Background
Tuberculosis (TB) is the leading infectious cause of death worldwide, including among people living with HIV. The WHO End TB goal of reducing TB incidence to <10 cases per 100,000 will not be achieved without a greater understanding of host mechanisms that mediate susceptibility to Mycobacterium tuberculosis (Mtb). A genetic basis for “resistance” to Mtb infection has been postulated, but the relationship between host genetics and Mtb infection is underexplored. We conducted a genome-wide association study (GWAS) to identify loci associated with Mtb resistance and infection among close contacts of TB patients in Brazil, India, and South Africa.
Methods
Among 4,370 close contacts of microbiologically-confirmed, active pulmonary TB patients, we categorized contacts as “resisters” if they had: high exposure (slept in the same room or >4 hours indoors), to a highly infectious index case (cavitary or high smear grade), and negative tuberculin skin tests (TST) and/or interferon-gamma release assays (IGRA). Contacts with positive TST and/or IGRA were categorized as Mtb infected. After quality control at sample and variant levels, we conducted country-specific GWAS and meta-analysis of the resister and infected phenotypes, adjusted for age, sex, population structure, and relatedness using TOPMed-imputed data.
Results
Among the contacts enrolled, we identified 457 individuals with resistance to Mtb infection, 1,903 with positive TST and/or IGRA; 361 with discordant or missing TST/IGRA results, and 1,168 with negative TST/IGRA but low or medium exposure to the TB index patient. In the meta-analysis for resistance to Mtb infection, we identified two genome-wide significant (GWS) loci associated with resistance: a chromosome 13 locus, close to MYO16 gene (rs1295104126, OR = 0.92 [95%CI: 0.89, 0.94]; p = 1.60×10-10), and a chromosome 2 locus, mapped to PARD3B gene (rs888091, OR = 0.83 [95%CI: 0.78, 0.89]; p = 4.64×10-9). In the meta-analysis for Mtb infection, we identified one GWS locus close to HLA-DQA1 gene on chromosome 6 (rs28752534, OR = 0.92 [95%CI: 0.89, 0.94], p = 6.58×10-12).
Conclusions
Our robust methods uncovered multiple statistically significant associations. Further investigation into the functional roles of these genetic loci is warranted. Consistent results from diverse ancestral groups may help us better understand the molecular mechanisms underlying Mtb resistance and infection, thus improving the generalizability of our findings across global populations with high TB burden.
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