Human genetic susceptibility for tuberculosis (TB) has been demonstrated by several studies, but few have examined the multiple innate and adaptive immunity genes comprehensively, age-specific effects and/or resistance to Mycobacterium tuberculosis (Mtb) infection (resistors (RSTRs)). We hypothesized that RSTRs, defined by a persistently negative tuberculin skin test, may have different genetic influences than Mtb disease. We examined 29 candidate genes in pathways that mediate immune responses to Mtb in subjects in a household contact study in Kampala, Uganda. We genotyped 546 haplotype-tagging single-nucleotide polymorphisms (SNPs) in 835 individuals from 481 families; 28.7% had TB, 10.5% were RSTRs, and the remaining 60.8% had latent Mtb infection. Among our most significant findings were SNPs in TICAM2 (P=3.6 × 10−6) and IL1B (P=4.3 × 10−5) associated with TB. Multiple SNPs in IL4 and TOLLIP were associated with TB (P<0.05). Age–genotype interaction analysis revealed SNPs in IL18 and TLR6 that were suggestively associated with TB in children aged ⩽10 years (P=2.9 × 10−3). By contrast, RSTR was associated with SNPs in NOD2, SLC6A3 and TLR4 (nominal P<0.05); these genes were not associated with TB, suggesting distinct genetic influences. We report the first association between TICAM2 polymorphisms and TB and between IL18 and pediatric TB.
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We acknowledge the invaluable contributions made by Dr Christopher Whalen, Dr Sarah Zalwango, Dr Lorna Nshuti, Dr Roy Mugerwa, Dr Deo Mulindwa, Allan Chiunda, Bonnie Thiel, Mark Breda, Dennis Dobbs, Hussein Kisingo, Mary Rutaro, Albert Muganda, Richard Bamuhimbisa, Yusuf Mulumba, Deborah Nsamba, Barbara Kyeyune, Faith Kintu, Gladys Mpalanyi, Janet Mukose, Grace Tumusiime, Pierre Peters, Dr Alphonse Okwera, Keith Chervenak, Denise Johnson, Karen Morgan, Alfred Etwom, Micheal Angel Mugerwa, Lisa Kucharski and Dr Feiyou Qiu. We thank Dr Francis Adatu Engwau, former Head of the Uganda National Tuberculosis and Leprosy Program, for his support of this project. We also thank the staff 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. This study would not be possible without the generous participation of the Ugandan patients and families. Funding for this work was provided by the Tuberculosis Research Unit (grants N01-AI95383 and HHSN266200700022C/N01-AI70022 from the NIAID), National Institute of Allergy and Infectious Disease grant K08AI083739 and National Heart Lung and Blood Institutes (NHLBI) grants R01HL096811, R01HL10566113 and T32HL007567.
The authors declare no conflict of interest.
Supplementary Information accompanies this paper on Genes and Immunity website
About this article
Long-term Stability of Resistance to Latent Mycobacterium tuberculosis Infection in Highly Exposed Tuberculosis Household Contacts in Kampala, Uganda
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