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

Abstract

BACKGROUND AND AIMS:

Primary sclerosing cholangitis (PSC) is a heterogeneous cholangiopathy characterized by progressive biliary fibrosis. RNA sequencing of liver tissue from patients with PSC (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.

APPROACH AND RESULTS:

The effect of fibrosis was subtracted from gene expression using a 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 were performed. Baseline demographic data were representative of PSC: median age 48 years, 71% male, 49% with inflammatory bowel disease, and 44% with bridging fibrosis or cirrhosis. The first principle component (PC1) of RNA-sequencing data accounted for 18% of variance and correlated with fibrosis stage (ρ = -0.80; P < 0.001). After removing the effect of fibrosis-related genes, the first principle component was not associated with fibrosis (ρ = -0.19; P = 0.11), and a semisupervised clustering approach identified two distinct patient clusters with differential risk of time to first PSC-related event (P < 0.0001). The two groups had similar fibrosis stage, hepatic collagen content, and α-smooth muscle actin expression by morphometry, Enhanced Liver Fibrosis score, and serum liver biochemistry, bile acids, and IL-8 (all P > 0.05). 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 (ATF6) 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-risk 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 unfolded protein response, which were associated with liver-related complications in PSC.

• Authors: Yevgeniy Gindin, Chuhan Chung, Zhaoshi Jiang, Jing Zhu Zhou, Jun Xu, Andrew N Billin, Robert P Myers, Zachary Goodman, Abdolamir Landi, Michael Houghton, Richard M Green, Cynthia Levy, Kris V Kowdley, Christopher L Bowlus, Andrew J Muir, Michael Trauner
• Journal: Hepatology (Baltimore, Md.) (Hepatology) Vol. 73 Issue 3 Pg. 1105-1116 (03 2021) ISSN: 1527-3350 [Electronic] United States
• PMID: 32745270 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2020 The Authors. Hepatology published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.

Chemical References

• Bile Acids and Salts
• Biomarkers
• Interleukin-8

Topics

• Bile Acids and Salts (chemistry)
• Biomarkers (analysis)
• Biopsy
• Cholangitis, Sclerosing (metabolism, pathology)
• Disease Progression
• Female
• Gene Expression Profiling
• Humans
• Interleukin-8 (analysis)
• Liver (metabolism, pathology)
• Liver Cirrhosis (metabolism, pathology)
• Male
• Middle Aged
• Principal Component Analysis
• Transcriptome