A Locus at 5q33.3 Confers Resistance to Tuberculosis in Highly Susceptible Individuals

Rafal S. Sobota, Catherine M. Stein, Nuri Kodaman, Laura B. Scheinfeldt, Isaac Maro, Wendy Wieland-Alter, Robert P. Igo, Albert Magohe, Lashaunda L. Malone, Keith Chervenak, Noemi B. Hall, Chawangwa Modongo, Nicola Zetola, Mecky Matee, Moses Joloba, Alain Froment, Thomas B. Nyambo, Jason H. Moore, William K. Scott, Timothy LaheyW. Henry Boom, C. Fordham Von Reyn, Sarah A. Tishkoff, Giorgio Sirugo, Scott M. Williams

Research output: Contribution to journalArticle

31 Scopus citations

Abstract

Immunosuppression resulting from HIV infection increases the risk of progression to active tuberculosis (TB) both in individuals newly exposed to Mycobacterium tuberculosis (MTB) and in those with latent infections. We hypothesized that HIV-positive individuals who do not develop TB, despite living in areas where it is hyperendemic, provide a model of natural resistance. We performed a genome-wide association study of TB resistance by using 581 HIV-positive Ugandans and Tanzanians enrolled in prospective cohort studies of TB; 267 of these individuals developed active TB, and 314 did not. A common variant, rs4921437 at 5q33.3, was significantly associated with TB (odds ratio = 0.37, p = 2.11 × 10-8). This variant lies within a genomic region that includes IL12B and is embedded in an H3K27Ac histone mark. The locus also displays consistent patterns of linkage disequilibrium across African populations and has signals of strong selection in populations from equatorial Africa. Along with prior studies demonstrating that therapy with IL-12 (the cytokine encoded in part by IL12B, associated with longer survival following MTB infection in mice deficient in CD4 T cells), our results suggest that this pathway might be an excellent target for the development of new modalities for treating TB, especially for HIV-positive individuals. Our results also indicate that studying extreme disease resistance in the face of extensive exposure can increase the power to detect associations in complex infectious disease.

Original languageEnglish (US)
Pages (from-to)514-524
Number of pages11
JournalAmerican journal of human genetics
Volume98
Issue number3
DOIs
StatePublished - Mar 3 2016

Keywords

  • East Africa
  • HIV
  • IL12B
  • UBLCP1
  • histone acetylation
  • selection

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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    Sobota, R. S., Stein, C. M., Kodaman, N., Scheinfeldt, L. B., Maro, I., Wieland-Alter, W., Igo, R. P., Magohe, A., Malone, L. L., Chervenak, K., Hall, N. B., Modongo, C., Zetola, N., Matee, M., Joloba, M., Froment, A., Nyambo, T. B., Moore, J. H., Scott, W. K., ... Williams, S. M. (2016). A Locus at 5q33.3 Confers Resistance to Tuberculosis in Highly Susceptible Individuals. American journal of human genetics, 98(3), 514-524. https://doi.org/10.1016/j.ajhg.2016.01.015