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Tuberculosis

Updated 25 March 2020

OPINION | Our genes can make us more susceptible to TB

Sadly, as we mark another World Tuberculosis Day (24 March), TB still remains a global public health problem with an estimated 25% of the global population infected with Mtb.

Classified as an epidemic by the World Health Organisation, tuberculosis (TB) is a devastating infectious disease that remains one of the top ten causes of death worldwide. Although TB has plagued human populations for millennia, it was not until 24 March 1882 that Robert Kock presented evidence identifying the bacterium Mycobacterium tuberculosis (Mtb), which spreads through the air, as the causative agent. In the ensuing decades, the tuberculin skin test, the Bacillus Calmette Guérin (BCG) vaccine and a number of anti-tuberculosis medications were developed, all of which promised to eradicate the disease.

Sadly, as we mark another World Tuberculosis Day (24 March), TB still remains a global public health problem with an estimated 25% of the global population being infected with Mtb. In 2018 alone, an estimated 10.8 million people fell sick with TB of whom approximately 1.4 million succumbed. Infection with Mtb does not always result in active disease for the majority of individuals. Instead, infection and TB disease progression are likely multiphase processes to which environmental and human factors significantly contribute. We know from several lines of evidence that a person’s genetic make-up (DNA) plays a crucial role in TB susceptibility. 

For example, a classic epidemiological study on the premature death of adoptees in Denmark suggested that the genetic contribution to infectious disease in general is greater than that for cancer or heart disease. A rare genetic syndrome called Mendelian Susceptibility to Mycobacterial Disease has helped to identify several genes that makes people susceptible to TB. Individuals born with this syndrome are very susceptible to Mtb, environmental mycobacteria (not usually disease-causing in humans), the BCG vaccine and bacteria that cause food poisoning (Salmonella).

Genetic studies identified mutations in the genes that code for proteins (interferon-gamma, interleukin 12, and interleukin 23) secreted by immune cells that plays a very important role in immunity against infections. This is now a well-studied pathway in TB susceptibility. What is proving to be extremely challenging, however, is identifying the genes and specific changes in these genes (genetic variants) that contribute to TB susceptibility in the general population. 

Various phases during TB infection

For the past three decades, several genetic association studies of TB susceptibility have been done to uncover the contributing genes and genetic variants in the general population. In such studies, the frequency of genetic variants in people with the disease is compared to that of people without the disease. Unfortunately, the results of these studies have been underwhelming and while there have been investigations linking certain genes and genetic variants to TB susceptibility, replicating those findings in independent studies has proven difficult. There could be several reasons for this. 

One reason is the way in which diseased or unaffected individuals were defined by initial studies. Since there are various phases during TB infection and the actual disease, these definitions are critical when designing genetic studies. For example, some of these studies grouped Mtb-infected, but not diseased individuals together with persons who have never been exposed to the bacterium. These unexposed individuals may very well have carried the disease-causing susceptibility variants, but because they were never exposed did not have the chance to become infected. Therefore clear definitions of healthy, infection and disease categories are now a priority for genetic association studies.

As an example, recently there has been a focus on people (called “resisters”) who despite being highly exposed to the bacterium, seemingly do not get infected as defined by current tests of Mtb infection. These tests rely on the part of our immune system that recognises previous infections. The one is administered as an injection of tuberculin (a protein extracted from Mtb) into the skin of the lower arm and the reaction is measured after two to three days, while the other is a newer test where blood is stimulated with Mtb proteins and the amount of interferon-gamma released is measured.

Again there may be complexity in how we define these “resisters”: some of these individuals may not get infected at all, while others get infected but manage to clear the bacteria before the adaptive immune system has time to react or perhaps these individuals' adaptive immune system responds in a different way. Even so, the idea is that “resisters” might carry genes and genetic variants that protect them against infection with Mtb and these findings could in future help to develop ways to prevent infection in the general population.

Sex-specific effects

In some cases, the genetic cause of disease might be specific to one population and not important in other groups. This then makes it impossible for follow-up studies to find the same genetic cause in another population. Although health disparities between populations exist and contribute to increased TB incidence in some communities, there is evidence that populations who have been exposed to Mtb for longer than others may have through natural selection developed resistance against the disease. 

There are also sex-specific effects: men are twice as likely to develop TB than women. Of course, there are behavioural, hormonal, and even socioeconomic differences between men and women; these differences, however, do not fully explain this bias towards male infection. The role of genetic factors, specifically the genes of the X chromosome, influencing the differences in TB susceptibility between males and females is now recognised as an important contributor to the higher proportion of male infections.

Unfortunately, some of the earlier genetic studies did not take this into account and analysed male and female samples together. This means that genetic variants that are protective in females, but detrimental in males could not be detected. This discovery means that new TB susceptibility variants have been found.

The human genetics field is progressing at enormous speed and technological developments have made it possible to investigate complete human genomes at an affordable price. Recently the South African Medical Research Council completed the first whole-genome sequence of a human in South Africa. These innovations will also impact on studies of genetic susceptibility to TB and will help to tease out how our genes contribute to Mtb infection and disease.

*Profs Marlo Möller and Craig Kinnear are affiliated with the DSI-NRF Centre of Excellence for Biomedical Tuberculosis Research in the Faculty of Medicine and Health Science at Stellenbosch University as well as the South African Medical Research Council (SAMRC) Centre for Tuberculosis Research and SAMRC Genomics Centre.

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