Génétique humaine de la tuberculose |
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Authors: | J. El Baghdadi A.-V. Grant A. Sabri S. El Azbaoui H. Zaidi A. Cobat E. Schurr S. Boisson-Dupuis J.-L. Casanova L. Abel |
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Affiliation: | 1. Unité de génétique, hôpital militaire d’instruction Mohammed V, Hay Riad, Rabat, Maroc;2. Inserm U980, laboratoire de génétique humaine des maladies infectieuses, faculté de médecine Necker – Paris Descartes, institut national de la santé et de la recherche médicale U980, branche Necker, 156, rue de Vaugirard, 75015 Paris, France;3. Université Paris Descartes Sorbonne Paris Cité, institut Imagine, Paris, France;4. McGill centre for the study of host resistance, the research institute of the McGill university health centre, Montreal, PQ, Canada;5. Saint-Giles laboratory of human genetics of infectious diseases, the Rockefeller university, Rockefeller branch, New York, États-Unis;6. Unité d’immuno-hématologie pédiatrique, hôpital Necker, AP–HP, Paris, France |
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Abstract: | Tuberculosis (TB), caused by Mycobacterium tuberculosis, remains a major public health problem worldwide, resulting in 8.7 million new cases and 1.4 million deaths each year. One third of the world's population is exposed to M. tuberculosis and, after exposure, most, but not all, individuals become infected. Among infected subjects, only a minority (∼10%) will eventually develop clinical disease, which is typically either a primary, often extra-pulmonary, TB in children, or a reactivation, pulmonary TB in adults. Considerable genetic epidemiological evidence has accumulated to support a major role for human genetic factors in the development of TB. Numerous association studies with various candidate genes have been conducted in pulmonary TB, with very few consistent results. Recent genome-wide association studies revealed only a modest role for two inter-genic polymorphisms. However, a first major locus for pulmonary TB was mapped to chromosome 8q12-q13 in a Moroccan population after a genome-wide linkage screen. Using a similar strategy, two other major loci controlling TB infection were recently identified. While the precise identification of these major genes is ongoing, the other fascinating observation of these last years was the demonstration that TB can also reflect a Mendelian predisposition. Following the findings obtained in the syndrome of Mendelian susceptibility to mycobacterial diseases, several children with complete IL-12Rβ1 deficiency, were found to have severe TB as their sole phenotype. Overall, these recent findings provide the proof of concept that the human genetics of TB involves a continuous spectrum from Mendelian to complex predisposition with intermediate major gene involvement. The understanding of the molecular genetic basis of TB will have fundamental immunological and medical implications, in particular for the development of new vaccines and treatments. |
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Keywords: | Tuberculose Mycobacté rie Variant gé né tique Polymorphisme Gé né tique humaine Susceptibilité /ré sistance É tude d&rsquo association Analyse de liaison gé né tique Pré disposition mendé lienne |
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