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Characterization of gene expression profile in HBV-related liver fibrosis patients

ABSTRACT: Hepatitis B virus (HBV) infection is a leading risk factor for liver fibrosis (LF) and hepatocellular carcinoma. Emerging evidence indicates that host genetic, virological and immunological factors will influence the fibrotic progress. Many previous studies have focused on specific pathways or genes included in LF mechanism, however global view of the whole genome expresion profile in HBV related LF patients never been studied, and the mechanisms underlying the promotion of liver fibrosis progression remain obscure. Here we collected liver biopsy samples from 124 chronic hepatitis B (CHB) patients and used Affymetrix HG U133 Plus 2.0 microarray to quantify the transcriptome of these patients. Through integrated data analysis, including geneset enrichment analysis (GSEA), weighted gene co-expression analysis (WGCNA), differential expressed gene (DEG) screening, trend test, principle component analysis (PCA) etc., we identified several key pathways and hub genes participated in the initiation and exacerbation of liver fibrotic progress. The function of these hub genes were also validated by in vitro and in vivo experiments using HepG2, Huh7 and LX-2 cell lines and transgenic mice. This is the first large-scale study investigating the gene expression profile in HBV-related LF patients which will be crucial for unlocking the gene functions and gene-gene correlations in fibrosis progess.

ORGANISM(S): Homo sapiens

PROVIDER: GSE84044 | GEO | 2016/08/21

SECONDARY ACCESSION(S): PRJNA327860

REPOSITORIES: GEO

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Project description:Hepatitis B virus (HBV)-associated acute liver failure (ALF) is a dramatic clinical syndrome due to a sudden loss of hepatic cells leading to multiorgan failure. The mechanisms whereby HBV induces ALF are unknown. We used gene expression profiling to establish a molecular definition of hepatitis B virus (HBV)-associated ALF. Two patients who underwent liver transplantation for HBV-associated ALF were studied. Gene expression profiling was performed on 8 liver specimens obtained from the two patients with ALF (4 samples per liver) and individual liver specimens from 8 liver donors and normal livers from 11 patients who underwent resection for angioma. Statistical analyses were used to identify the signature genes of HBV-associated ALF. Multivariate permutation analysis identified 1,368 transcripts that were differentially expressed in ALF; 709 were up-regulated and 659 down-regulated. The most represented up-regulated transcripts were those involved in the immune response, whereas the most abundant down-regulated transcripts were those involved in metabolism and hepatic synthesis. ALF was characterized by overriding B-cell signature comprising genes related to mature B cells and plasma cells with abundant polyclonal expression of immunoglobulin genes. By contrast, there was a limited T-cell signature and up-regulation of several inhibitors of T-cell activation. Immunohistochemical analysis confirmed the prominent B-cell signature showing diffuse liver infiltration by plasma blasts and plasma cells with strong cytoplasmic staining for IgM and IgG, associated with a significant deposition of complement factors. Using phage display technology, we demonstrated that the molecular target of the massive intrahepatic antibody response is the hepatitis B core antigen (HBcAg). These data suggest that the humoral immunity may exert a primary role in the pathogenesis of HBV-associated ALF. Liver samples were obtained from explanted livers of two patients with HBV-associated ALF (4 samples per liver), 8 normal liver donors and 11 patients who underwent resection for angioma. Gene expression profiling was used to establish a molecular definition of ALF. Patient data derived from associated publication Table S2. This dataset is part of the TransQST collection.

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Characterization of gene expression profile in HBV-related liver fibrosis patients

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