No association between interferon-  receptor-1 gene polymorphism and pulmonary tuberculosis in a Gambian population sample

Abstract

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, ...

Linkage and association analysis of candidate genes for TB and TNFα cytokine expression: evidence for association with IFNGR1, IL-10, and TNF receptor 1 genes

“…Association between a SNP in IFNGR1 and disease caused by specifically M. tuberculosis was recently reported in a Gambian population (Cooke et al 2006), though previous analyses of microsatellites within IFNGR1 were inconsistent (Awomoyi et al 2004;Fraser et al 2003). Our analysis independently confirms that of Cooke and colleagues who found the CC genotype at the -56 SNP (rs2234711) to be associated with increased risk for TB disease.…”

Association of IFN-γ and P2X7 Receptor Gene Polymorphisms in Susceptibility to Tuberculosis Among Iranian Patients

“…On the contrary to our results, Varahram et al, did not fi nd any signifi cant association between IFN-γR1-611 SNP and susceptibility to TB among Iranian studied cases [14]. Also, few studies declines the correlation of IFN-γR1 polymorphism with M. tuberculosis infection [18,19]. At present, we have no explanation for such discrepancy, but these observations may outline the alternative pathways for enhancing host immune response against mycobacterial infections.…”

Lack of association between interferon‐gamma receptor‐1 polymorphism and pulmonary TB in Iranian population sample

“…In a research conducted recently by Awomoyi et al, regarding interferon gamma receptor-1 gene polymorphism; 16 despite a sample size of 340 TB patients with an equal number in the control group, still significant difference could not be detected between the two groups. This finding was similar to ours.…”

“…However, no significant relation was detected. Basically, our study was based on that fact that both the researches that were performed by Awomoyi 16 Although previous studies had shown that locus 395 was a genetic predisposition factor, but it had not been evaluated individually. In other words, different parts of the gene in the intron, extron and promoter regions had been studied in this research as well as in the last two researches.…”

“…Actually, our investigation was a supplementary one for the two of such studies present in the world. In the two studies conducted by Awomoyi 16 and Fraser, 17 at least 10 different parts of interferon gamma receptor-1 gene was studied. However, no significant relation was detected.…”