A Fibrosis-Independent Hepatic Transcriptomic Signature Identifies Drivers of Disease Progression in Primary Sclerosing Cholangitis
| Autor: | Jun Xu, Kris V. Kowdley, Yevgeniy Gindin, Richard M. Green, Andrew J. Muir, Michael Trauner, Michael Houghton, Cynthia Levy, Abdolabdolamir Landi, Zhaoshi Jiang, Andrew N. Billin, Chuhan Chung, Christopher L. Bowlus, Robert P. Myers, Jing Zhu Zhou, Zachary Goodman |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
Liver Cirrhosis
Male 0301 basic medicine medicine.medical_specialty Cirrhosis Biopsy Cholangitis Sclerosing Clinical Sciences Immunology Medical Biochemistry and Metabolomics Inflammatory bowel disease Gastroenterology Primary sclerosing cholangitis Bile Acids and Salts Transcriptome 03 medical and health sciences 0302 clinical medicine Fibrosis Internal medicine Gene expression medicine Humans Principal Component Analysis Hepatology Gastroenterology & Hepatology business.industry ATF6 Gene Expression Profiling Interleukin-8 Original Articles Middle Aged medicine.disease Autoimmune Cholestatic and Biliary Disease 030104 developmental biology Liver Disease Progression Biomarker (medicine) Female Original Article 030211 gastroenterology & hepatology business Biomarkers |
| Zdroj: | Hepatology (Baltimore, Md.), vol 73, iss 3 Hepatology (Baltimore, Md.) |
| Popis: | Background and aimsPrimary 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 resultsThe 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 48years, 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; P0.05). 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 |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|