Polymorphism in the Interferon‐γ Receptor‐1 Gene and Susceptibility to Pulmonary Tuberculosis in The Gambia

The interferon-γ receptor-1 gene (IFNGR1), which encodes the ligand-binding chain of the IFN-γ receptor complex, was the first human mycobacterial susceptibility gene to be identified (MIM #107470) [1, 2]. All IFNGR1 mutations identified to date occur within rare families and mostly predispose to infection with less virulent mycobacterial species [3]. However, there have been reports of Mycobacterium tuberculosis infection in IFNGR1-deficient patients [4], and the correlation between the severity of the IFNGR1 mutation and clinical outcome raises the hypothesis that more subtle variation in IFNGR1 might influence susceptibility to tuberculosis (TB) in an outbred population [5]. A study recently published in the Scandinavian Journal of Immunology presented evidence for an association between variation in IFNGR1 and susceptibility to pulmonary TB in a Croatian population sample [6]. One allele of a polymorphic microsatellite was associated with protection from disease, while a number of alleles showed a trend towards association with the disease. Interestingly, this study also reports an increased frequency of homozygosity at this locus in TB cases. We too have investigated the role of this microsatellite in TB, and present data from a large case-control study undertaken in a Gambian population (Table 1), described in more detail elsewhere [7]. We did not find any association between variants of the microsatellite and TB in this African population. Also, the overall frequency of homozygotes was similar in the case and control groups. Conflicting conclusions are common in genetic association studies [8], and there are a number of possible explanations for this discrepancy. Firstly, the epidemiology of TB is very different in the two countries, and although both studies focus on pulmonary TB, there may be phenotypic differences such that they are not directly comparable. Secondly, the studies have been conducted in genetically different populations, and the relative contribution of specific genes to a given phenotype may vary between populations. The differences between the two populations considered here are highlighted by the differences in allele frequencies between the Croatian and the Gambian samples. Thirdly, different polymorphisms within the same gene may be associated with disease in different populations because the polymorphism studied is not itself functional (this is the case for microsatellites generally), but is in linkage disequilibrium (LD) with a functional variant. As patterns of LD vary considerably between genetically different groups, associations will also vary [9]. Finally, it has been reported that the magnitude of effect detected differs significantly in large versus small studies, with larger studies yielding more conservative results [8]. Given the relatively small Croatian sample size and the fact that the cases and controls were not matched for sex (cases were 70.8% male compared to 17.6% in the control group) or age (54.8 years versus 40 years), it is also possible the associations between alleles of the IFNGR1 microsatellite and TB in a Croatian population sample have arisen by chance, and further studies to replicate the findings would be valuable.