u00a0=\u00a0\u22120.19;\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      \u00a0=\u00a00.11), and a semisupervised clustering approach identified two distinct patient clusters with differential risk of time to first PSC\u2010related event (\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      \u00a0&lt;\u00a00.0001). The two groups had similar fibrosis stage, hepatic collagen content, and \u03b1\u2010smooth muscle actin expression by morphometry, Enhanced Liver Fibrosis score, and serum liver biochemistry, bile acids, and IL\u20108 (all\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      \u00a0&gt;\u00a00.05). The top pathways identified by Ingenuity Pathway Analysis were eukaryotic translation inhibition factor 2 (eIF2) signaling and regulation of eIF4\/p70S6K signaling. Genes involved in the unfolded protein response, activating transcription factor 6 (\n                      <jats:italic toggle=\"yes\">ATF6<\/jats:italic>\n                      ) and\n                      <jats:italic toggle=\"yes\">eIF2<\/jats:italic>\n                      , were differentially expressed between the PSC clusters (down\u2010regulated in the high\u2010risk group by log\u2010fold changes of \u22120.18 [\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      \u00a0=\u00a00.02] and \u22120.16 [\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      \u00a0=\u00a00.02], respectively). Clinical events were enriched in the high\u2010risk versus low\u2010risk group (38% [12\/32] vs. 2.4% [1\/42],\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      \u00a0&lt;\u00a00.0001).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Removing the contribution of fibrosis\u2010related pathways uncovered alterations in the unfolded protein response, which were associated with liver\u2010related complications in PSC.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/hep.31488","type":"journal-article","created":{"date-parts":[[2020,8,3]],"date-time":"2020-08-03T17:12:07Z","timestamp":1596474727000},"page":"1105-1116","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":18,"title":["A Fibrosis\u2010Independent Hepatic Transcriptomic Signature Identifies Drivers of Disease Progression in Primary Sclerosing Cholangitis"],"prefix":"10.1097","volume":"73","author":[{"given":"Yevgeniy","family":"Gindin","sequence":"first","affiliation":[{"name":"Gilead Sciences, Inc.,Foster City,CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chuhan","family":"Chung","sequence":"additional","affiliation":[{"name":"Gilead Sciences, Inc.,Foster City,CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhaoshi","family":"Jiang","sequence":"additional","affiliation":[{"name":"Gilead Sciences, Inc.,Foster City,CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing Zhu","family":"Zhou","sequence":"additional","affiliation":[{"name":"Gilead Sciences, Inc.,Foster City,CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Xu","sequence":"additional","affiliation":[{"name":"Gilead Sciences, Inc.,Foster City,CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew N.","family":"Billin","sequence":"additional","affiliation":[{"name":"Gilead Sciences, Inc.,Foster City,CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert P.","family":"Myers","sequence":"additional","affiliation":[{"name":"Gilead Sciences, Inc.,Foster City,CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zachary","family":"Goodman","sequence":"additional","affiliation":[{"name":"Inova Fairfax Hospital,Falls Church,VA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abdolamir","family":"Landi","sequence":"additional","affiliation":[{"name":"Department of Medical Microbiology and Immunology,Li Ka Shing Institute of Virology,University of Alberta,Edmonton,AB,Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Houghton","sequence":"additional","affiliation":[{"name":"Department of Medical Microbiology and Immunology,Li Ka Shing Institute of Virology,University of Alberta,Edmonton,AB,Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard M.","family":"Green","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology,Department of Medicine,Feinberg School of Medicine at,Northwestern University,Chicago,IL"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cynthia","family":"Levy","sequence":"additional","affiliation":[{"name":"University of Miami,Miami,FL"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kris V.","family":"Kowdley","sequence":"additional","affiliation":[{"name":"Liver Institute Northwest,Seattle,WA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher L.","family":"Bowlus","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology,University of California at Davis,Sacramento,CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0206-1179","authenticated-orcid":false,"given":"Andrew J.","family":"Muir","sequence":"additional","affiliation":[{"name":"Duke University School of Medicine,Durham,NC"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Trauner","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology,Department of Medicine III,Medical University of Vienna,Vienna,Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","published-online":{"date-parts":[[2021,2,28]]},"reference":[{"key":"hep31488-bib-0001-20250824","first-page":"2501","article-title":"Primary sclerosing cholangitis","volume":"375","year":"2016","journal-title":"N Engl J Med"},{"key":"hep31488-bib-0002-20250824","doi-asserted-by":"crossref","first-page":"1298","DOI":"10.1016\/j.jhep.2017.07.022","article-title":"Primary sclerosing 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