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Identification of tuberculosis susceptibility genes with human macrophage gene expression profiles.

ABSTRACT: Although host genetics influences susceptibility to tuberculosis (TB), few genes determining disease outcome have been identified. We hypothesized that macrophages from individuals with different clinical manifestations of Mycobacterium tuberculosis (Mtb) infection would have distinct gene expression profiles and that polymorphisms in these genes may also be associated with susceptibility to TB. We measured gene expression levels of >38,500 genes from ex vivo Mtb-stimulated macrophages in 12 subjects with 3 clinical phenotypes: latent, pulmonary, and meningeal TB (n = 4 per group). After identifying differentially expressed genes, we confirmed these results in 34 additional subjects by real-time PCR. We also used a case-control study design to examine whether polymorphisms in differentially regulated genes were associated with susceptibility to these different clinical forms of TB. We compared gene expression profiles in Mtb-stimulated and unstimulated macrophages and identified 1,608 and 199 genes that were differentially expressed by >2- and >5-fold, respectively. In an independent sample set of 34 individuals and a subset of highly regulated genes, 90% of the microarray results were confirmed by RT-PCR, including expression levels of CCL1, which distinguished the 3 clinical groups. Furthermore, 6 single nucleotide polymorphisms (SNPs) in CCL1 were found to be associated with TB in a case-control genetic association study with 273 TB cases and 188 controls. To our knowledge, this is the first identification of CCL1 as a gene involved in host susceptibility to TB and the first study to combine microarray and DNA polymorphism studies to identify genes associated with TB susceptibility. These results suggest that genome-wide studies can provide an unbiased method to identify critical macrophage response genes that are associated with different clinical outcomes and that variation in innate immune response genes regulate susceptibility to TB.

SUBMITTER: Thuong NT

PROVIDER: S-EPMC2585058 | biostudies-other | 2008 Dec

REPOSITORIES: biostudies-other

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Identification of tuberculosis susceptibility genes with human macrophage gene expression profiles.

Thuong Nguyen Thuy Thuong NT Dunstan Sarah J SJ Chau Tran Thi Hong TT Thorsson Vesteinn V Simmons Cameron P CP Quyen Nguyen Than Ha NT Thwaites Guy E GE Thi Ngoc Lan Nguyen N Hibberd Martin M Teo Yik Y YY Seielstad Mark M Aderem Alan A Farrar Jeremy J JJ Hawn Thomas R TR

PLoS pathogens 20081205 12

Although host genetics influences susceptibility to tuberculosis (TB), few genes determining disease outcome have been identified. We hypothesized that macrophages from individuals with different clinical manifestations of Mycobacterium tuberculosis (Mtb) infection would have distinct gene expression profiles and that polymorphisms in these genes may also be associated with susceptibility to TB. We measured gene expression levels of >38,500 genes from ex vivo Mtb-stimulated macrophages in 12 sub ...[more]

PMID: 19057661

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Project description:Although host genetics influences susceptibility to tuberculosis, few genes determining disease outcome have been identified. We hypothesized that macrophages from individuals with different clinical manifestations of tuberculosis infection would have distinct gene expression profiles, and that polymorphisms in these genes may also be associated with susceptibility to TB. We measured gene expression levels of >38,500 genes from ex vivo Mtb- stimulated macrophages in 12 subjects with 3 clinical phenotypes: latent, pulmonary and meningeal tuberculosis (n=4 per group). After identifying differentially expressed genes, we confirmed these results in 34 additional subjects by real-time PCR. We also used a case-control study design to examine whether polymorphisms in differentially regulated genes were associated with susceptibility to these different clinical forms of TB. We compared gene expression profiles in Mtb-stimulated and unstimulated macrophages and identified 1608 and 199 genes that were differentially expressed by >2 and >5-fold, respectively. Using cluster analysis, we identified gene expression patterns that distinguished the different clinical forms of tuberculosis. In an independent sample set of 34 individuals and a subset of highly regulated genes, 90% of the microarray results were confirmed by RT-PCR, including expression levels of CCL1, which distinguished the 3 clinical groups. Furthermore, 6 single nucleotide polymorphisms (SNPs) in CCL1 were found to be associated with TB in a case-control genetic association study with 273 TB cases and 188 controls. To our knowledge, this is the first identification of CCL1 as a gene involved in host susceptibility to TB and the first study to combine microarray and DNA polymorphism studies to identify genes associated with TB susceptibility. These results suggest that genome-wide studies can provide an unbiased method to identify critical macrophage response genes that are associated with different clinical outcomes and that variation in innate immune response genes regulate susceptibility to tuberculosis. Keywords: tuberculosis, tuberculous meningitis, macrophage, gene expression, microarray

Project description:Atherosclerotic cardiovascular disease (ASCVD) caused by atherosclerosis (AS) is one of the highest causes of mortality worldwide. Although there have been many studies on AS, its etiology remains unclear. In order to carry out molecular characterization of different types of AS, we retrieved two datasets composed of 151 AS samples and 32 normal samples from the Gene Expression Omnibus database. Using the non-negative matrix factorization (NMF) algorithm, we successfully divided the 151 AS samples into two subgroups. We then compared the molecular characteristics between the two groups using weighted gene co-expression analysis (WGCNA) and identified six key modules associated with the two subgroups. Kyoto Encyclopedia of Genes and Genomes (KEGG) and gene ontology (GO) enrichment analysis were used to identify the potential functions and pathways associated with the modules. In addition, we used the cytoscape software to construct and visualize protein-protein networks so as to identify key genes in the modules of interest. Three hub genes including PTGER3, GNAI1, and IGFBP5 were further screened using the least absolute shrinkage and selection operator (LASSO) and support vector machine-recursive feature elimination (SVM-RFE) algorithms. Since the modules were associated with immune pathways, we performed immune cell infiltration analysis. We discovered a significant difference in the level of immune cell infiltration by naïve B cells, CD8 T cells, T regulatory cells (Tregs), resting NK cells, Monocytes, Macrophages M0, Macrophages M1, and Macrophages M2 between the two subgroups. In addition, we observed the three hub genes were positively correlated with Tregs but negatively correlated with Macrophages M0. We also found that the three key genes are differentially expressed between normal and diseased tissue, as well as in the different subgroups. Receiver operating characteristic (ROC) results showed a good performance in the validation dataset. These results may provide novel insight into cellular and molecular characteristics of AS and potential markers for diagnosis and targeted therapy.

Project description:BackgroundMelanoma is the deadliest type of skin cancer. Until now, its pathological mechanisms, particularly the mechanism of metastasis, remain largely unknown. Our study on the identification of genes in association with metastasis for melanoma provides a novel understanding of melanoma.MethodsFrom the Gene Expression Omnibus (GEO) database, the gene expression microarray datasets GSE46517, GSE7553, and GSE8401 were downloaded. We made use of R aiming at analyzing the differentially expressed genes (DEGs) between metastatic and nonmetastatic melanoma. R was also used in differentially expressed miRNA (DEM) data mining from GSE18509, GSE19387, GSE24996, GSE34460, GSE35579, GSE36236, and GSE54492 datasets referring to Li's study. Based on the DEG and DEM data, we performed functional enrichment analysis through the application of the DAVID database. Furthermore, we constructed the protein-protein interaction (PPI) network and established functional modules by making use of the STRING database. Through making use of Cytoscape, the PPI results were visualized. We predicted the targets of the DEMs through applying TargetScan, miRanda, and PITA databases and identified the overlapping genes between DEGs and predicted targets, followed by the construction of DEM-DEG pair network. The expressions of these keratinocyte differentiation-involved genes in Module 1 were identified based on the data from TCGA.Results239 DEGs were screened out in all 3 datasets, which were inclusive of 21 positively regulated genes and 218 negatively regulated genes. Based on these 239 DEGs, we finished constructing the PPI network which was formed from 225 nodes and 846 edges. We finished establishing 3 functional modules. And we analyzed 92 overlapping genes and 26 miRNA, including 11 upregulated genes targeted by 11 negatively regulated DEMs and 81 downregulated genes targeted by 15 positively regulated DEMs. As proof of the differential expression of metastasis-associated genes, eleven keratinocyte differentiation-involved genes, including LOR, EVPL, SPRR1A, FLG, SPRR1B, SPRR2B, TGM1, DSP, CSTA, CDSN, and IVL in Module 1, were obviously downregulated in metastatic melanoma tissue in comparison with primary melanoma tissue based on the data from TCGA.Conclusion239 melanoma metastasis-associated genes and 26 differentially expressed miRNA were identified in our study. The keratinocyte differentiation-involved genes may take part in melanoma metastasis, providing a latent molecular mechanism for this disease.

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Identification of tuberculosis susceptibility genes with human macrophage gene expression profiles.

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Identification of tuberculosis susceptibility genes with human macrophage gene expression profiles.

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