A chromosome 5q31.1 locus associates with tuberculin skin test reactivity in HIV-positive individuals from tuberculosis hyper-endemic regions in east Africa

Rafal S. Sobota, Catherine M. Stein, Nuri Kodaman, Isaac Maro, Wendy Wieland-Alter, Robert P. Igo, Albert Magohe, La Shaunda L. Malone, Keith Chervenak, Noemi B. Hall, Mecky Matee, Harriet Mayanja-Kizza, Moses Joloba, Jason H. Moore, William K Scott, Timothy Lahey, W. Henry Boom, C. Fordham von Reyn, Scott M. Williams, Giorgio Sirugo

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

One in three people has been infected with Mycobacterium tuberculosis (MTB), and the risk for MTB infection in HIV-infected individuals is even higher. We hypothesized that HIV-positive individuals living in tuberculosis-endemic regions who do not get infected by Mycobacterium tuberculosis are genetically resistant. Using an “experiment of nature” design that proved successful in our previous work, we performed a genome-wide association study of tuberculin skin test positivity using 469 HIV-positive patients from prospective study cohorts of tuberculosis from Tanzania and Uganda to identify genetic loci associated with MTB infection in the context of HIV-infection. Among these individuals, 244 tested were tuberculin skin test (TST) positive either at enrollment or during the >8 year follow up, while 225 were not. We identified a genome-wide significant association between a dominant model of rs877356 and binary TST status in the combined cohort (Odds ratio = 0.2671, p = 1.22x10-8). Association was replicated with similar significance when examining TST induration as a continuous trait. The variant lies in the 5q31.1 region, 57kb downstream from IL9. Two-locus analyses of association of variants near rs877356 showed a haplotype comprised of rs877356 and an IL9 missense variant, rs2069885, had the most significant association (p = 1.59x10-12). We also replicated previously linked loci on chromosomes 2, 5, and 11. IL9 is a cytokine produced by mast cells and TH2 cells during inflammatory responses, providing a possible link between airway inflammation and protection from MTB infection. Our results indicate that studying uninfected, HIV-positive participants with extensive exposure increases the power to detect associations in complex infectious disease.

Original languageEnglish (US)
Article numbere1006710
JournalPLoS Genetics
Volume13
Issue number6
DOIs
StatePublished - 2017

Fingerprint

Eastern Africa
Tuberculin Test
tuberculin
tuberculosis
skin tests
Mycobacterium tuberculosis
human immunodeficiency virus
Skin Tests
Interleukin-9
chromosome
skin
Tuberculosis
Chromosomes
Mycobacterium Infections
HIV
chromosomes
loci
HIV infections
inflammation
Chromosomes, Human, Pair 5

ASJC Scopus subject areas

  • Ecology, Evolution, Behavior and Systematics
  • Molecular Biology
  • Genetics
  • Genetics(clinical)
  • Cancer Research

Cite this

A chromosome 5q31.1 locus associates with tuberculin skin test reactivity in HIV-positive individuals from tuberculosis hyper-endemic regions in east Africa. / Sobota, Rafal S.; Stein, Catherine M.; Kodaman, Nuri; Maro, Isaac; Wieland-Alter, Wendy; Igo, Robert P.; Magohe, Albert; Malone, La Shaunda L.; Chervenak, Keith; Hall, Noemi B.; Matee, Mecky; Mayanja-Kizza, Harriet; Joloba, Moses; Moore, Jason H.; Scott, William K; Lahey, Timothy; Boom, W. Henry; von Reyn, C. Fordham; Williams, Scott M.; Sirugo, Giorgio.

In: PLoS Genetics, Vol. 13, No. 6, e1006710, 2017.

Research output: Contribution to journalArticle

Sobota, RS, Stein, CM, Kodaman, N, Maro, I, Wieland-Alter, W, Igo, RP, Magohe, A, Malone, LSL, Chervenak, K, Hall, NB, Matee, M, Mayanja-Kizza, H, Joloba, M, Moore, JH, Scott, WK, Lahey, T, Boom, WH, von Reyn, CF, Williams, SM & Sirugo, G 2017, 'A chromosome 5q31.1 locus associates with tuberculin skin test reactivity in HIV-positive individuals from tuberculosis hyper-endemic regions in east Africa', PLoS Genetics, vol. 13, no. 6, e1006710. https://doi.org/10.1371/journal.pgen.1006710
Sobota, Rafal S. ; Stein, Catherine M. ; Kodaman, Nuri ; Maro, Isaac ; Wieland-Alter, Wendy ; Igo, Robert P. ; Magohe, Albert ; Malone, La Shaunda L. ; Chervenak, Keith ; Hall, Noemi B. ; Matee, Mecky ; Mayanja-Kizza, Harriet ; Joloba, Moses ; Moore, Jason H. ; Scott, William K ; Lahey, Timothy ; Boom, W. Henry ; von Reyn, C. Fordham ; Williams, Scott M. ; Sirugo, Giorgio. / A chromosome 5q31.1 locus associates with tuberculin skin test reactivity in HIV-positive individuals from tuberculosis hyper-endemic regions in east Africa. In: PLoS Genetics. 2017 ; Vol. 13, No. 6.
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abstract = "One in three people has been infected with Mycobacterium tuberculosis (MTB), and the risk for MTB infection in HIV-infected individuals is even higher. We hypothesized that HIV-positive individuals living in tuberculosis-endemic regions who do not get infected by Mycobacterium tuberculosis are genetically resistant. Using an “experiment of nature” design that proved successful in our previous work, we performed a genome-wide association study of tuberculin skin test positivity using 469 HIV-positive patients from prospective study cohorts of tuberculosis from Tanzania and Uganda to identify genetic loci associated with MTB infection in the context of HIV-infection. Among these individuals, 244 tested were tuberculin skin test (TST) positive either at enrollment or during the >8 year follow up, while 225 were not. We identified a genome-wide significant association between a dominant model of rs877356 and binary TST status in the combined cohort (Odds ratio = 0.2671, p = 1.22x10-8). Association was replicated with similar significance when examining TST induration as a continuous trait. The variant lies in the 5q31.1 region, 57kb downstream from IL9. Two-locus analyses of association of variants near rs877356 showed a haplotype comprised of rs877356 and an IL9 missense variant, rs2069885, had the most significant association (p = 1.59x10-12). We also replicated previously linked loci on chromosomes 2, 5, and 11. IL9 is a cytokine produced by mast cells and TH2 cells during inflammatory responses, providing a possible link between airway inflammation and protection from MTB infection. Our results indicate that studying uninfected, HIV-positive participants with extensive exposure increases the power to detect associations in complex infectious disease.",
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AU - Maro, Isaac

AU - Wieland-Alter, Wendy

AU - Igo, Robert P.

AU - Magohe, Albert

AU - Malone, La Shaunda L.

AU - Chervenak, Keith

AU - Hall, Noemi B.

AU - Matee, Mecky

AU - Mayanja-Kizza, Harriet

AU - Joloba, Moses

AU - Moore, Jason H.

AU - Scott, William K

AU - Lahey, Timothy

AU - Boom, W. Henry

AU - von Reyn, C. Fordham

AU - Williams, Scott M.

AU - Sirugo, Giorgio

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