RT Journal Article
T1 A variant in the MICA gene is associated with liver fibrosis progression in chronic hepatitis C through TGF-β1 dependent mechanisms.
A1 Sharkawy, Rasha El
A1 Bayoumi, Ali
A1 Metwally, Mayada
A1 Mangia, Alessandra
A1 Berg, Thomas
A1 Romero-Gomez, Manuel
A1 Abate, Maria Lorena
A1 Irving, William L
A1 Sheridan, David
A1 Dore, Gregory J
A1 Spengler, Ulrich
A1 Lampertico, Pietro
A1 Bugianesi, Elisabetta
A1 Weltman, Martin
A1 Mollison, Lindsay
A1 Cheng, Wendy
A1 Riordan, Stephen
A1 Santoro, Rosanna
A1 Gallego-Durán, Rocío
A1 Fischer, Janett
A1 Nattermann, Jacob
A1 D'Ambrosio, Roberta
A1 McLeod, Duncan
A1 Powell, Elizabeth
A1 Latchoumanin, Olivier
A1 Thabet, Khaled
A1 Najim, Mustafa A M
A1 Douglas, Mark W
A1 Liddle, Christopher
A1 Qiao, Liang
A1 George, Jacob
A1 Eslam, Mohammed
A1 International Liver Disease Genetics Consortium (ILDGC), 
AB 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.
YR 2019
FD 2019-02-05
LK http://hdl.handle.net/10668/13519
UL http://hdl.handle.net/10668/13519
LA en
DS RISalud
RD Apr 11, 2025