ReviewCurrent findings, challenges and novel approaches in human genetic susceptibility to tuberculosis
Introduction
The precise factors which interact to produce the scenario where only 10% of the population infected with Mycobacterium tuberculosis progress to active tuberculosis (TB), still remain largely uncharacterised. It is however known that the outcome of infection is modulated by the environment as well as bacterial and host genetic components. Many investigations have confirmed that genetic factors are involved in the disease, and these include adoption studies,1 twin studies,2, 3, 4, 5, 6, 7 genome-wide linkage8, 9 and population-based case–control association studies.10, 11, 12, 13
Initially, differences in susceptibility to TB were recognised through numerous observations, such as the wide range of responses seen after exposure to M. tuberculosis. This variable outcome of disease was emphasised in 1926 when 251 children were unintentionally immunised with the same dosage of a virulent TB strain. Of these infants, 47 did not develop clinical disease, 77 died and 127 had radiological signs of TB.14 It has also been noted that populations not previously exposed to the bacterium, such as the Qu'Appelle Indians,15 at first had a high annual TB mortality rate (10%), with a subsequent decrease in deaths (to 0.2%) after years of exposure and the eradication of half of the families. Motulsky suggested that this could have been due to strong selection against susceptibility genes for TB.15 Natural selection against susceptibility genes could also be the explanation for the seemingly different TB resistance of various populations: European individuals seem to be less susceptible to TB, possibly due to many centuries of contact with the bacterium in Europe which resulted in the selection of a more resistant population. In contrast, sub-Saharan Africa was only recently exposed to M. tuberculosis16 and modern-day TB treatment, although important for the affected individual, may hamper the selection against susceptibility variants in African populations. This difference between populations is not due to socio-economic factors alone, as first suggested by a study done in a USA nursing home. There, individuals with African ancestry were twice as likely to be infected with M. tuberculosis as individuals with European ancestry, even though they shared the same environment.17 A second study found that white US-born TB cases were more likely to be homeless than black US-born TB cases,18 which supported the initial finding that socio-economic circumstances are not the only factors that determine susceptibility. Even though it is close to impossible to control for the various environmental and social factors, it does appear that genetic factors in certain populations may contribute to susceptibility. Additional evidence that corroborated the idea that the human genome may be involved in TB susceptibility was the discovery of individuals with the rare human syndrome of Mendelian susceptibility to mycobacterial disease (MSMD). These individuals have mutations in genes of the interleukin-12/interleukin-23/interferon-γ (IFN-γ) axis, such as interleukin-12 (IL-12) beta, IL-12 receptor beta 1, IFN-γ receptor-1, IFN-γ receptor-2, NF kappa B essential modulator and signal transducer and activator of transcription-1, and have an increased susceptibility to even non-pathogenic mycobacteria.19, 20 The affected patients are also susceptible to M. tuberculosis and Salmonella, but not to other infections.
Given the complexity of TB disease, it can be assumed that susceptibility to M. tuberculosis has numerous genetic contributing factors (as well as social and environmental causes). Complex susceptibility to common infectious diseases such as TB is best explained by multiple genes targeted by weak purifying selection,21 which is the process resulting in stabilization of a particular trait. As a result a single method would not be able to identify all the genes involved22 and new approaches should be considered to overcome challenges in the investigation of TB susceptibility. The International HapMap Project identified over 3.1 million single nucleotide polymorphisms (SNP)s in only 270 individuals23 and more will be identified in the 1000 Genomes Project.24 In this review, we will consider the impact of this information on the field, and cover methods past, present and those planned for future studies.
Section snippets
Heritability analyses
Heritability analysis is a population genetics technique which measures the strength of a genetic influence on a particular phenotype. The method most commonly used to assess heritability is the twin study which compares monozygous twins (genetically identical) and dizygous twin pairs (who share approximately 50% of their genome25) to determine the degree of concordance for the phenotype of interest. Several twin studies in the twentieth century investigated TB heritability,2, 3, 4, 5, 6, 7 but
Linkage studies
Linkage and candidate gene association studies are currently two commonly used approaches to find the genetic loci that determine susceptibility to TB. Linkage studies can identify the estimated genetic location of TB susceptibility by testing for co-segregation between a genetic marker and a possible disease locus. Ideally, linkage studies should indicate major susceptibility genes in a disease. In the majority of genome scans, this has not been the case. A single linkage study investigating a
Association studies
The most widely employed approach to investigate TB susceptibility is arguably candidate gene association studies. They usually employ either a population-based case–control design or a family-based design. The population-based case–control association study investigates the relationship between TB and genetic markers by comparing genotype frequencies from unrelated patients and controls, while the family-based association study makes use of pedigrees and evaluates the transmission of a marker
Challenges in TB susceptibility studies
Although several heritability, linkage and candidate gene association studies have been done to investigate TB susceptibility, the exact causative genetic variants have not been characterised. This is in stark contrast with diseases such as Crohn's disease133 and type 1 diabetes.134 In fact, some are of the opinion that these studies have yielded mostly unsatisfactory results when applied to TB susceptibility.135, 136 Factors such as population stratification, inadequate sample size, incorrect
Gene interaction studies
Since TB is influenced by multiple genetic, environmental and bacterial factors, it is likely that gene interactions could determine the outcome of infection with M. tuberculosis. The idea that interactions play a far more important part in an individual's susceptibility to a complex disease than single polymorphisms alone has become increasingly well-accepted.139, 140, 141 Interaction studies are therefore a logical progression in our investigation of TB susceptibility. Statistical analyses of
Conclusion
The linkage and candidate gene association studies discussed here illustrate the involvement of genetic make-up in susceptibility to TB, but the specifics of the involvement of many genes is not yet clear, nor is the magnitude of their effect. Many exciting developments are currently underway to investigate complex infectious diseases such as TB. These include the expanding fields of interactomics, metabolomics and proteomics which can all, together with mathematical modelling, be incorporated
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