A variant in the MICA gene is associated with liver fibrosis progression in chronic hepatitis C through TGF-\u03b21 dependent mechanisms

Rasha El Sharkawy,Ulrich Spengler,Stephen M Riordan ,Olivier Latchoumanin,Mark W Douglas,Mostafa Metwally ,Duncan Mcleod,Elisabetta Bugianesi,Gregory J Dore,Rocío Gallego‐Durán ,William L Irving,Jacob George,Roberta D’Ambrosio,Khaled Thabet,Alessandra Mangia,Elizabeth E Powell ,Wendy Cheng,Jacob Nattermann,Ali Bayoumi,Christopher Liddle,Manuel Romero‐Gómez ,Thomas Berg,Janett Fischer,David Sheridan,Liang Qiao,Pietro Lampertico,Mustafa A Najim ,Lindsay Mollison,Martin Weltman,Rosanna Santoro,Maria Lorena Abate,Mohammed Eslam

doi:10.1038/s41598-018-35736-2

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.

Highlights

To explore if baseline clinical variables differ between chronic hepatitis C virus (HCV) patients according to MHC class I-related chain A (MICA) rs2596542 or DEPDC5 rs1012068 genotype, we examined the association of the genotypes with baseline clinical variables; the results are presented in Supplementary Tables 3 and 4, respectively
We report that a genetic variant in MICA originally identified by genome wide association studies (GWAS) as a risk variant for susceptibility to HCV-associated hepatocellular carcinoma (HCC) in Japanese patients[6] associates with fibrosis severity and progression, but not with HCC
Following the data for effects on fibrosis progression, we show MICA genotype-dependent reductions in hepatic MICA gene expression and soluble MICA protein levels

Summary

Introduction

In chronic HCV infection, host genetics play a pivotal role in shaping the immune response, virus-host interactions and the predilection to and progress of liver fibrosis[3,4]. This risk is likely polygenic and dependent on multiple genetic and epigenetic factors since variations in single loci are usually of modest effect size and explain only a small fraction of the phenotype[5]. The function of DEPDC5 is not well understood, but has been linked with hereditary forms of epilepsy[9], bladder cancer[10] and malignant glioblastomas[11]

Methods

Results

Conclusion