Identification of tuberculosis susceptibility genes with human macrophage gene expression profiles

Nguyen Thuy Thuong Thuong, Sarah J. Dunstan, Tran Thi Hong Chau, Vesteinn Thorsson, Cameron P. Simmons, Nguyen Than Ha Quyen, Guy E. Thwaites, Nguyen Thi Ngoc Lan, Martin Hibberd, Yik Y. Teo, Mark Seielstad, Alan Aderem, Jeremy J. Farrar, Thomas R. Hawn

Research output: Contribution to journalArticleResearchpeer-review

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.

Original languageEnglish
Article numbere1000229
JournalPLoS Pathogens
Volume4
Issue number12
DOIs
Publication statusPublished - 1 Dec 2008

Cite this

Thuong, N. T. T., Dunstan, S. J., Chau, T. T. H., Thorsson, V., Simmons, C. P., Quyen, N. T. H., ... Hawn, T. R. (2008). Identification of tuberculosis susceptibility genes with human macrophage gene expression profiles. PLoS Pathogens, 4(12), [e1000229]. https://doi.org/10.1371/journal.ppat.1000229
Thuong, Nguyen Thuy Thuong ; Dunstan, Sarah J. ; Chau, Tran Thi Hong ; Thorsson, Vesteinn ; Simmons, Cameron P. ; Quyen, Nguyen Than Ha ; Thwaites, Guy E. ; Lan, Nguyen Thi Ngoc ; Hibberd, Martin ; Teo, Yik Y. ; Seielstad, Mark ; Aderem, Alan ; Farrar, Jeremy J. ; Hawn, Thomas R. / Identification of tuberculosis susceptibility genes with human macrophage gene expression profiles. In: PLoS Pathogens. 2008 ; Vol. 4, No. 12.
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title = "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.",
author = "Thuong, {Nguyen Thuy Thuong} and Dunstan, {Sarah J.} and Chau, {Tran Thi Hong} and Vesteinn Thorsson and Simmons, {Cameron P.} and Quyen, {Nguyen Than Ha} and Thwaites, {Guy E.} and Lan, {Nguyen Thi Ngoc} and Martin Hibberd and Teo, {Yik Y.} and Mark Seielstad and Alan Aderem and Farrar, {Jeremy J.} and Hawn, {Thomas R.}",
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Thuong, NTT, Dunstan, SJ, Chau, TTH, Thorsson, V, Simmons, CP, Quyen, NTH, Thwaites, GE, Lan, NTN, Hibberd, M, Teo, YY, Seielstad, M, Aderem, A, Farrar, JJ & Hawn, TR 2008, 'Identification of tuberculosis susceptibility genes with human macrophage gene expression profiles' PLoS Pathogens, vol. 4, no. 12, e1000229. https://doi.org/10.1371/journal.ppat.1000229

Identification of tuberculosis susceptibility genes with human macrophage gene expression profiles. / Thuong, Nguyen Thuy Thuong; Dunstan, Sarah J.; Chau, Tran Thi Hong; Thorsson, Vesteinn; Simmons, Cameron P.; Quyen, Nguyen Than Ha; Thwaites, Guy E.; Lan, Nguyen Thi Ngoc; Hibberd, Martin; Teo, Yik Y.; Seielstad, Mark; Aderem, Alan; Farrar, Jeremy J.; Hawn, Thomas R.

In: PLoS Pathogens, Vol. 4, No. 12, e1000229, 01.12.2008.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - Identification of tuberculosis susceptibility genes with human macrophage gene expression profiles

AU - Thuong, Nguyen Thuy Thuong

AU - Dunstan, Sarah J.

AU - Chau, Tran Thi Hong

AU - Thorsson, Vesteinn

AU - Simmons, Cameron P.

AU - Quyen, Nguyen Than Ha

AU - Thwaites, Guy E.

AU - Lan, Nguyen Thi Ngoc

AU - Hibberd, Martin

AU - Teo, Yik Y.

AU - Seielstad, Mark

AU - Aderem, Alan

AU - Farrar, Jeremy J.

AU - Hawn, Thomas R.

PY - 2008/12/1

Y1 - 2008/12/1

N2 - 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.

AB - 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.

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DO - 10.1371/journal.ppat.1000229

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