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 - International Liver Disease Genetics Consortium (ILDGC)
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, Roberta
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 - White, Rose
AU - Rojas, Angela
AU - Bassendine, Margaret
AU - Rosso, Chiara
AU - Mezzabotta, Lavinia
AU - Leung, Reynold
AU - Malik, Barbara
AU - Matthews, Gail
AU - Grebely, Jason
AU - Fragomeli, Vincenzo
AU - Jonsson, Julie R.
PY - 2019/12/1
Y1 - 2019/12/1
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.
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U2 - 10.1038/s41598-018-35736-2
DO - 10.1038/s41598-018-35736-2
M3 - Article
C2 - 30723271
AN - SCOPUS:85061103561
VL - 9
JO - Scientific Reports
JF - Scientific Reports
SN - 2045-2322
IS - 1
M1 - 1439
ER -