ORCID
- Sheridan, David: 0000-0001-5100-814X
Abstract
Hepatocarcinogenesis is tightly linked to liver fibrosis. Recently, two GWAS variants, MICA rs2596542 and DEPDC5 rs1012068 were identified as being associated with the development of HCV-induced hepatocellular carcinoma (HCC) in Japanese patients. The role of these variants on hepatic inflammation and fibrosis that are closely associated with HCC development is not known, nor are the biological mechanisms underlying their impact on the liver. Here, we demonstrate in 1689 patients with chronic hepatitis C (CHC) (1,501 with CHC and 188 with HCV-related HCC), that the MICA (T) allele, despite not being associated with HCC susceptibility, is associated with increased fibrosis stage (OR: 1.47, 95% CI: 1.05-2.06, p = 0.02) and fibrosis progression rate (hazards ratio: 1.41, 95% CI: 1.04-1.90, p = 0.02). The DEPDC5 variant was not associated with any of these phenotypes. MICA expression was down-regulated in advanced fibrosis stages. Further, (T) allele carriage was associated with lower MICA expression in liver and serum. Transforming growth factor-β1 (TGF-β1) expression suppresses MICA expression in hepatic stellate cells. Our findings suggest a novel mechanism linking susceptibility to advanced fibrosis and subsequently indirectly to HCC, to the level of MICA expression through TGF-β1-dependent mechanisms.
DOI
10.1038/s41598-018-35736-2
Publication Date
2019-02-05
Publication Title
Scientific Reports
Volume
9
Issue
1
ISSN
2045-2322
Embargo Period
2019-02-12
Organisational Unit
Peninsula Medical School
First Page
1439
Last Page
1439
Recommended Citation
Sharkawy, R. E., Bayoumi, A., Metwally, M., Mangia, A., Berg, T., Romero-Gomez, M., Abate, M., Irving, W., Sheridan, D., Dore, G., Spengler, U., Lampertico, P., Bugianesi, E., Weltman, M., Mollison, L., Cheng, W., Riordan, S., Santoro, R., Gallego-Durán, R., Fischer, J., Nattermann, J., D'Ambrosio, R., McLeod, D., Powell, E., latchoumanin, O., Thabet, K., Najim, M., Douglas, M., Liddle, C., Qiao, L., George, J., Eslam, M., & International, L. (2019) 'A variant in the MICA gene is associated with liver fibrosis progression in chronic hepatitis C through TGF-β1 dependent mechanisms.', Scientific Reports, 9(1), pp. 1439-1439. Available at: https://doi.org/10.1038/s41598-018-35736-2
