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Polymorphism within the Interferon-/Receptor Complex Is Associated with Pulmonary Tuberculosis

Graham S. Cooke, Sarah J. Campbell, Jackson Sillah, Per Gustafson, Boubacar Bah, Georgio Sirugo, Steve Bennett, Keith P. W. J. McAdam, Oumou Sow, Christian Lienhardt and Adrian V. S. Hill

Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford; London School of Hygiene and Tropical Medicine, London, United Kingdom; Medical Research Council Laboratories, Fajara, The Gambia; CHU Ignace Deen, Conakry, Republique de Guinee; Danish Epidemiology Science Centre, Bissau, Guinea-Bissau; and Institut de Recherche pour le Developpement (IRD), Dakar, Senegal

Correspondence and requests for reprints should be addressed to Dr. Graham S. Cooke, M.R.C.P., Wellcome Trust Centre for Human Genetics, Roosevelt Drive, Churchill Hospital, Headington, Oxford OX3 7BN, UK. E-mail: graham.cooke{at}st-marys.nhs.uk

Rationale: Interferon- (IFN-) is of central interest in the study of tuberculosis. A number of single-gene mutations have been identified in the IFN- 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- 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- production and responsiveness influences the risk of developing tuberculosis.

Key Words: interferon- • polymorphism • receptor • tuberculosis

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