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Am J Hum Genet. 2016 Mar 3;98(3):514-524. doi: 10.1016/j.ajhg.2016.01.015.

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

Author information

1
Vanderbilt Genetics Institute, Vanderbilt University, Nashville, TN 37232, USA; Geisel School of Medicine, Dartmouth College, Hanover, NH 03755, USA.
2
Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, OH 44106, USA; Tuberculosis Research Unit, Case Western Reserve University, Cleveland, OH 44106, USA.
3
Vanderbilt Genetics Institute, Vanderbilt University, Nashville, TN 37232, USA; Geisel School of Medicine, Dartmouth College, Hanover, NH 03755, USA; Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, OH 44106, USA.
4
Department of Genetics, University of Pennsylvania, Philadelphia, PA 19104, USA; Coriell Institute for Medical Research, Camden, NJ 08103, USA.
5
Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan.
6
Geisel School of Medicine, Dartmouth College, Hanover, NH 03755, USA.
7
Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, OH 44106, USA.
8
Muhimbili University of Health and Allied Sciences, Dar es Salaam, Tanzania.
9
Tuberculosis Research Unit, Case Western Reserve University, Cleveland, OH 44106, USA.
10
Division of Infectious Diseases, University of Pennsylvania, Philadelphia, PA 19104, USA; Botswana-UPenn Partnership, 214 Independence Avenue, Gaborone, Botswana; Department of Medicine, University of Botswana, Gaborone, Botswana.
11
Uganda-CWRU Research Collaboration, Kampala, Uganda; College of Health Sciences Makerere University and Mulago Hospital, Kampala, Uganda.
12
UMR 208, Institut de Recherche pour le Développement and Musée de l'Homme, Muséum National d'Histoire Naturelle, 75116 Paris, France.
13
Department of Biochemistry, Muhimbili University of Health and Allied Sciences, Dar es Salaam, Tanzania.
14
Geisel School of Medicine, Dartmouth College, Hanover, NH 03755, USA; Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
15
John P. Hussman Institute for Human Genomics, University of Miami, Miami, FL 33136, USA.
16
Tuberculosis Research Unit, Case Western Reserve University, Cleveland, OH 44106, USA; Uganda-CWRU Research Collaboration, Kampala, Uganda.
17
Department of Genetics, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Biology, University of Pennsylvania, Philadelphia, PA 19104, USA.
18
Centro di Ricerca, Ospedale San Pietro Fatebenefratelli, 00189 Rome, Italy.
19
Geisel School of Medicine, Dartmouth College, Hanover, NH 03755, USA; Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, OH 44106, USA. Electronic address: smw154@case.edu.

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.

KEYWORDS:

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

PMID:
26942285
PMCID:
PMC4800052
DOI:
10.1016/j.ajhg.2016.01.015
[Indexed for MEDLINE]
Free PMC Article

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