Genome-Wide Association Study Of Resistance To Mycobacterium Tuberculosis Infection Identifies A Locus At 10q26.2 In Three Distinct Populations

The natural history of tuberculosis (TB) is characterized by a large inter-individual outcome variability after exposure to Mycobacterium tuberculosis. Specifically, some highly exposed individuals remain resistant to M. tuberculosis infection, as inferred by tuberculin skin test (TST) or interferon-gamma release assays (IGRAs). We performed a genome-wide association study of resistance to M. tuberculosis infection in an endemic region of Southern Vietnam. We enrolled household contacts (HHC) of pulmonary TB cases and compared subjects who were negative for both TST and IGRA (n = 185) with infected individuals (n = 353) who were either positive for both TST and IGRA or had a diagnosis of TB. We found a genome-wide significant locus on chromosome 10q26.2 with a cluster of variants associated with strong protection against M. tuberculosis infection (OR = 0.42, 95%CI 0.35-0.49, P = 3.71x10(-8), for the genotyped variant rs17155120). The locus was replicated in a French multi-ethnic HHC cohort and a familial admixed cohort from a hyper-endemic area of South Africa, with an overall OR for rs17155120 estimated at 0.50 (95%CI 0.45-0.55, P = 1.26x10(-9)). The variants are located in intronic regions and upstream of C10orf90, a tumor suppressor gene which encodes an ubiquitin ligase activating the transcription factor p53. In silico analysis showed that the protective alleles were associated with a decreased expression in monocytes of the nearby gene ADAM12 which could lead to an enhanced response of Th17 lymphocytes. Our results reveal a novel locus controlling resistance to M. tuberculosis infection across different populations.Author summaryThere is strong epidemiological evidence that a proportion of highly exposed individuals remain resistant to M. tuberculosis infection, as shown by a negative result for Tuberculin Skin Test (TST) or IFN-gamma Release Assays (IGRAs). We performed a genome-wide association study between resistant and infected individuals, which were carefully selected employing a household contact design to maximize exposure by infectious index patients. We employed stringently defined concordant results for both TST and IGRA assays to avoid misclassifications. We discovered a locus at 10q26.2 associated with resistance to M. tuberculosis infection in a Vietnamese discovery cohort. This locus could be replicated in two independent cohorts from different epidemiological settings and of diverse ancestries enrolled in France and South Africa.