title: Differential combination of cytokine and interferon- γ +874 T/A polymorphisms determines disease severity in pulmonary tuberculosis.
abstract: BACKGROUND
  Mycobacterium tuberculosis infects nearly 1/3 of the world population and this reservoir forms the largest pool from which new cases arise. Among the cytokines, IFN-γ is a key determinant in protection against tuberculosis. Single nucleotide polymorphisms (SNPs) in IFN-γ gene (+874 T/A) which determine TT high ((hi)), AA low ((lo)) and TA intermediate ((int)) responder phenotypes have shown variable associations with tuberculosis disease outcome in different ethnic populations. The objective of the current study was to analyze IFN-γ gene combinations with other IFN-γ regulating cytokine genes (IL-10, TNF -α, IL-6) to see the effect of gene- combinations on disease severity outcome in pulmonary tuberculosis.
  
  
  RESULTS
  Study groups comprised of pulmonary TB patients stratified according to lung tissue involvement into mild (Pmd = 74) or advance (Pad = 23) lung disease and compared with healthy controls (TBNA = 166). Genotype analysis was carried out using amplification refractory mutation system-PCR (ARMS-PCR). IFN-γ gene (+874 T/A) functional SNP combinations in TNFα (-308 G/A), IL-10 (-1082 A/G) and IL-6 (-174 G/C) were analyzed. Single gene analysis (Pearson χ²) showed a dominant association of IFN-γ TT (hi) genotype (p = 0.001) and T allele (p = 0.001) with mild disease. IFN-γ(lo) -IL-10(lo) genotype combination was associated with advanced disease (p = 0.002). IFN-γ(hi) -IL-6(hi) combination was associated with mild disease (p = 0.0005) while IFN-γ(lo) -IL-6(int) was associated with protection against both forms of pulmonary disease (p = 0.002).
  
  
  CONCLUSIONS
  Our results show that a limited number of IFN-γ gene combinations with other cytokine functional SNPs determine the outcome of disease severity in tuberculosis.
authors.affiliation: Department of Pathology and Microbiology, Aga Khan University, Karachi, Pakistan.
authors.forename: Ambreen
authors.initials: A
authors.lastname: Ansari
authors.forename: Zahra
authors.initials: Z
authors.lastname: Hasan
authors.forename: Ghaffar
authors.initials: G
authors.lastname: Dawood
authors.forename: Rabia
authors.initials: R
authors.lastname: Hussain
mesh_terms: D000328:Adult; D003710:Demography; D005260:Female; D005787:Gene Frequency / Q000235:genetics; D020022:Genetic Predisposition to Disease; D006801:Humans; D007371:Interferon-gamma / Q000235:genetics*; D016753:Interleukin-10 / Q000235:genetics*; D015850:Interleukin-6 / Q000235:genetics*; D008297:Male; D010154:Pakistan; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012720:Severity of Illness Index; D014019:Tissue Donors; D014397:Tuberculosis, Pulmonary / Q000235:genetics* / Q000276:immunology
chemical_list: C508609:IL10 protein, human; C508600:IL6 protein, human; D015850:Interleukin-6; D016753:Interleukin-10; D007371:Interferon-gamma