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• W2017077979 abstract "Rationale: Genetic variation influences susceptibility to clinical tuberculosis (TB). Activation of the P2X7 receptor on human macrophages induces killing of mycobacteria. We have identified polymorphisms in the P2X7 gene that markedly reduce this killing.Objective: To determine if polymorphisms in P2X7 are associated with increased risk of TB, the prevalence of four polymorphisms was assessed in individuals from Southeast Asia, where the majority of patients with TB in our study originate. The association of these polymorphisms with clinical TB was subsequently investigated in two separate case-control cohorts and the function of P2X7 was assessed in subjects from one cohort.Methods: Genotyping of P2X7 polymorphisms was performed from subjects in a nested case-control study of a longitudinal refugee cohort and a separate case-control study. The functional capacity of P2X7 was investigated by measuring ATP-mediated mycobacterial killing and apoptosis.Results: Only the 1513A-C polymorphism was present in Southeast Asians and the allele was associated with reduced killing of Mycobacterium tuberculosis. The 1513C allele was strongly associated with extrapulmonary, but not pulmonary, TB in the first (odds ratio, 3.8; 95% confidence interval, 1.6–9.0) and second cohorts (odds ratio, 3.7; 95% confidence interval, 1.7–8.0). ATP-mediated killing of mycobacteria was ablated in macrophages from subjects homozygous for the 1513C allele and significantly impaired in macrophages from heterozygous subjects. There was strong correlation between the degree of mycobacterial killing and ATP-induced apoptosis.Conclusions: The 1513C allele increases susceptibility to extrapulmonary TB, and this defect is associated with the reduction in the capacity of macrophages to kill M. tuberculosis." @default.
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• W2017077979 date "2007-02-15" @default.
• W2017077979 modified "2023-10-09" @default.
• W2017077979 title "A Polymorphism in the P2X₇Gene Increases Susceptibility to Extrapulmonary Tuberculosis" @default.
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• W2017077979 doi "https://doi.org/10.1164/rccm.200607-970oc" @default.
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