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J Infect Dis. 2016 Apr 1;213(7):1173-9. doi: 10.1093/infdis/jiv757. Epub 2015 Dec 21.

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.

Author information

1
Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163 Paris Descartes University, Sorbonne Paris Cité, Imagine Institute.
2
Centre de Lutte Anti-Tuberculeuse, Centre Hospitalier Intercommunal de Créteil.
3
Centre National de Génotypage, Institut de Génomique, CEA, Evry, France.
4
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.
5
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.
6
McGill International TB Centre, McGill University, Montreal, Canada Department of Human Genetics, McGill University, Montreal, Canada Department of Medicine, McGill University, Montreal, Canada.
7
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.
8
Pediatric Pneumology Unit, Necker Hospital for Sick Children, AP-HP, Paris.

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.

KEYWORDS:

genetic control; genetic linkage analysis; interferon gamma release assays; mycobacteria; tuberculosis

PMID:
26690346
PMCID:
PMC4779307
DOI:
10.1093/infdis/jiv757
[Indexed for MEDLINE]
Free PMC Article

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