Keywords: tuberculosis, human susceptibility, virulence gene polymorphisms
Tuberculosis (TB) is a major public health problem that causes 2 million deaths each year globally. Current TB treatment programmes have a long duration and drug resistance to standard TB therapy continues to increase, particularly in eastern Europe. New preventive strategies and therapies are required.
The majority of people infected with Mycobacterium tuberculosis have the infection, while only a minority develop active TB; the reasons for this remain largely unknown. Genetic variation in both humans and M. tuberculosis, along with environmental factors, may influence the course of the disease. Identification of host and pathogen factors affecting susceptibility to the disease and its progression in humans is required.
To approach this problem, large, statistically powerful collections of samples from ethnically diverse TB patients and matched healthy controls combined with detailed clinical information are required.
The major aim of TB-EURO-GEN is to identify major pathogen-related factors such as host susceptibility genetic factors and how they interact and affect TB.
An existing collection of DNA extracts from TB patients and their corresponding TB DNA will be extended to establish the world’s largest resource of extracts from a population of TB patients with 5 000 ethnically matched healthy controls. The bank will comprise 5 000 host (human) DNA extracts paired with the DNA and cultures of the strain of M tuberculosis causing their disease.
A genome-wide scan to discover human genes predisposing to TB will be performed initially on 1 000 human DNA specimens resulting in the detection of 50 to 100 most-associated polymorphisms followed by a detection of these polymorphisms in the additional 4 000 samples and 2 000 samples from Ghana. Variants in human genes associated with TB susceptibility/resistance will be localised, and molecular mechanisms of this association will be studied.
TB strains from a population in Russia will be extensively characterised using various sets of genetic markers, and polymorphisms in genes putatively associated with virulence will be detected. Analysis of the host-pathogen interaction will allow identification of the mycobacterial genes affecting the course of TB, the innate response to TB and the outcome at a genetic level.
The results of genome-wide association (GWA) scans and TB genotyping will be published on the project website and made available to the scientific community for long-term use.
TB-EURO-GEN's approach will hopefully lead to the discovery of genes involved in susceptibility/resistance to TB in humans. Deciphering effects of the natural variation between M. tuberculosis strains will help to identify virulence factors, and influence prognosis for TB patients. These results will improve the understanding of TB pathogenesis and may have an impact on TB vaccine research, opening new targets for TB prevention. Discovery of interaction between polymorphisms of the pathogen’s virulence and host resistance factors will lead to a more directed treatment and prevention strategy for TB control.
Prof. Francis Drobniewski
Barts and the London School of Medicine
|Official Address||Other Information|
|1||Dr Sergey Nejentsev||University of Cambridge
|2||Prof. Sven Hoffner||Karolinska Institute
|3||Prof. Rolf Horstmann||Bernhard Nocht Institute of Tropical Medicine
|4||Prof. Peter Nuernberg||University of Cologne,