title: Major Loci on Chromosomes 8q and 3q Control Interferon γ Production Triggered by Bacillus Calmette-Guerin and 6-kDa Early Secretory Antigen Target, Respectively, in Various Populations.
abstract: BACKGROUND
  Interferon γ (IFN-γ) release assays (IGRAs) provide an in vitro measurement of antimycobacterial immunity that is widely used as a test for Mycobacterium tuberculosis infection. IGRA outcomes are highly heritable in various populations, but the nature of the involved genetic factors remains unknown.
  
  
  METHODS
  We conducted a genome-wide linkage analysis of IGRA phenotypes in families from a tuberculosis household contact study in France and a replication study in families from South Africa to confirm the loci identified.
  
  
  RESULTS
  We identified a major locus on chromosome 8q controlling IFN-γ production in response to stimulation with live bacillus Calmette-Guerin (BCG; LOD score, 3.81; P = 1.40 × 10(-5)). We also detected a second locus, on chromosome 3q, that controlled IFN-γ levels in response to stimulation with 6-kDa early secretory antigen target, when accounting for the IFN-γ production shared with that induced by BCG (LOD score, 3.72; P = 1.8 × 10(-5)). Both loci were replicated in South African families, where tuberculosis is hyperendemic. These loci differ from those previously identified as controlling the response to the tuberculin skin test (TST1 and TST2) and the production of TNF-α (TNF1).
  
  
  CONCLUSIONS
  The identification of 2 new linkage signals in populations of various ethnic origins living in different M. tuberculosis exposure settings provides new clues about the genetic control of human antimycobacterial immunity.
authors.affiliation: Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163 Paris Descartes University, Sorbonne Paris Cité, Imagine Institute.
authors.forename: Fabienne
authors.initials: F
authors.lastname: Jabot-Hanin
authors.affiliation: Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163 Paris Descartes University, Sorbonne Paris Cité, Imagine Institute.
authors.forename: Aurélie
authors.initials: A
authors.lastname: Cobat
authors.affiliation: Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163 Paris Descartes University, Sorbonne Paris Cité, Imagine Institute.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Feinberg
authors.affiliation: Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163 Paris Descartes University, Sorbonne Paris Cité, Imagine Institute.
authors.forename: Ghislain
authors.initials: G
authors.lastname: Grange
authors.affiliation: Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163 Paris Descartes University, Sorbonne Paris Cité, Imagine Institute.
authors.forename: Natascha
authors.initials: N
authors.lastname: Remus
authors.affiliation: Centre de Lutte Anti-Tuberculeuse, Centre Hospitalier Intercommunal de Créteil.
authors.forename: Christine
authors.initials: C
authors.lastname: Poirier
authors.affiliation: Centre National de Génotypage, Institut de Génomique, CEA, Evry, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Boland-Auge
authors.affiliation: Centre National de Génotypage, Institut de Génomique, CEA, Evry, France.
authors.forename: Céline
authors.initials: C
authors.lastname: Besse
authors.affiliation: Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163 Paris Descartes University, Sorbonne Paris Cité, Imagine Institute.
authors.forename: Jacinta
authors.initials: J
authors.lastname: Bustamante
authors.affiliation: Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163 Paris Descartes University, Sorbonne Paris Cité, Imagine Institute St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Boisson-Dupuis
authors.affiliation: Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163 Paris Descartes University, Sorbonne Paris Cité, Imagine Institute Pediatric Hematology-Immunology Unit, Necker Hospital for Sick Children, AP-HP, Paris St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University Howard Hughes Medical Institute, New York, New York.
authors.forename: Jean-Laurent
authors.initials: JL
authors.lastname: Casanova
authors.affiliation: McGill International TB Centre, McGill University, Montreal, Canada Department of Human Genetics, McGill University, Montreal, Canada Department of Medicine, McGill University, Montreal, Canada.
authors.forename: Erwin
authors.initials: E
authors.lastname: Schurr
authors.affiliation: Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163 Paris Descartes University, Sorbonne Paris Cité, Imagine Institute St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Alcaïs
authors.affiliation: Division of Molecular Biology and Human Genetics, MRC Centre for Molecular and Cellular Biology and DST/NRF Centre of Excellence for Biomedical TB Research, Faculty of Health Sciences, Stellenbosch University, Tygerberg, South Africa.
authors.forename: Eileen G
authors.initials: EG
authors.lastname: Hoal
authors.affiliation: Pediatric Pneumology Unit, Necker Hospital for Sick Children, AP-HP, Paris.
authors.forename: Christophe
authors.initials: C
authors.lastname: Delacourt
authors.affiliation: Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163 Paris Descartes University, Sorbonne Paris Cité, Imagine Institute St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University.
authors.forename: Laurent
authors.initials: L
authors.lastname: Abel
mesh_terms: D000942:Antigens, Bacterial / Q000276:immunology*; D001426:Bacterial Proteins / Q000276:immunology*; D002893:Chromosomes, Human, Pair 3; D002898:Chromosomes, Human, Pair 8; D015331:Cohort Studies; D005260:Female; D005602:France; D015964:Gene Expression Regulation, Bacterial / Q000276:immunology*; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism*; D008297:Male; D009163:Mycobacterium bovis / Q000276:immunology*; D010641:Phenotype; D011446:Prospective Studies; D013019:South Africa; D014376:Tuberculosis / Q000235:genetics / Q000276:immunology
chemical_list: D000942:Antigens, Bacterial; D001426:Bacterial Proteins; C093276:ESAT-6 protein, Mycobacterium tuberculosis; D007371:Interferon-gamma
keywords: genetic control; genetic linkage analysis; interferon gamma release assays; mycobacteria; tuberculosis