Dataset Information

Host gene-encoded severe lung TB: from genes to the potential pathways.

ABSTRACT: We are reporting that the two-locus genotype -2518 macrophage chemoattractant protein (MCP)-1 GG and -1607 matrix metalloproteinase (MMP)-1 2G/2G promotes the expression of hyperinflammation in response to Mycobacterium tuberculosis infection, inducing extensive tissue damage and severe tuberculosis (TB) disease. Carriers of this two-locus genotype have a 13-fold higher chance of developing severe disease and 6.5-fold higher chance of developing permanent lesions, and a 3.864-fold higher chance of delayed response to first-line standardized treatment than carriers of any other relevant combination of genotypes at those two loci. Thus, these persons have an increased likelihood of poor health-related quality of life and of transmitting M. tuberculosis to other members of the community. In addition, through the analysis of human lung tissues, serum/plasma and in vitro experiments, including in vitro infections of THP-1 cells with M. tuberculosis and microarray analysis, we determined that this hyperinflammation state is potentially driven by the MCP-1/MMP-1/PAR-1 pathway. Hence, we are providing markers for the identification of TB cases that may develop severe pulmonary disease and delayed response to treatment, and are providing the basis for development of novel host-targeted clinical interventions to ameliorate the severity of pulmonary TB.

SUBMITTER: Ganachari M

PROVIDER: S-EPMC3518758 | biostudies-literature | 2012 Dec

REPOSITORIES: biostudies-literature

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Host gene-encoded severe lung TB: from genes to the potential pathways.

Ganachari M M Guio H H Zhao N N Flores-Villanueva P O PO

Genes and immunity 20120920 8

We are reporting that the two-locus genotype -2518 macrophage chemoattractant protein (MCP)-1 GG and -1607 matrix metalloproteinase (MMP)-1 2G/2G promotes the expression of hyperinflammation in response to Mycobacterium tuberculosis infection, inducing extensive tissue damage and severe tuberculosis (TB) disease. Carriers of this two-locus genotype have a 13-fold higher chance of developing severe disease and 6.5-fold higher chance of developing permanent lesions, and a 3.864-fold higher chance ...[more]

PMID: 22992722

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Project description:Preeclampsia is a complication of pregnancy characterized by new-onset hypertension and proteinuria of gestation, with serious consequences for mother and infant. Although a vast amount of research has been performed on the pathogenesis of preeclampsia, the underlying mechanisms of this multisystemic disease have remained to be fully elucidated. Data were retrieved from Gene Expression Omnibus database GSE40182 dataset. After data preprocessing, differentially expressed genes of placental cells cultured in vitro from preeclampsia and normal pregnancy were determined and subjected to Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis to identify the associated pathways. Furthermore, functional principal component analysis (FPCA) was used to calculate the corresponding F-value of each gene. In order to further study the key signaling pathways of preeclampsia, an elastic-net regression model and the Mann-Whitney U (MWU) test were used to estimate the weight of the signaling pathways. Finally, a co-expression network was generated and hub genes were identified based on the topological features. A total of 134 pathways with a role in preeclampsia were identified. The gene expression data of placenta cells cultured in vitro for different durations were determined and F-values of genes were estimated using the FPCA model. The top 1,000 genes were identified as the differentially expressed genes and subjected to further analysis by elastic-net regression and MWU test. Two key signaling pathways were different between the preeclampsia and control groups, namely hsa05142 Chagas disease and hsa05204 Chemical carcinogenesis. Among the genes involved in these two key pathways, 13 hub genes were identified from the co-expression network. Clustering analysis demonstrated that depending on these hub genes, it was possible to divide the sample into four distinct groups based on different incubation time. The top 3 candidates were Toll-like receptor 2 (TLR2), glutathione S-transferase omega 1 (GSTO1) and mitogen-activated protein kinase 13 (MAPK13). TLR2 and associated pathways are known to be closely associated with preeclampsia, indirectly demonstrating the applicability of the analytic process applied. However, the role of GSTO1 and MAPK13 in preeclampsia has remained poorly investigated, and elucidation thereof may be a worthwhile endeavor. The present study may provide a basis for exploring potential novel genes and pathways as therapeutic targets for preeclampsia.

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Host gene-encoded severe lung TB: from genes to the potential pathways.

Publications

Host gene-encoded severe lung TB: from genes to the potential pathways.

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