Genome-wide association study of resistance to Mycobacterium tuberculosis infection identifies a locus at 10q26.2 in three distinct populations

• Published in: PLoS genetics Vol. 17; no. 3; p. e1009392
• Main Authors: Quistrebert, Jocelyn, Orlova, Marianna, Kerner, Gaspard, Ton, Le Thi, Luong, Nguyễn Trong, Danh, Nguyễn Thanh, Vincent, Quentin B., Jabot-Hanin, Fabienne, Seeleuthner, Yoann, Bustamante, Jacinta, Boisson-Dupuis, Stéphanie, Huong, Nguyen Thu, Ba, Nguyen Ngoc, Casanova, Jean-Laurent, Delacourt, Christophe, Hoal, Eileen G., Alcaïs, Alexandre, Thai, Vu Hong, Thành, Lai The, Abel, Laurent, Schurr, Erwin, Cobat, Aurélie
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 04.03.2021; Public Library of Science (PLoS)
• Subjects: Alleles; Analysis; Biology and Life Sciences; Chromosome 10; Chromosomes; Diagnosis; Drug therapy; Extensively drug-resistant tuberculosis; Gene frequency; Genetic aspects; Genome-wide association studies; Genomes; Genotype & phenotype; Genotypes; Identification and classification; Immunoreactivity; Infections; Medicine and Health Sciences; Mycobacterium tuberculosis; Natural history; Patient outcomes; People and Places; Population; Quantitative trait loci; Skin tests; Tuberculin; Tuberculosis; γ-Interferon; France; South Africa; Vietnam
• ISSN: 1553-7404; 1553-7390; 1553-7404
• DOI: 10.1371/journal.pgen.1009392

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 = 3.71×10 −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 = 1.26×10 −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.