In:
PLOS Genetics, Public Library of Science (PLoS), Vol. 17, No. 3 ( 2021-3-4), p. e1009392-
Abstract:
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.
Type of Medium:
Online Resource
ISSN:
1553-7404
DOI:
10.1371/journal.pgen.1009392
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10.1371/journal.pgen.1009392.g001
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10.1371/journal.pgen.1009392.g002
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10.1371/journal.pgen.1009392.g003
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10.1371/journal.pgen.1009392.r001
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10.1371/journal.pgen.1009392.r003
DOI:
10.1371/journal.pgen.1009392.r004
Language:
English
Publisher:
Public Library of Science (PLoS)
Publication Date:
2021
detail.hit.zdb_id:
2186725-2
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