Published ahead of print on November 9, 2006, doi:10.1164/rccm.200607-970OC Am. J. Respir. Crit. Care Med., Volume 175, Number 4, February 2007, 360-366 A more recent version of this article appeared on February 15, 2007
Submitted on July 17, 2006 A Polymorphism in the P2X7 Gene Increases Susceptibility to Extrapulmonary TuberculosisSuran L Fernando1,1 Mycobacterial Research Programme, Centenary Institute, Newtown, NSW, Australia, 2 Mycobacterial Research Programme, Centenary Institute, Newtown, NSW, Australia; Discipline of Medicine, University of Sydney, Central Clinical School, Sydney, NSW, Australia, 3 Discipline of Medicine, University of Sydney, Western Clinical School, Sydney, NSW, Australia, 4 Chest Clinic, Royal Prince Alfred Hospital, Camperdown, NSW, Australia, 5 Department of Medicine, University of New South Wales, Liverpool Clinical School, Sydney, NSW, Australia; Woolcock Institute of Medical Research, Camperdown, NSW, Australia * To whom correspondence should be addressed. E-mail: wbritton{at}med.usyd.edu.au.
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 which 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 TB patients 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 M. tuberculosis. The 1513C allele was strongly associated with extrapulmonary, but not pulmonary, TB in the first (Odds ratio [OR] 3.8, 95% confidence intervals [95% CI] 1.6-9.0) and second cohorts (OR 3.7, 95% CI 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. Key words: Macrophage, Tuberculosis, P2X7, genes, susceptibility
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