Genome-wide association study of resistance to Mycobacterium tuberculosis infection identifies a locus at 10q26.2 in three distinct populations.
PLoS Genet
; 17(3): e1009392, 2021 03.
Article
en En
| MEDLINE
| ID: mdl-33661925
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.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Tuberculosis
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Cromosomas Humanos Par 10
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Predisposición Genética a la Enfermedad
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Sitios de Carácter Cuantitativo
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Estudio de Asociación del Genoma Completo
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Resistencia a la Enfermedad
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Mycobacterium tuberculosis
Tipo de estudio:
Prognostic_studies
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Risk_factors_studies
/
Systematic_reviews
Límite:
Humans
País/Región como asunto:
Africa
/
Asia
/
Europa
Idioma:
En
Revista:
PLoS Genet
Asunto de la revista:
GENETICA
Año:
2021
Tipo del documento:
Article
País de afiliación:
Francia