Distilled database identifies genetic links to rare diseases
24 March 2023
Published online 21 December 2018
Analysis of modern-day and ancient human genes sheds new light on tuberculosis susceptibility.
An international team of more than 60 scientists reports compelling evidence that tuberculosis (TB) has a strong genetic basis.
As the most lethal of infectious diseases, TB caused an estimated 1.6 million deaths in 2017.
Close to a quarter of the world’s human population is infected with Mycobacterium tuberculosis, but less than ten percent go on to develop clinical TB. Although a genetic link has long been thought to account for this variability, only rare mutations had so far been associated with the disease.
“We have now discovered the first common variant responsible for monogenic, or single-gene, predisposition to tuberculosis,” says lead author Stéphanie Boisson-Dupuis of the Rockefeller University in New York.
Researchers, which included scientists in Qatar and Morocco, compared the genomes of 454 patients with TB, 463 with Mendelian susceptibility to mycobacterial disease (MSMD, a rare syndrome known to make people susceptible to infections by low-virulence mycobacteria that do not cause tuberculosis), and a control group of 2,835 people, as well as 2,504 individuals from the 1000 Genomes Project. They found that a variant in the gene coding for the TYK2 enzyme (TYK2 P1104A) strongly predisposed homozygous carriers — people with two copies of the mutated allele — to develop TB.
The variant is relatively frequent in Europe, where it is found in one in 600 people. It occurs in one in 1,000 to one in 10,000 people in other regions, apart from East Asia, where it is almost absent.
This means in Europe, TYK2 P1104A homozygosity is a genetic disorder occurring almost as frequently as the iron disorder haemochromatosis, and is more common than cystic fibrosis.
To investigate broader patterns of human disease over time, the researchers also examined ancient DNA dating back to the Neolithic era. They observed that the variant has likely been “a major genetic determinant of primary TB during the course of human history.”
In addition, the study suggests that people who are homozygous for the variant are prone to TB due to insufficient interferon-gamma (IFN-γ) production; a crucial step in immunological defense.
There are several clinical implications, as these patients could benefit from IFN-γ injections, which are now widely available. Also, genetic testing for people travelling to TB-endemic areas or working in contact with TB patients could help evaluate whether they are susceptible to the disease.
“We will continue searching for other common monogenic causes of TB,” says Boisson-Dupuis. “Our goal is to decipher human predisposition and resistance to TB to provide foundations for personalised treatment. New avenues are needed to respond to the emergence of multidrug-resistant strains.”
Boisson-Dupuis, S. et al. Tuberculosis and impaired IL-23–dependent IFN-γ immunity in humans homozygous for a common TYK2 missense variant. Sci. Immunol. 3, eaau8714 (2018).