Abstract
BACKGROUND: Tuberculosis (TB) is the most deadly infectious disease globally and is highly prevalent in the developing world. For individuals infected with both Mycobacterium tuberculosis (Mtb) and human immunodeficiency virus (HIV), the risk of active TB is 10% or more annually. Previously, we identified in a genome-wide association study (GWAS) a region on chromosome 5 associated with resistance to TB, which included epigenetic marks that could influence gene regulation. We hypothesized that HIV-infected individuals exposed to Mtb who remain disease free carry epigenetic changes that strongly protect them from active TB. METHODS: We conducted a methylome-wide study in HIV-infected, TB-exposed cohorts from Uganda and Tanzania and integrated data from our GWAS. RESULTS: We identified 3 regions of interest that included markers that were differentially methylated between TB cases and controls with latent TB infection: chromosome 1 (RNF220, P = 4 × 10-5), chromosome 2 (between COPS8 and COL6A3, P = 2.7 × 10-5), and chromosome 5 (CEP72, P = 1.3 × 10-5). These methylation results co-localized with associated single-nucleotide polymorphisms (SNPs), methylation QTLs, and methylation × SNP interaction effects. These markers were in regions with regulatory markers for cells involved in TB immunity and/or lung. CONCLUSIONS: Epigenetic regulation is a potential biologic factor underlying resistance to TB in immunocompromised individuals that can act in conjunction with genetic variants.