CORDIS - Forschungsergebnisse der EU

Human Genetics of Tuberculosis

Final Report Summary - GENTB (Human Genetics of Tuberculosis)

The general objective of the ERC research program “GENTB” was to identify the genetic variants controlling the critical steps of the process from exposure to Mtb to the development of clinical tuberculosis (TB). The program focused on the investigation of 3 key tuberculosis (TB) phenotypes and the following results have been obtained:

1) Identification of the Mendelian mutations causing disseminated TB in children
From the 200 patients with severe TB who had whole exome sequencing (WES), we identified several patients carrying homozygous mutations in TYK2, including two who had severe TB as their sole clinical phenotype. We also found several TB patients who are homozygous for a rather common variant in TYK2 (P1104A), and we showed that P1104A is impairing the response to IL-23. We are currently testing the hypothesis that homozygosity for P1104A, estimated to affect more than 0.2% of the European population, may confer predisposition to TB in subjects living in endemic areas. We identified two siblings with complete autosomal recessive deficiency in ITK, encoding a protein involved in TCR signaling. We are conducting the functional experiments to assess the causal role of these mutations in the development of TB. Finally, out of our 200 children with severe TB, we selected for whole genome sequencing (WGS) 20 patients with no obvious mutations in coding regions by WES. In these patients, we are presently conducting an original analysis based on trios (including the two parents) which is especially powerful to identify de novo mutations.

2) Identification of the main variants involved in pulmonary TB (PTB)
We have identified TOX variants as associated with early-onset PTB, deciphering part of the genetic variation accounting for the PTB1 locus we previously mapped. Functional studies investigating the impact of the associated variant on TOX transcription in T-cells are ongoing. By an association study focusing on genes related to the IL-12/IFN-gamma pathway, we also identified variants in the STAT4 gene as associated with pulmonary TB. Our genome-wide association study (GWAS) conducted in Moroccan did not show any strong association of PTB with a common variant, consistent with the results recently published GWAS in other populations. These GWAS results provide a strong rationale to search for rare variants that could not be detected by GWAS. In this context we have completed WES in 120 PTB Moroccan patients with extreme phenotypes (familial cases, early onset, recurrent TB forms) and 135 Moroccan healthy infected controls, and the analysis of these data are ongoing using the methods we are developing in the laboratory. The identification of rare variants that may have a strong effect in the development of PTB will be a major breakthrough for the understanding of the pathogenesis of this disease.

3) Identification of the main variants involved in the control of infection by Mtb
We have pursued our studies in the already collected South African and French samples. We identified in the South African sample a major locus controlling the TNF production in the same region as the TST1 locus. We replicated in our French sample the mapping of the locus TST1 initially found in South Africa. We identified by linkage analysis two novel major loci in the French and the South African samples controlling the production of IFN-γ upon BCG, and ESAT6 stimulation, respectively. We are conducting refined association studies with the linkage regions to identify the genetic variants underlying these linkage peaks. We have completed the collection of subjects with sustained and recent exposure to M. tuberculosis both in Vietnam (1430 subjects in 450 families) and in Morocco (1900 independent subjects). These subjects who are contacts of an active case of PTB had both Tuberculin skin test (TST) and IGRA tests. We are conducting high throughput genotyping in a subset of these samples to search for variants involved in resistance to TB infection by linkage and GWAS approaches in these populations. We also performed WES in 15 highly resistor subjects (double negative while very high exposure to Mtb), to search for rare variants with a strong effect on resistance against TB infection. Overall, the objectives of our ongoing studies are not only to identify the genetic basis of resistance in these individuals, but also to teach us about the pathways that are capable of mediating innate resistance to TB infection, which are presently unknown.