TUBERCULOSIS: Human genetic susceptibility to Tuberculosis

30 July 2010
The infectious disease tuberculosis is still widespread and according to the World Health Organisation two billion people are infected with the causative bacillus Mycobacterium tuberculosis. One in ten individuals infected with the airborne bacterium will develop active tuberculosis in their lifetime, but human immunodeficiency virus (HIV) positive individuals are even more likely to progress to disease. Currently, more than one million deaths annually can be attributed to tuberculosis ( www.who.int/tb/en). Research have not yet revealed precisely why the majority of infected individuals never progress to active tuberculosis, but it is known that host genes, the environment and the bacterium may all contribute to the final outcome of infection.
Even before the advent of modern genetics and the discovery of M. tuberculosis, it was observed that there were differences in susceptibility to tuberculosis in diverse populations. After the inhabitants of the Qu’Appelle Indian Reservation originally came into contact with the bacterium almost 10% of the population died per annum, partly because they have not previously been exposed. After 40 years more than half of the families were eradicated, but the death rate had significantly declined to 0.2%. This decrease can be attributed to a strong selection against tuberculosis susceptibility genes [1]. An accident in Lübeck, Germany resulted in the inadvertent immunisation of 251 children with a virulent strain of M. tuberculosis and illustrated the wide range of responses in individuals exposed to the bacterium. Even though all the children received the same dose of bacteria, 47 showed no indication of disease, 127 had radiological signs of disease and 77 died [2]. More convincing evidence that implicate human genes in tuberculosis susceptibility has been provided by classical twin studies as well as animal models [3-8]. Heritability analyses for tuberculosis have resulted in estimates ranging from 28% to 71%, depending on the phenotype investigated [9-13].
To date several genetic studies have identified tuberculosis susceptibility loci and genes. These studies were either done in large families (linkage studies or family-based association studies) or in collections of unrelated tuberculosis cases and controls (population-based case-control association studies). Depending on the study, the discovery approach can be genome-wide or may target specific genes. The human leukocyte antigen (HLA), interferon gamma (IFNG) and the natural resistance associated macrophage protein 1 (NRAMP1) genes are the most frequently investigated candidates and have been studied in diverse populations. These genes have been comprehensively reviewed previously (Figure 1, [14-17]). One of the latest case-control association studies investigated the cytokine-inducible SRC homology (SH2) domain protein (CISH) gene in more than 2000 tuberculosis patients and controls from Malawi, Hong Kong and Gambia [18]. The study also included individuals with bacteremia and malaria from Kenya, Gambia and Vietnam, resulting in data from 8402 people from 7 different studies. Variants of CISH were associated with all the diseases studied, while the -292 polymorphism accounted for most of the association signal. A tuberculosis genome-wide association study, which allows the genotyping of the most frequent genetic polymorphisms in the genome, has been done by the Wellcome Trust Case-Control Consortium [19, 20].
A recent study [21] set out to find genetic variants controlling susceptibility to infection by studying about 400 children and young adults in 128 families in the Western Cape, where TB is highly endemic, by means of a genome-wide linkage search. Most of the subjects tested were likely to have been exposed to TB, but about 20% did not show delayed type hypersensitivity (DTH) in a skin antigen test, appearing to be naturally resistant to infection by M. tuberculosis. This strong resistance mapped to a 6-Mbp chromosome region, 11p14 (p = 1.5x10 -5) called TST1. The existence of a locus like this suggests that we could one day manipulate cellular mechanisms to achieve TB prevention - an important goal given the lack of an effective vaccine and the rise in drug-resistant strains. The second locus, in the 2.9-Mbp 5p15 region (p < 10 -5) called TST2, segregated with differing extents of TB skin test response or the intensity of T-cell-mediated DTH to tuberculin. These genetic factors might contribute to whether an infected individual keeps the bacterium dormant or develops the disease. The measurement of TST did not correlate with interferon-γ release, indicating that other pathways could be more important than this well-known cytokine. Fine mapping of the 5p15 region identified SLC6A3 as a promising candidate gene. This gene is a solute carrier (SLC) family member, which could influence granuloma responses to mycobacteria, and loss of the mouse SLC6A3 protein reduces DTH response to ovalbumin. This work resulted in the first genetic resistance factor for TB infection being reported. The study identified one major locus that determines innate resistance to M. tuberculosis infection in endemic areas and a second that controls the extent of that response via critical regulators of T-cell dependent DTH. These results indicate that one major genetic locus may control resistance to the pathogen in humans [21].
Tuberculosis has proven to be difficult (or even impossible) to eradicate, but the discovery of the genetic factors that underlie susceptibility to the disease may in the future be useful to determine treatment or to prevent infection and progression to active disease.
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