Susceptibility to tuberculosis genetically determined

The X-chromosome has a gene that influences the likelihood of contracting tuberculosis.  This accounts for part of the difference in susceptibility between men and women and between different population groups,  according to an article by researchers from Leiden University Medical Center (LUMC), the Radboud University Nijmegen and institutes in Singapore and Indonesia, in the online journal PLoS Genetics of 10 October.

The likelihood of contracting pulmonary tuberculosis is partly determined by which variant of the toll-like receptor 8 (TLR8) gene a person has.  Like the other toll-like receptors, TLR8 is probably involved in the recognition of pathogens and the activation of the immune system. The exact role of the gene is not yet fully understood. 

Image: The tuberculosis bacillum

More common in men

It is interesting that the gene which has now been identified is on the X chromosome.  Women have two X chromosomes, whereas men have only one.  Women are therefore twice as likely as men to have an effective version of the gene.  This may explain why tuberculosis (TBC) is more common in men than in women.
 
In both men and women, the risk of pulmonary tuberculosis seems to depend on which variant(s) of TLR8 they have.  Researcher Prof. Tom Ottenhoff from the LUMC: ‘Men with the version of the gene which exhibits the highest risk were twice as likely to suffer from TBC as the average.  A different variant of this gene seems to protect men against TBC: carriers had only half the normal risk of contracting TBC.  We observed the same trend in women.' The findings of this research are reinforced by a second study, among the population of Russia, which confirmed the link between TLR8 and TBC.

Photo: Prof. Tom Ottenhoff from the LUMC: ‘Men with the most risk-related version of the gene were twice as likely to suffer from TBC.’

Racial differences

The researchers not only examined the DNA of their test subjects, they also selected 18 genes which are known to be involved in inherited immunity. These genes were examined in a group of 750 Indonesian test subjects.  Half the test subjects had pulmonary tuberculosis, a common form of contagious TBC. 'They clearly had different variants of TLR8 from the other half of the test subjects, who were infected but did not have the illness,' according to Ottenhoff. 'In addition, it appeared that the expression of the TLR 8 protein was raised during illness and during an infection emulated in cell cultures in the lab. This indicates that the gene plays a role in TBC infections.' The researchers found no clear link for the other 17 genes examined.  
 
The variation in TLR8 which has now been discovered goes part way to explaining why the tuberculosis bacterium causes some people to become ill, but not others.  This variation in TLR8 could also account for the racial differences in vulnerability to TBC. 'Particular tribes of Indians, for example, appear to be very susceptible to TBC,' explains Ottenhoff. 'It may be that the variant of TLR8 which causes this susceptibility is more common in these tribes than in others.'

More genes

Only 5 to 10 per cent of people contract TBC following infection with the tuberculosis bacterium  Mycobacterium tuberculosis. This is the reason for the long-held assumption that there are genetic differences between people which determine their sensitivity to TBC. 'The gene which has now been identified goes some way to explaining this susceptibility, but there are certainly many more genes which interact to influence the risk of TBC.  This will have to be verified by further research,' comments Ottenhoff.