Polymorphism within the Interferon-gamma/Receptor complex is associated with pulmonary tuberculosis

Cooke, GS; Campbell, SJ; Sillah, J; Gustafson, P; Bah, B; Sirugo, G; Bennett, S; McAdam, Kpwj; Sow, O; Lienhardt, C; Hill, AVS; (2006) Polymorphism within the Interferon-gamma/Receptor complex is associated with pulmonary tuberculosis. American journal of respiratory and critical care medicine, 174 (3). pp. 339-343. ISSN 1073-449X DOI: https://doi.org/10.1164/rccm.200601-088OC

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Rationale: Interferon-gamma (IFN-gamma) is of central interest in the study of tuberculosis. A number of single-gene mutations have been identified in the IFN-gamma signaling pathway that predispose to severe mycobacterial disease, but the relevance of polymorphism within these genes to the common phenotype of tuberculosis remains unclear. Methods: A total of 1,301 individuals were included in a large, detailed study of West African populations with pulmonary tuberculosis. We investigated disease association with the genes encoding IFN-gamma and its receptor subunits (IFNG, IFNGR1, and IFNGR2). Results: Within the IFNG gene, two promoter variants showed evidence of novel disease association: -1616GG (odds ratio [OR], 1.49; 95% confidence interval [CI], 1.11-2.00; p = 0.008) and +3234TT (OR, 1.40; 95% CI, 1.09-1.80; p = 0.009). The +874AA genotype was not significantly more frequent among cases over control subjects (OR, 1.16; 95%CI, 0.89-1.51; p = 0.25). In addition, novel disease association was also found with the -56CC genotype of the IFNGR1 promoter (OR, 0.75; 95% CI, 0.57-0.99; p = 0.041). No disease association was seen with the IFNGR2 locus. Conclusions: These results provide evidence of a significant role for genetic variation at the IFNG locus and provide detailed understanding of the genetic mechanisms underlying this association. The disease association with IFNGR1 is novel, and together these findings support the hypothesis that genetically determined variation in both IFN-gamma production and responsiveness influences the risk of developing tuberculosis.

Item Type: Article
Keywords: interferon-gamma, polymorphism, receptor, tuberculosis, Gamma receptor-1 gene, single nucleotide polymorphism, ifn-gamma, mycobacterium-tuberculosis, transcriptional responses, linkage, disequilibrium, promoter variant, risk-factors, 1st intron, infection, Adult, Africa, Western, Alleles, Genotype, Humans, Logistic Models, Polymorphism, Single Nucleotide, Promoter Regions (Genetics), Receptors, Interferon, genetics, Research Support, Non-U.S. Gov't, Tuberculosis, Pulmonary, genetics, Variation (Genetics)
Faculty and Department: Faculty of Infectious and Tropical Diseases > Dept of Clinical Research
Faculty of Epidemiology and Population Health > Dept of Infectious Disease Epidemiology
PubMed ID: 16690980
Web of Science ID: 239415200019
URI: http://researchonline.lshtm.ac.uk/id/eprint/11418


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