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Series GSE11199 Query DataSets for GSE11199
Status Public on Feb 23, 2009
Title Identification of Tuberculosis Susceptibility Genes with Human Macrophage Gene Expression Profiles
Organism Homo sapiens
Experiment type Expression profiling by array
Summary 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
 
Overall design Latent TB (LTB) subjects were healthy nursing staff members who had worked at a tuberculosis hospital, for more than 20 years and were positive in ESAT-6 and CFP-10- specific IFN-gamma ELISPOT assays. All subjects with pulmonary (PTB) and meningeal (TBM) disease had been treated and were free of symptoms at the time of venipuncture. Gene expression of monocyte derived macrophages (MDMs) from subjects with three clinical forms of TB including LTB, PTB and TBM (n = 4 in each group) was examined by microarray. MDMs were stimulated either with a whole cell lysate of M. tuberculosis H37Rv or PBS for 4 hours. RNA expression was analyzed using a Human Genome U133 Plus 2.0 Array (Affymetrix, USA) which contains probe sets for 47,000 transcripts including 38,500 well-characterized human genes.
 
Citation(s) 19057661
Submission date Apr 17, 2008
Last update date Mar 25, 2019
Contact name Sarah J Dunstan
E-mail(s) sdunstan@oucru.org
Phone 84 8 9241761
Fax 84 8 9238904
Organization name 1. Oxford University Clinical Research Unit
Department Hospital for Tropical Diseases
Street address 190 Ben Ham Tu, Quan 5
City Ho Chi Minh City
ZIP/Postal code 5
Country Viet Nam
 
Platforms (1)
GPL570 [HG-U133_Plus_2] Affymetrix Human Genome U133 Plus 2.0 Array
Samples (24)
GSM280331 LTB1 stim
GSM280332 LTB1 unstim
GSM280333 PTB3 stim
Relations
BioProject PRJNA106795

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Supplementary file Size Download File type/resource
GSE11199_RAW.tar 112.1 Mb (http)(custom) TAR (of CEL)
Processed data included within Sample table

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