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Recherche des facteurs génétiques contrôlant la réponse à l’infection par Mycobacterium tuberculosis et le développement d’une tuberculose maladie

Abstract : Tuberculosis remains a major public health concern, with approximately 10.4 million new cases and 1.8 million deaths due to the disease in 2015 according to WHO. While an estimated one third of the world population is estimated to be infected with Mycobacterium tuberculosis, only about 10% of infected individuals go on to develop a clinical disease. Among them, half will declare the disease in the 2 years following infection, which is generally considered as primary tuberculosis. The other patients will develop the disease more distant in time of primary infection, sometimes several tens of years latter; these are classical pulmonary forms in adults. In humans, the role of genetic factors have been demonstrated in the development of active tuberculosis, in pulmonary forms as in disseminated forms in childhood, et also in the control of M.tuberculosis infection. Nevertheless, most of these genetic factors remain to identify. The first aim of my PhD was to identify genetic factors controlling in vitro interferon-gamma production phenotypes (IGRA) after exposure to M.tuberculosis in a sample of 590 subjects who were in contact with a proven tuberculous patient in Val-de-Marne, Paris suburbs, and in a second time, to try to replicate the findings in a south African familial sample where the tuberculosis is highly endemic. For this purpose, I first performed genome-wide genetic linkage analysis for several quantitative IGRA phenotypes. They led to identify 2 major loci (p<10-4) replicated in South-Africa and linked to the interferon-gamma production induced by live BCG for the first one, and for the second one, by the specific part of the ESAT6 antigen of M.tuberculosis (absent from most of environmental mycobacteria and from BCG), independently of intrinsic ability to respond to mycobacteria. The second step was an association study in the identified linkage regions. A variant associated to the specific ESAT6 phenotype was found (p<10-5), which was significantly contributing to the linkage peak (p<0.001) and previously reported as eQTL of ZXDC gene. The second objective of my PhD was the identification of rare genetic variants underlying the development of pulmonary tuberculosis in infected individuals. To this end, I compared exome data from 120 tuberculous patients and 136 infected individuals without any clinical symptoms. All of them were from Morocco. This study resulted in the lighting of BTNL2 gene, very closed to the HLA region, in which around 10% of patients had a rare loss of function variant whereas the controls didn’t have any.
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Fabienne Jabot-Hanin. Recherche des facteurs génétiques contrôlant la réponse à l’infection par Mycobacterium tuberculosis et le développement d’une tuberculose maladie. Génétique humaine. Université Sorbonne Paris Cité, 2017. Français. ⟨NNT : 2017USPCB253⟩. ⟨tel-02117942⟩



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