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.

A variant in the MICA gene is associated with liver fibrosis progression in chronic hepatitis C through TGF-β1 dependent mechanisms / R.E. Sharkawy, A. Bayoumi, M. Metwally, A. Mangia, T. Berg, M. Romero-Gomez, M.L. Abate, W.L. Irving, D. Sheridan, G.J. Dore, U. Spengler, P. Lampertico, E. Bugianesi, M. Weltman, L. Mollison, W. Cheng, S. Riordan, R. Santoro, R. Gallego-Durán, J. Fischer, J. Nattermann, R. D’Ambrosio, D. Mcleod, E. Powell, O. Latchoumanin, K. Thabet, M.A.M. Najim, M.W. Douglas, C. Liddle, L. Qiao, J. George, M. Eslam, R. White, A. Rojas, M. Bassendine, C. Rosso, L. Mezzabotta, R. Leung, B. Malik, G. Matthews, J. Grebely, V. Fragomeli, J.R. Jonsson. - In: SCIENTIFIC REPORTS. - ISSN 2045-2322. - 9:1(2019 Feb), pp. 1439.1-1439.10. [10.1038/s41598-018-35736-2]

A variant in the MICA gene is associated with liver fibrosis progression in chronic hepatitis C through TGF-β1 dependent mechanisms

P. Lampertico;R. D’Ambrosio;C. Rosso;
2019-02

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.
Multidisciplinary
Settore MED/12 - Gastroenterologia
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2434/641037
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