Identification of tuberculosis susceptibility genes with human macrophage gene expression profiles.
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 expressio...
| Main Authors: | , , , , , , , , , , , , , |
|---|---|
| Format: | Journal article |
| Language: | English |
| Published: |
Public Library of Science
2008
|
| _version_ | 1797084376652054528 |
|---|---|
| author | Thuong, N Dunstan, S Chau, T Thorsson, V Simmons, C Quyen, N Thwaites, G Thi Ngoc Lan, N Hibberd, M Teo, Y Seielstad, M Aderem, A Farrar, J Hawn, T |
| author_facet | Thuong, N Dunstan, S Chau, T Thorsson, V Simmons, C Quyen, N Thwaites, G Thi Ngoc Lan, N Hibberd, M Teo, Y Seielstad, M Aderem, A Farrar, J Hawn, T |
| author_sort | Thuong, N |
| collection | OXFORD |
| description | 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. |
| first_indexed | 2024-03-07T01:54:33Z |
| format | Journal article |
| id | oxford-uuid:9b426154-2a42-4f31-8f1e-681dd79702b9 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T01:54:33Z |
| publishDate | 2008 |
| publisher | Public Library of Science |
| record_format | dspace |
| spelling | oxford-uuid:9b426154-2a42-4f31-8f1e-681dd79702b92022-03-27T00:27:33ZIdentification of tuberculosis susceptibility genes with human macrophage gene expression profiles.Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:9b426154-2a42-4f31-8f1e-681dd79702b9EnglishSymplectic Elements at OxfordPublic Library of Science2008Thuong, NDunstan, SChau, TThorsson, VSimmons, CQuyen, NThwaites, GThi Ngoc Lan, NHibberd, MTeo, YSeielstad, MAderem, AFarrar, JHawn, TAlthough 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. |
| spellingShingle | Thuong, N Dunstan, S Chau, T Thorsson, V Simmons, C Quyen, N Thwaites, G Thi Ngoc Lan, N Hibberd, M Teo, Y Seielstad, M Aderem, A Farrar, J Hawn, T Identification of tuberculosis susceptibility genes with human macrophage gene expression profiles. |
| title | Identification of tuberculosis susceptibility genes with human macrophage gene expression profiles. |
| title_full | Identification of tuberculosis susceptibility genes with human macrophage gene expression profiles. |
| title_fullStr | Identification of tuberculosis susceptibility genes with human macrophage gene expression profiles. |
| title_full_unstemmed | Identification of tuberculosis susceptibility genes with human macrophage gene expression profiles. |
| title_short | Identification of tuberculosis susceptibility genes with human macrophage gene expression profiles. |
| title_sort | identification of tuberculosis susceptibility genes with human macrophage gene expression profiles |
| work_keys_str_mv | AT thuongn identificationoftuberculosissusceptibilitygeneswithhumanmacrophagegeneexpressionprofiles AT dunstans identificationoftuberculosissusceptibilitygeneswithhumanmacrophagegeneexpressionprofiles AT chaut identificationoftuberculosissusceptibilitygeneswithhumanmacrophagegeneexpressionprofiles AT thorssonv identificationoftuberculosissusceptibilitygeneswithhumanmacrophagegeneexpressionprofiles AT simmonsc identificationoftuberculosissusceptibilitygeneswithhumanmacrophagegeneexpressionprofiles AT quyenn identificationoftuberculosissusceptibilitygeneswithhumanmacrophagegeneexpressionprofiles AT thwaitesg identificationoftuberculosissusceptibilitygeneswithhumanmacrophagegeneexpressionprofiles AT thingoclann identificationoftuberculosissusceptibilitygeneswithhumanmacrophagegeneexpressionprofiles AT hibberdm identificationoftuberculosissusceptibilitygeneswithhumanmacrophagegeneexpressionprofiles AT teoy identificationoftuberculosissusceptibilitygeneswithhumanmacrophagegeneexpressionprofiles AT seielstadm identificationoftuberculosissusceptibilitygeneswithhumanmacrophagegeneexpressionprofiles AT aderema identificationoftuberculosissusceptibilitygeneswithhumanmacrophagegeneexpressionprofiles AT farrarj identificationoftuberculosissusceptibilitygeneswithhumanmacrophagegeneexpressionprofiles AT hawnt identificationoftuberculosissusceptibilitygeneswithhumanmacrophagegeneexpressionprofiles |