A Fibrosis‐Independent Hepatic Transcriptomic Signature Identifies Drivers of Disease Progression in Primary Sclerosing Cholangitis

Abstract

Primary sclerosing cholangitis (PSC) is a heterogeneous cholangiopathy characterized by progressive biliary fibrosis. RNA sequencing (RNA‐Seq) of liver tissue from PSC patients (n=74) enrolled in a 96‐week clinical trial was performed to identify associations between biological pathways that were independent of fibrosis and clinical events. The effect of fibrosis was subtracted from gene expression using a novel computational approach. The fibrosis‐adjusted gene expression patterns were associated with time to first PSC‐related clinical event (e.g. cholangitis, hepatic decompensation) and differential expression based on risk groups and Ingenuity Pathway Analysis (IPA) were performed. Baseline demographic data were representative of PSC: median age 48 years, 71% male, 49% with IBD, and 44% with bridging fibrosis or cirrhosis. The first principle component (PC1) of RNA‐Seq data accounted for 18% of variance and correlated with fibrosis stage (ρ=‐0.80; PATF6 and eIF2 , were differentially expressed between the PSC clusters (down‐regulated in the high‐risk group by log‐fold‐changes of ‐0.18 [P=0.02] and ‐0.16 [P=0.02], respectively). Clinical events were enriched in the high versus low‐risk group (38% [12/32] vs 2.4% [1/42], p<0.0001). Conclusions: Removing the contribution of fibrosis‐related pathways uncovered alterations in the UPR, which were associated with liver‐related complications in PSC.