title: Polymorphism within the interferon-gamma/receptor complex is associated with pulmonary tuberculosis.
abstract: BACKGROUND
  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.
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK. graham.cooke@st-marys.nhs.uk
authors.forename: Graham S
authors.initials: GS
authors.lastname: Cooke
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Campbell
authors.forename: Jackson
authors.initials: J
authors.lastname: Sillah
authors.forename: Per
authors.initials: P
authors.lastname: Gustafson
authors.forename: Boubacar
authors.initials: B
authors.lastname: Bah
authors.forename: Georgio
authors.initials: G
authors.lastname: Sirugo
authors.forename: Steve
authors.initials: S
authors.lastname: Bennett
authors.forename: Keith P W J
authors.initials: KP
authors.lastname: McAdam
authors.forename: Oumou
authors.initials: O
authors.lastname: Sow
authors.forename: Christian
authors.initials: C
authors.lastname: Lienhardt
authors.forename: Adrian V S
authors.initials: AV
authors.lastname: Hill
mesh_terms: D000328:Adult; D000354:Africa, Western; D000483:Alleles; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D016015:Logistic Models; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D017471:Receptors, Interferon / Q000235:genetics*; D014397:Tuberculosis, Pulmonary / Q000235:genetics*; D000096743:Interferon gamma Receptor
chemical_list: D017471:Receptors, Interferon; D000096743:Interferon gamma Receptor; C086185:IFNGR2 protein, human