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Background: Tuberculosis (TB) is a major global cause of mortality and morbidity, and host genetic factors influence disease susceptibility. Interferon-c mediates immunity to mycobacteria and rare mutations in the interferon-c receptor-1 gene (IFNGR1) result in increased susceptibility to mycobacterial infection, including TB, in affected families. The role of genetic variation in IFNGR1 in susceptibility to common mycobacterial diseases such as pulmonary TB in outbred populations has not previously been investigated. Methods: The association between IFNGR1 and susceptibility to pulmonary TB was investigated in a Gambian adult population sample using a case-control study design. The coding and promoter regions of IFNGR1 were sequenced in 32 patients with pulmonary TB, and the frequencies of six common IFNGR1 polymorphisms were determined using PCR based methods in 320 smear positive TB cases and 320 matched controls. Haplotypes were estimated from the genotype data using the expectation-maximisation algorithm.Results: There was no association between the IFNGR1 variants studied and TB in this Gambian population sample. Three common haplotypes were identified within the study population, none of which was associated with TB. Conclusions: These data represent an important negative finding and suggest that, while IFNGR1 is implicated in rare Mendelian susceptibility to mycobacterial disease, the common variants studied here do not have a major influence on susceptibility to pulmonary TB in The Gambian population. and signal transducer and activator of transcription-1 (MIM #600555) 9 also result in increased susceptibility to mycobacterial infection. Several other IFNGR1 mutations have since been identified in patients with MSMI, the majority of which result either in complete absence of surface expression of the protein or expression of an abnormal protein that does not bind IFN-c signalling is completely abrogated and the clinical phenotype correspondingly severe, often resulting in death from disseminated infection at an early age. Other mutations, however, lead to the expression of a dysfunctional protein and impairment-but not complete abrogation-of IFN-c signalling. In this partial form of IFN-c receptor-1 deficiency the phenotype is less severe and patients respond to IFN-c treatment.10 Infection with virulent M tuberculosis has been reported in partial IFN-c receptor-1 deficiency. 11These observations suggest a spectrum in which disease severity correlates with the degree of functional impairment in the IFN-c receptor.Host genetic factors have an important role in the development of clinical disease following infection with M tuberculosis, but inheritance of TB susceptibility in the general population is non-Mendelian. The correlation between the molecular pathology, mycobacterial virulence, and clinical phenotype in inherited IFN-c receptor-1 deficiency suggests that more subtle variation in IFNGR1 could contribute to M tuberculosis disease susceptibility in an outbred population. To test this hypothesis, ...

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