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Interferon- and Host Susceptibility to Tuberculosis

Kintampo, Ghana

It has been estimated that only 10% of persons infected with Mycobacterium tuberculosis will ever develop clinical disease (1). Convincing evidence exists from twin studies that host genetic factors are important in determining who will succumb to the pathogen and who will not (2, 3). Substantial efforts have been made to attempt to identify host genes involved in tuberculosis susceptibility in the hope that this will provide new insight into the host–pathogen relationship. Much of the focus of this work has been on genes in the interferon- pathway.

Mendelian susceptibility to atypical mycobacterial infections (MIM 209950) can be caused by genetic mutations in one of five genes in the interferon- pathway. Patients inheriting these conditions suffer recurrent infections with mycobacteria that are usually nonpathogenic, such as Mycobacterium bovis bacille Calmette-Guerin, M. avium, M. kansasii, M. fortuitum, M. chelonae, and M. smegmatis (4). The immune deficiency is a relatively specific one. Although recurrent salmonella infections also occur, there does not seem to be increased susceptibility to a wider range of pathogens (4).

The first gene defect identified in the interferon- pathway was autosomal recessive interferon- receptor ligand-binding chain deficiency (5, 6). Subsequently, patients were described as those who had complete interferon- receptor signal transduction chain deficiency (7), autosomal-dominant partial deficiency of the interferon- receptor ligand-binding chain (8), and autosomal-dominant partial deficiency of signal transducer and activator of transcription 1 (a cell surface transmitter in the interferon- pathway) (9). Interleukin-12 stimulates interferon- production by lymphocytes. Autosomal-recessive mutations in the gene encoding the interleukin-12 p40 subunit (10) and recessive mutations in the gene encoding the interleukin-12 receptor ß1 subunit have also been reported (11, 12). Interestingly, there are as yet no published reports of patients with increased susceptibility to atypical mycobacteria due to deleterious mutations in the interferon- gene itself.

Mendelian susceptibility to mycobacterial infections is a group of extremely rare conditions. Therefore, the vast majority of persons who develop tuberculosis are not affected by one of the currently recognized interferon- pathway gene defects. The link between these gene mutations and host susceptibility to mycobacterial infections, however, has raised the possibility that common gene variants in one or more interferon- pathway genes could account for some of the host variation in tuberculosis susceptibility. In this issue of AJRCCM (pp. 970–975), López-Maderuelo and coworkers (13) suggest that this is likely to be the case as a common interferon- gene variant is found to be associated with tuberculosis in a European population (13).

López-Maderuelo and colleagues (13) typed one single nucleotide polymorphism in the first intron of the interferon- gene (+874 T/A) and a further polymorphism in the 5' promoter region of the interleukin-10 gene (-1082 G/A). Their sample consisted of 113 patients with culture-proven pulmonary tuberculosis, 125 tuberculin-positive contacts, 82 tuberculin-negative contacts, and 100 unrelated blood donors. No association was found between tuberculosis and the frequency of the interleukin-10 gene variant. Patients with tuberculosis, however, had 3.75 times the odds of possessing the interferon- +874 AA genotype as compared with the healthy control individuals in a multivariable logistic regression analysis. The authors also measured purified protein derivative–induced production of interferon- by peripheral blood mononuclear cells from the patients with tuberculosis, their contacts, and healthy blood donors. Those with the homozygous +874 AA genotype had significantly lower interferon- production than those with the other genotypes. Among the patients with tuberculosis, this difference remained significant 6 months after completion of tuberculosis therapy.

Could the authors' results be explained by unidentified confounding factors or by chance? Ethnic group stratification is the most likely confounding factor to produce spurious associations in a genetic study. The ideal method of eliminating this is to perform family-based association studies where the frequencies of inherited and noninherited parental alleles are compared. This is not always feasible in studies of adult diseases because parental DNA is often not obtainable. López-Maderuelo and colleagues (13) used a single ethnic group, Spanish whites, to reduce the risk of confounding by unrecognized ethnic group differences, but this does not entirely eliminate the possibility. Their use of tuberculosis-contacts among the control groups, however, also helps minimize the risk of ethnic group stratification, so it is unlikely that their results are explained by confounding. Although chance is always a possible explanation for associations between gene variants and disease, this is unlikely to be the explanation in this study for four reasons. First, there were good prior reasons to suspect interferon- gene variants may influence tuberculosis susceptibility. Second, the results are supported by those of a previous study on a smaller group of Sicilian patients with tuberculosis (14). Third, López-Maderuelo and colleagues' finding that peripheral blood mononuclear cells from those with the homozygous AA genotype produce less interferon- than those with the TT and TA genotypes adds biological plausibility to the observed association with tuberculosis. Finally, decreased interferon- production has previously been found in patients with tuberculosis compared with healthy control individuals (15). It is therefore very likely that the association between the +874 T/A interferon- gene variant and tuberculosis is true in this population.

Does this article explain host genetic variability in susceptibility to tuberculosis? As López-Maderuelo and colleagues correctly state there are likely to be many more genes involved in host susceptibility to tuberculosis. It is important to confirm the interferon- association in another white population and to determine whether the association is also present in other ethnic groups. The interferon- association with tuberculosis is of comparable size with that previously reported for the natural resistance–associated macrophage protein gene (16). The population impact of these gene variants is relatively small and can only explain a small percentage of the total familial clustering effect seen in tuberculosis. Therefore, it is likely that there are many more genes involved in tuberculosis susceptibility. Other genes in the interferon- pathway will be useful candidates for polymorphisms that may influence host susceptibility to this important disease.

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