Current findings, challenges and novel approaches in human genetic susceptibility to tuberculosis

Summary

The evidence for a human genetic component in susceptibility to tuberculosis (TB) is incontrovertible. Quite apart from studies of rare disease events illustrating the importance of key genes in humans and animals, TB at the population level is also influenced by the genetics of the host. Heritability of disease concordance and immune responses to mycobacterial antigens has been clearly shown, and ranges up to 71%. Linkage studies, designed to identify major susceptibility genes in a disease, have produced a number of candidate loci but few, except for regions on chromosome 5p15, 20p and 20q, have been replicated. The region on 5p15 regulates the intensity of the response to the tuberculin skin test, and another locus on 11p14 appears to control resistance to the bacterium. In addition, numerous genes and pathways have been implicated in candidate gene association studies, with validation of polymorphisms in IFNG, NRAMP1, and NOS2A and equivocal results for IL10, CCL2, DC-SIGN, P2RX7, VDR, TLR2, TLR9 and SP110. Other more recently researched candidate genes such as TNFRSF1B remain to be validated, preferably in meta-analyses. New approaches have provided early evidence for the importance of gene–gene interactions in regulating resistance to disease, and also the prospect that applying host genetics in the field of vaccinomics could lead to a more targeted approach in designing interventions to aid the human immune system in combating mycobacteria. Genome-wide association studies and admixture mapping are approaches that remain to be applied to TB, and it is not clear, as is the case with other complex diseases, how much of the heritability of the TB susceptibility phenotype will be determined by multiple genes of small effect versus rare variants with disproportionately large effects.

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.