Journal
GENES AND IMMUNITY
Volume 16, Issue 2, Pages 127-133Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/gene.2014.77
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Funding
- Tuberculosis Research Unit [N01-AI95383, HHSN266200700022C/N01-AI70022]
- National Institute of Allergy and Infectious Disease [K08AI083739]
- National Heart Lung and Blood Institutes (NHLBI) [R01HL096811, R01HL10566113, T32HL007567]
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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 x 10(-6)) and IL1B (P = 4.3 x 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 x 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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