TY - JOUR
T1 - A chromosome 5q31.1 locus associates with tuberculin skin test reactivity in HIV-positive individuals from tuberculosis hyper-endemic regions in east Africa
AU - Sobota, Rafal S.
AU - Stein, Catherine M.
AU - Kodaman, Nuri
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
N1 - Funding Information:
RSS was supported by Public Health Service award T32 GM07347 from the National Institute of General Medical Studies for the Vanderbilt Medical-Scientist Training Program. RSS, NK, and SMW were partially supported by National Institutes of Health grant P20 GM103534. CMS, LLM, KC, and WHB were partially supported by Tuberculosis Research Unit (grant N01-AI95383) and UO1-AI-09-001 from the National Institutes of Health. CMS, WHB, and RPI were also supported by National Institutes of Health grant R01HL096811. JHM and SMW were supported by National Institutes of Health grants LM010098. JHM was supported by National Institutes of Health grants AI59694, AI116794, and LM009012. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. We would like to acknowledge the invaluable contribution made by the study medical officers, health visitors, laboratory and data personnel: Dr. Lorna Nshuti, Dr. Roy Mugerwa, Dr. Sarah Zalwango, Allan Chiunda, Bonnie Thiel, Mark Breda, Dennis Dobbs, Hussein Kisingo, Mary Rutaro, Albert Muganda, Richard Bamuhimbisa, Yusuf Mulumba, Deborah Nsamba, Barbara Kyeyune, Faith Kintu, Dr. Mary Nsereko, Gladys Mpalanyi, Janet Mukose, Grace Tumusiime, Pierre Peters, Annet Kawuma, Saidah Menya, Joan Nassuna, Alphonse Okwera, Keith Chervenak, Karen Morgan, Alfred Etwom, Micheal Angel Mugerwa, Dr. Brenda Okware, and Lisa Kucharski. We would like to acknowledge and thank Dr. Francis Adatu Engwau, Head of the Uganda National Tuberculosis and Leprosy Program, for his support of this project. We would like to acknowledge the medical officers, nurses and counselors at the National Tuberculosis Treatment Centre, Mulago Hospital, the Ugandan National Tuberculosis and Leprosy Program and the Uganda Tuberculosis Investigation Bacteriological Unit, Wandegeya, for their contributions to this study. We would also like to thank the staff at the Infectious Disease Center in Dar es Salaam, Tanzania, and Betty Mchaki at Muhimbili University of Health and Allied Sciences. This study would not be possible without the generous participation of the Ugandan and Tanzanian patients and their families.
Publisher Copyright:
© 2017 Sobota et al.
PY - 2017
Y1 - 2017
N2 - 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.
AB - 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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U2 - 10.1371/journal.pgen.1006710
DO - 10.1371/journal.pgen.1006710
M3 - Article
C2 - 28628665
AN - SCOPUS:85021834122
VL - 13
JO - PLoS Genetics
JF - PLoS Genetics
SN - 1553-7390
IS - 6
M1 - e1006710
ER -