1% of cases of tuberculosis in Europe would be because of a specific genetic predisposition

Tuberculosis is an infectious disease which affects 10.4 million people worldwide and causes 1.7 million deaths. It develops after mycobacterial infection - Mycobacterium tuberculosis. Only about 10% of infected people develop tuberculosis. The Inserm teams of the Imagine Institute, at Necker-Enfants malades university hospital AP-HP of Dr. Laurent Abel and Prof. Jean-Laurent Casanova, also head of a team at Rockefeller University in New York, therefore went to the heart of the DNA, in our genes, to find out if sensitivity or resistance to this disease could be explained.

Published on 09.05.2019

Research Acceleration

  • Immunology
  • Genetics

When genetics highlights infectious diseases...

“We recently discovered that homozygous individuals, i.e. with two copies of a quite common mutation of the TYK2 gene, the one inherited from the mother and the one from the father, were more vulnerable to the bacteria at the origin of tuberculosis” recalls Laurent Abel. The frequency of these homozygous individuals is around 1/600 in Europe, and 1/5,000 in most other regions outside South-East Asia, where it is very rare.

Using a British cohort of over 500,000 people, called UK Biobank, researchers have been able to explore the connections between tuberculosis and this gene in more detail. “This biobank is a great source of information since it provides the medical history and genetic data of 500,000 British volunteers aged 40 to 69 years and recruited between 2006 and 2010” enthused Gaspard Kerner, PhD student in the team. They identified 620 people who had tuberculosis in this cohort.

The frequency of the homozygosity of the TYK2 gene is 1% in people with tuberculosis against 0.2% in others. “In this homozygous population, 1% of cases of tuberculosis can therefore be attributed to the alteration of both copies of the TYK2 genes” sums up Prof. Jean-Laurent Casanova. In this case, genetics seems to explain why an infectious disease develops in some people and not in others.

...and opens up avenues for predictive medicine

This discovery could have several consequences in terms of predictive medicine. In the future, we cannot look for this homozygosity in people who are considering a trip to tuberculosis endemic areas, to Africa, South-East Asia or Latin America. As long as people stay in Europe where tuberculosis is practically eradicated, the risk is low, but in a region where it is very common, the risk is consistent with that.

At the same time, uncovering the mechanisms involved in patients with a susceptibility to tuberculosis offers therapeutic prospects. The presence of this homozygous mutation of the TYK2 gene blocks the signaling pathways involving interleukin IL-23, for which the purpose is to produce interferon gamma, which has an antimycobacterial action. In homozygous individuals with tuberculosis, the interferon gamma injection could then be considered to overcome this deficiency in addition to the classic anti-TB drugs.

Finally, it has also been shown that homozygosity for this TYK2 mutation has a protective, mirrored role against some inflammatory diseases such as rheumatoid arthritis or Crohn’s disease. This result led to studies for the development of new anti-TYK2 treatments in these diseases. If these treatments were to emerge, then administration precautions similar to those for anti-TNF treatments would have to be taken to avoid side effects associated with the increased risk of tuberculosis in these patients.

In conclusion, Laurent Abel recalls that in the last 2,000 years, it is estimated that tuberculosis would have caused about 1 billion deaths in Europe and that as result 10 million of these victims could be due to homozygosity for this variant of TYK2.


Learning more about tuberculosis

Today, tuberculosis is one of the 3 major diseases in the world, with 10.4 million new cases and 1.7 million deaths per year. In some countries an increased incidence has been observed in the last few years, particularly because of the greater risk of HIV-infected patients developing this infection. In addition, more and more cases of resistance to antibiotic treatments are also reported, which makes the search for therapeutic alternatives even more crucial. And they will emerge from a better knowledge of the disease mechanisms.


Homozygosity for TYK2 P1104A underlies tuberculosis in about 1% of patients in a cohort of European ancestry

Gaspard Kerner, Noe Ramirez-Alejo, Yoann Seeleuthner, Rui Yang, Masato Ogishi, Aurélie Cobat, Etienne Patin, Lluis Quintana-Murci, Stéphanie Boisson-Dupuis, Jean-Laurent Casanova, and Laurent Abel

PNAS first published May 8, 2019 https://doi.org/10.1073/pnas.1903561116