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

• Published in: American journal of respiratory and critical care medicine Vol. 174; no. 3; pp. 339 - 343
• Main Authors: Cooke, Graham S., Campbell, Sarah J., Sillah, Jackson, Gustafson, Per, Bah, Boubacar, Sirugo, Georgio, Bennett, Steve, McAdam, Keith P. W. J., Sow, Oumou, Lienhardt, Christian, Hill, Adrian V. S.
• Format: Journal Article
• Language: English
• Published: New York, NY American Lung Association 01.08.2006
• Subjects: Adult; Africa, Western; Alleles; Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy; Biological and medical sciences; Cardiology. Vascular system; Clinical Medicine; Coronary heart disease; Genetic Variation; Genotype; Heart; Humans; Intensive care medicine; Interferon gamma Receptor; Klinisk medicin; Logistic Models; Lungmedicin och allergi; Medical and Health Sciences; Medical sciences; Medicin och hälsovetenskap; Pneumology; Polymorphism, Single Nucleotide; Promoter Regions, Genetic; Pulmonary hypertension. Acute cor pulmonale. Pulmonary embolism. Pulmonary vascular diseases; Receptors, Interferon - genetics; Respiratory Medicine and Allergy; Tuberculosis, Pulmonary - genetics; Lung disease; Intensive care; interferon-γ; Respiratory disease; Cytokine; Pulmonary tuberculosis; tuberculosis; Mycobacterial infection; Infection; receptor; Bacteriosis; Interferon; Resuscitation; Polymorphism
• ISSN: 1073-449X; 1535-4970; 1535-4970
• DOI: 10.1164/rccm.200601-088OC

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. 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). 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. 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.