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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.    Methods and Findings  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 χ 2 ) 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).    Conclusion  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.

Differential Combination of Cytokine and Interferon- γ +874 T/A Polymorphisms Determines Disease Severity in Pulmonary Tuberculosis