Project description:Chronic hepatitis B virus (HBV) infection is a serious global public health problem. To identify susceptibility loci for disease progression of HBV infection, we performed this genome-wide association study using DNA pools of case and control constructed by progressed HBV carriers (acute liver failure, liver cirrhosis, hepatocellular carcinoma) and asymptomatic HBV carriers separately. Performing GWAS on pools of DNA samples is an effective strategy to reduce the costs of studies and pooling DNA has been shown to be an efficient method to select candidate susceptibility loci for follow-up by individual genotyping. Affymetrix Genome-Wide Human Mapping SNP6.0 Arrays were performed for DNA pools, which were constructed by pooling 120 ng DNA from each participant. Four independent pools were created: case A was acute liver failure group (n = 86), case B was liver cirrhosis group (n = 88), case C was hepatocellular carcinoma group (n = 90) and case D was asymptomatic HBV carriers (n = 66) that was considered as control. Twelve chips (each pool was replicated in triplicate) were finished according to the manufacturer's instruction.
Project description:Chronic hepatitis B virus (HBV) infection is a serious global public health problem. To identify susceptibility loci for disease progression of HBV infection, we performed this genome-wide association study using DNA pools of case and control constructed by progressed HBV carriers (acute liver failure, liver cirrhosis, hepatocellular carcinoma) and asymptomatic HBV carriers separately. Performing GWAS on pools of DNA samples is an effective strategy to reduce the costs of studies and pooling DNA has been shown to be an efficient method to select candidate susceptibility loci for follow-up by individual genotyping.
Project description:We compared transcriptome of monocyte-derived macrophages of 5 patients with GBA-PD (4 L444P/N, 1 N370S/N) and 4 asymptomatic GBA mutation carriers (GBA-carriers) (3 L444P/N, 1 N370S/N) and 4 controls. We also conducted comparative transcriptome analysis for L444P/N only GBA-PD patients and GBA-carriers. Revealed deregulated genes in GBA-PD independently of GBA mutations (L444P or N370S) were involved in immune response, neuronal function. We found upregulated pathway associated with zinc metabolism in L444P/N GBA-PD patients. The potential important role of DUSP1 in the pathogenesis of GBA-PD was suggested.
Project description:We compared transcriptome of monocyte-derived macrophages of 5 patients with GBA-PD (4 L444P/N, 1 N370S/N) and 4 asymptomatic GBA mutation carriers (GBA-carriers) (3 L444P/N, 1 N370S/N) and 4 controls. We also conducted comparative transcriptome analysis for L444P/N only GBA-PD patients and GBA-carriers. Revealed deregulated genes in GBA-PD independently of GBA mutations (L444P or N370S) were involved in immune response, neuronal function. We found upregulated pathway associated with zinc metabolism in L444P/N GBA-PD patients. The potential important role of DUSP1 in the pathogenesis of GBA-PD was suggested.
Project description:The low frequency of HBV-specific CD8+ T cells in the peripheral blood of CHB patients has limited studies of the mechanisms underlying HBV-induced T cell exhaustion. Similar to the expansion defect displayed in HBV-specific CD8+ T cells, TCR-induced proliferation of global CD8+ T cells is impaired in a fraction of chronic HBV (CHB) patients. Thus, examining the molecular regulation of global CD8+ T cell function in CHB patients may provide insight into the exhaustion of HBV-specific CD8+ T cells. We used microarrays to detail the global programme of gene expression of CD8 T cells from CHB patients who have not received anti-viral treatment. Fifteen milliliters of blood was drawn from eachof three CHB patients and three healthy donors. PBMCs were enriched using Ficoll, and CD8+ T cells were purified using positive selection beads to a purity of >95% (Miltenyi Biotec, Auburn, CA). Total RNA was extracted using a mirVana isolation kit (Life Technologies, Carlsbad, CA).
Project description:The low frequency of HBV-specific CD8+ T cells in the peripheral blood of CHB patients has limited studies of the mechanisms underlying HBV-induced T cell exhaustion. Similar to the expansion defect displayed in HBV-specific CD8+ T cells, TCR-induced proliferation of global CD8+ T cells is impaired in a fraction of chronic HBV (CHB) patients. Thus, examining the molecular regulation of global CD8+ T cell function in CHB patients may provide insight into the exhaustion of HBV-specific CD8+ T cells. We used microarrays to detail the global programme of gene expression of CD8 T cells from CHB patients who have not received anti-viral treatment.
Project description:HBV-specific CD8 cells are deeply exhausted in chronic hepatitis B and their function can only be partially corrected by modulation of up-regulated inhibitory pathways, suggesting a more complex molecular interplay. With the aim of identifying more suitable molecular targets to correct T cell dysfunction, we compared the transcriptome profile of HBV-specific CD8 cells of acute and chronic patients with the reference profile of HBV- and Flu-specific CD8 cells from patients able to resolve HBV infection spontaneously and from healthy subjects. The results indicate that exhausted HBV-specific CD8 cells are deeply impaired at a metabolic and energetic level with a prevalent down-regulation of different key cellular processes centered on an extensive alteration of mitocondrial functions. Mitochondrial modulation by antioxidant compounds could improve significantly the HBV-specific T cell function with minimal effect on T cells of different specificity. The results identify mitochondria as ideal targets for functional T cell reconstitution strategies to cure HBV infection