@article{3a562a9cfeed4147b59ac1a6e9e1fc88,
title = "A Locus at 5q33.3 Confers Resistance to Tuberculosis in Highly Susceptible Individuals",
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",
author = "Sobota, {Rafal S.} and Stein, {Catherine M.} and Nuri Kodaman and Scheinfeldt, {Laura B.} and Isaac Maro and Wendy Wieland-Alter and Igo, {Robert P.} and Albert Magohe and Malone, {Lashaunda L.} and Keith Chervenak and Hall, {Noemi B.} and Chawangwa Modongo and Nicola Zetola and Mecky Matee and Moses Joloba and Alain Froment and Nyambo, {Thomas B.} and Moore, {Jason H.} and Scott, {William K.} and Timothy Lahey and Boom, {W. Henry} and {Von Reyn}, {C. Fordham} and Tishkoff, {Sarah A.} and Giorgio Sirugo and Williams, {Scott M.}",
note = "Funding Information: R.S.S. was supported by Public Health Service award T32 GM07347 from the National Institute of General Medical Studies for the Vanderbilt Medical-Scientist Training Program. R.S.S., N.K., and S.M.W. were partially supported by NIH grant P20 GM103534. C.M.S., L.L.M., K.C., and W.H.B. were partially supported by the Tuberculosis Research Unit (grants N01-AI95383 and HHSN266200700022C/N01-AI70022 from the National Institute of Allergy and Infectious Diseases). C.M.S.,W.H.B., and R.P.I. were supported by National Heart, Lung, and Blood Institute (NHLBI) grant R01HL096811. C.M.S. and W.H.B. were partially supported by NHLBI grant R01HL10566113, and N.B.H. was supported by NHLBI grant T32HL007567. J.H.M. and S.M.W. were supported by NIH grant LM010098. J.H.M. was supported by NIH grants AI59694, AI116794, and LM009012. S.A.T. was partially supported by NIH grants 1R01GM113657-01 and 8DP1ES022577-04. Funding Information: R.S.S. was supported by Public Health Service award T32 GM07347 from the National Institute of General Medical Studies for the Vanderbilt Medical-Scientist Training Program. R.S.S., N.K., and S.M.W. were partially supported by NIH grant P20 GM103534. C.M.S., L.L.M., K.C., and W.H.B. were partially supported by the Tuberculosis Research Unit (grants N01-AI95383 and HHSN266200700022C/ N01-AI70022 from the National Institute of Allergy and Infectious Diseases). C.M.S., W.H.B., and R.P.I. were supported by National Heart, Lung, and Blood Institute (NHLBI) grant R01HL096811. C.M.S. and W.H.B. were partially supported by NHLBI grant R01HL10566113, and N.B.H. was supported by NHLBI grant T32HL007567. J.H.M. and S.M.W. were supported by NIH grant LM010098. J.H.M. was supported by NIH grants AI59694, AI116794, and LM009012. S.A.T. was partially supported by NIH grants 1R01GM113657-01 and 8DP1ES022577-04. Publisher Copyright: {\textcopyright} 2016 The American Society of Human Genetics.",
year = "2016",
month = mar,
day = "3",
doi = "10.1016/j.ajhg.2016.01.015",
language = "English (US)",
volume = "98",
pages = "514--524",
journal = "American Journal of Human Genetics",
issn = "0002-9297",
publisher = "Cell Press",
number = "3",
}