M. Respiratoires, [. Cdtmr-]-of-hay-mohammadi-), I. Sentissi, F. Bourkadi, E. Ranaivoson et al., El Bordi for recruitment of PTB-affected subjects We thank N. El Amraoui and M. Hakam (National Blood Transfusion Center) for recruiting healthy donors We thank B. Rakotondrasoa and D. Rakotomanajanahary for recruiting PTB-affected subjects and family members in Madagascar We thank Ramarinarisoa, and the staff at the Dispensaire Anti-tuberculeux de Tananarive, as well as Professors H. Raobijaona and N. Ravelomanana and the staff of the pediatric units of Antananarivo hospitals, for assistance. We thank the Centre National de Génotypage for carrying out the genotyping for the initial fine-mapping screen. This work was supported by grants from the French National Agency for Research, European Commission (HEALTH-F3- Global tuberculosis control, European Research Council Pasteur Institute of Paris (Progamme Transversal de Recherche PTR202), Bill and Melinda Gates Foundation, St. Giles Foundation, 2008.

J. Casanova, A. , and L. , : The Human Model, Annual Review of Immunology, vol.20, issue.1, pp.581-620, 2002.
DOI : 10.1146/annurev.immunol.20.081501.125851

J. D. Ernst, The immunological life cycle of tuberculosis, Nature Reviews Immunology, vol.208, issue.8, pp.581-591, 2012.
DOI : 10.1038/nri3259

A. Cobat, C. J. Gallant, L. Simkin, G. F. Black, K. Stanley et al., High Heritability of Antimycobacterial Immunity in an Area of Hyperendemicity for Tuberculosis Disease, The Journal of Infectious Diseases, vol.201, issue.1, pp.15-19, 2010.
DOI : 10.1086/648611

A. Cobat, L. F. Barrera, H. Henao, P. Arbeláez, L. Abel et al., Tuberculin Skin Test Reactivity Is Dependent on Host Genetic Background in Colombian Tuberculosis Household Contacts, Clinical Infectious Diseases, vol.54, issue.7, pp.968-971, 2012.
DOI : 10.1093/cid/cir972

A. Jepson, A. Fowler, W. Banya, M. Singh, S. Bennett et al., Genetic Regulation of Acquired Immune Responses to Antigens of Mycobacterium tuberculosis: a Study of Twins in West Africa, Infection and Immunity, vol.69, issue.6, pp.3989-3994, 2001.
DOI : 10.1128/IAI.69.6.3989-3994.2001

R. L. Sepulveda, I. M. Heiba, C. Navarrete, R. C. Elston, B. Gonzalez et al., Tuberculin reactivity after newborn BCG immunization in mono- and dizygotic twins, Tubercle and Lung Disease, vol.75, issue.2, pp.138-143, 1994.
DOI : 10.1016/0962-8479(94)90043-4

A. Cobat, C. J. Gallant, L. Simkin, G. F. Black, K. Stanley et al., Two loci control tuberculin skin test reactivity in an area hyperendemic for tuberculosis, The Journal of Experimental Medicine, vol.151, issue.12, pp.2583-2591, 2009.
DOI : 10.1084/jem.189.12.1863

M. Möller and E. G. Hoal, Current findings, challenges and novel approaches in human genetic susceptibility to tuberculosis, Tuberculosis, vol.90, issue.2, pp.71-83, 2010.
DOI : 10.1016/j.tube.2010.02.002

S. Boisson-dupuis, J. Baghdadi, N. Parvaneh, A. Bousfiha, J. Bustamante et al., IL-12Rb1 deficiency in two of fifty children with severe tuberculosis from Iran, Morocco, and Turkey, PLoS ONE, vol.6, 2011.

A. Alca?¨salca?¨s, C. Fieschi, L. Abel, and J. Casanova, Tuberculosis in children and adults, The Journal of Experimental Medicine, vol.54, issue.12, pp.1617-1621, 2005.
DOI : 10.1086/338625

O. Filipe-santos, J. Bustamante, A. Chapgier, G. Vogt, L. De-beaucoudrey et al., Inborn errors of IL-12/23- and IFN-??-mediated immunity: molecular, cellular, and clinical features, Seminars in Immunology, vol.18, issue.6, pp.347-361, 2006.
DOI : 10.1016/j.smim.2006.07.010

J. Bustamante, A. A. Arias, G. Vogt, C. Picard, L. B. Galicia et al., Germline CYBB mutations that selectively affect macrophages in kindreds with X-linked predisposition to tuberculous mycobacterial disease, Nature Immunology, vol.67, issue.3, pp.213-221, 2011.
DOI : 10.1182/blood.V99.8.2653

S. Hambleton, S. Salem, J. Bustamante, V. Bigley, S. Boisson-dupuis et al., Mutations and Human Dendritic-Cell Immunodeficiency, New England Journal of Medicine, vol.365, issue.2, pp.127-138, 2011.
DOI : 10.1056/NEJMoa1100066

D. Bogunovic, M. Byun, L. A. Durfee, A. Abhyankar, O. Sanal et al., Mycobacterial Disease and Impaired IFN-?? Immunity in Humans with Inherited ISG15 Deficiency, Science, vol.337, issue.6102, pp.1684-1688, 2012.
DOI : 10.1126/science.1224026

F. Altare, A. Durandy, D. Lammas, J. F. Emile, S. Lamhamedi et al., Impairment of Mycobacterial Immunity in Human Interleukin-12 Receptor Deficiency, Science, vol.280, issue.5368, pp.1432-1435, 1998.
DOI : 10.1126/science.280.5368.1432

C. Fieschi, S. Dupuis, E. Catherinot, J. Feinberg, J. Bustamante et al., Low Penetrance, Broad Resistance, and Favorable Outcome of Interleukin 12 Receptor ??1 Deficiency, The Journal of Experimental Medicine, vol.2, issue.4, pp.527-535, 2003.
DOI : 10.1007/s004310050583

L. De-beaucoudrey, A. Samarina, J. Bustamante, A. Cobat, S. Boisson-dupuis et al., Revisiting Human IL-12R??1 Deficiency, Medicine, vol.89, issue.6, pp.381-402, 2010.
DOI : 10.1097/MD.0b013e3181fdd832

P. Tabarsi, M. Marjani, N. Mansouri, P. Farnia, S. Boisson-dupuis et al., Lethal Tuberculosis in a Previously Healthy Adult with IL-12 Receptor Deficiency, Journal of Clinical Immunology, vol.16, issue.1, 2011.
DOI : 10.1007/s10875-011-9523-9

F. Altare, A. Ensser, A. Breiman, J. Reichenbach, J. E. Baghdadi et al., Interleukin???12 Receptor ??1 Deficiency in a Patient with Abdominal Tuberculosis, The Journal of Infectious Diseases, vol.184, issue.2, pp.231-236, 2001.
DOI : 10.1086/321999

I. Caragol, M. Raspall, C. Fieschi, J. Feinberg, M. N. Larrosa et al., Clinical Tuberculosis in 2 of 3 Siblings with Interleukin-12 Receptor ??1 Deficiency, Clinical Infectious Diseases, vol.37, issue.2, pp.302-306, 2003.
DOI : 10.1086/375587

G. W. Comstock, Tuberculosis in twins: A re-analysis of the Prophit survey, Am. Rev. Respir. Dis, vol.117, pp.621-624, 1978.

E. A. Van-der-eijk, E. Van-de-vosse, J. P. Vandenbroucke, and J. T. Van-dissel, Heredity versus Environment in Tuberculosis in Twins, American Journal of Respiratory and Critical Care Medicine, vol.176, issue.12, pp.1281-1288, 2007.
DOI : 10.1164/rccm.200703-435OC

R. R. Puffer, Familial Susceptibility to Tuberculosis: Its Importance as a Public Health Problem, 1944.
DOI : 10.4159/harvard.9780674428720

R. J. Dubos, D. , and J. , The White Plague: Tuberculosis, 1987.

A. E. Goldfeld, J. C. Delgado, S. Thim, M. V. Bozon, A. M. Uglialoro et al., Association of an HLA-DQ Allele With Clinical Tuberculosis, JAMA, vol.279, issue.3, pp.226-228, 1998.
DOI : 10.1001/jama.279.3.226

R. Bellamy, C. Ruwende, T. Corrah, K. P. Mcadam, H. C. Whittle et al., Variations in the NRAMP1 gene and susceptibility to tuberculosis in West Africans, N. Engl, 1998.

C. M. Greenwood, T. M. Fujiwara, L. J. Boothroyd, M. A. Miller, D. Frappier et al., Linkage of Tuberculosis to Chromosome 2q35 Loci, Including NRAMP1, in a Large Aboriginal Canadian Family, The American Journal of Human Genetics, vol.67, issue.2, pp.405-416, 2000.
DOI : 10.1086/303012

W. Zhang, L. Shao, X. Weng, Z. Hu, A. Jin et al., Variants of the Natural Resistance-Associated Macrophage Protein 1 Gene (NRAMP1) Are Associated with Severe Forms of Pulmonary Tuberculosis, Clinical Infectious Diseases, vol.40, issue.9, pp.1232-1236, 2005.
DOI : 10.1086/428726

M. P. Berry, C. M. Graham, F. W. Mcnab, Z. Xu, S. A. Bloch et al., An interferon-inducible neutrophil-driven blood transcriptional signature in human tuberculosis, Nature, vol.195, issue.7309, pp.973-977, 2010.
DOI : 10.1038/nature09247

T. Thye, F. O. Vannberg, S. H. Wong, E. Owusu-dabo, I. Osei et al., Genome-wide association analyses identifies a susceptibility locus for tuberculosis on chromosome 18q11.2, Nature Genetics, vol.5, issue.9, pp.739-741, 2010.
DOI : 10.1038/ng.639

T. Thye, E. Owusu-dabo, F. O. Vannberg, R. Van-crevel, J. Curtis et al., Common variants at 11p13 are associated with susceptibility to tuberculosis, Nature Genetics, vol.44, issue.3, pp.257-259, 2012.
DOI : 10.1016/j.tube.2004.09.011

I. Comas, J. Chakravartti, P. M. Small, J. Galagan, S. Niemann et al., Human T cell epitopes of Mycobacterium tuberculosis are evolutionarily hyperconserved, Nature Genetics, vol.1, issue.6, pp.498-503, 2010.
DOI : 10.1093/bioinformatics/bti403

J. E. Baghdadi, M. Orlova, A. Alter, B. Ranque, M. Chentoufi et al., An autosomal dominant major gene confers predisposition to pulmonary tuberculosis in adults, The Journal of Experimental Medicine, vol.58, issue.7, pp.1679-1684, 2006.
DOI : 10.1086/301958

M. T. Mira, A. Alca?¨salca?¨s, V. T. Nguyen, M. O. Moraes, D. Flumeri et al., Susceptibility to leprosy is associated with PARK2 and PACRG, Nature, vol.427, issue.6975, pp.636-640, 2004.
DOI : 10.1038/nature02326

A. Alca?¨salca?¨s, A. Alter, G. Antoni, M. Orlova, V. T. Nguyen et al., Stepwise replication identifies a low-producing lymphotoxin-?? allele as a major risk factor for early-onset leprosy, Nature Genetics, vol.63, issue.4, pp.517-522, 2007.
DOI : 10.1038/ng2000

A. Alter, N. T. Huong, M. Singh, M. Orlova, N. Van-thuc et al., Human Leukocyte Antigen Class I Region Single-Nucleotide Polymorphisms are Associated with Leprosy Susceptibility in Vietnam and India, Journal of Infectious Diseases, vol.203, issue.9, pp.1274-1281, 2011.
DOI : 10.1093/infdis/jir024

P. Kraft, Curses???Winner??s and Otherwise???in Genetic Epidemiology, Epidemiology, vol.19, issue.5, pp.649-651, 2008.
DOI : 10.1097/EDE.0b013e318181b865

A. D. Johnson, R. E. Handsaker, S. L. Pulit, M. M. Nizzari, C. J. O-'donnell et al., SNAP: a web-based tool for identification and annotation of proxy SNPs using HapMap, Bioinformatics, vol.24, issue.24, pp.2938-2939, 2008.
DOI : 10.1093/bioinformatics/btn564

J. F. Degner, A. A. Pai, R. Pique-regi, J. Veyrieras, D. J. Gaffney et al., DNase???I sensitivity QTLs are a major determinant of human expression variation, Nature, vol.4, issue.7385, pp.390-394, 2012.
DOI : 10.1038/nature10808

J. Ernst, P. Kheradpour, T. S. Mikkelsen, N. Shoresh, L. D. Ward et al., Mapping and analysis of chromatin state dynamics in nine human cell types, Nature, vol.125, issue.7345, pp.43-49, 2011.
DOI : 10.1038/nature09906

L. B. Barreiro, L. Tailleux, A. A. Pai, B. Gicquel, J. C. Marioni et al., Deciphering the genetic architecture of variation in the immune response to Mycobacterium tuberculosis infection, Proc. Natl. Acad. Sci. USA, pp.1204-1209, 2012.
DOI : 10.1073/pnas.1115761109

S. Tofanelli, S. Bertoncini, L. Castr?-`,-castr?-`, D. Luiselli, F. Calafell et al., On the Origins and Admixture of Malagasy: New Evidence from High-Resolution Analyses of Paternal and Maternal Lineages, Molecular Biology and Evolution, vol.26, issue.9, pp.2109-2124, 2009.
DOI : 10.1093/molbev/msp120

A. Alter, V. M. Fava, N. T. Huong, M. Singh, M. Orlova et al., Linkage disequilibrium pattern and age-at-diagnosis are critical for replicating genetic associations across ethnic groups in leprosy, Human Genetics, vol.361, issue.27, pp.107-116, 2013.
DOI : 10.1007/s00439-012-1227-6

A. Alca?¨salca?¨s, L. Quintana-murci, D. S. Thaler, E. Schurr, L. Abel et al., Life-threatening infectious diseases of childhood: single-gene inborn errors of immunity?, Annals of the New York Academy of Sciences, vol.43, issue.1, pp.18-33, 2010.
DOI : 10.1111/j.1749-6632.2010.05834.x

P. Aliahmad, A. Seksenyan, K. , and J. , The many roles of TOX in the immune system, Current Opinion in Immunology, vol.24, issue.2, pp.173-177, 2012.
DOI : 10.1016/j.coi.2011.12.001

P. Aliahmad, K. , and J. , Development of all CD4 T lineages requires nuclear factor TOX, The Journal of Experimental Medicine, vol.4, issue.1, pp.245-256, 2008.
DOI : 10.1016/S0092-8674(05)80068-6

A. M. Cooper, T cells in mycobacterial infection and disease, Current Opinion in Immunology, vol.21, issue.4, pp.378-384, 2009.
DOI : 10.1016/j.coi.2009.06.004

A. Montfort, B. De-badts, V. Douin-echinard, P. G. Martin, J. Iacovoni et al., FAN Stimulates TNF??-Induced Gene Expression, Leukocyte Recruitment, and Humoral Response, The Journal of Immunology, vol.183, issue.8, pp.5369-5378, 2009.
DOI : 10.4049/jimmunol.0803384

URL : https://hal.archives-ouvertes.fr/inserm-00473894