TY - JOUR
T1 - A variant in the MICA gene is associated with liver fibrosis progression in chronic hepatitis C through TGF-β1 dependent mechanisms.
AU - Sharkawy, Rasha El
AU - Bayoumi, Ali
AU - Metwally, Mayada
AU - Mangia, Alessandra
AU - Berg, Thomas
AU - Romero-Gomez, Manuel
AU - Abate, Maria Lorena
AU - Irving, William L.
AU - Sheridan, David
AU - Dore, Gregory J.
AU - Spengler, Ulrich
AU - Lampertico, Pietro
AU - Bugianesi, Elisabetta
AU - Weltman, Martin
AU - Mollison, Lindsay
AU - Cheng, Wendy
AU - Riordan, Stephen
AU - Santoro, Rosanna
AU - Gallego-Durán, Rocío
AU - Fischer, Janett
AU - Nattermann, Jacob
AU - D'Ambrosio, R
AU - McLeod, Duncan
AU - Powell, Elizabeth
AU - latchoumanin, Olivier
AU - Thabet, Khaled
AU - Najim, Mustafa A.M.
AU - Douglas, Mark W.
AU - Liddle, Christopher
AU - Qiao, Liang
AU - George, Jacob
AU - Eslam, Mohammed
AU - International, Liver Disease Genetics Consortium (ILDGC)
PY - 2019/2/5
Y1 - 2019/2/5
N2 - 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.
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.
U2 - 10.1038/s41598-018-35736-2
DO - 10.1038/s41598-018-35736-2
M3 - Article
SN - 2045-2322
VL - 9
SP - 1439
EP - 1439
JO - Scientific Reports
JF - Scientific Reports
IS - 1
ER -
