title: No significant impact of IFN-γ pathway gene variants on tuberculosis susceptibility in a West African population.
abstract: The concept of interferon-γ (IFN-γ) having a central role in cell-mediated immune defence to Mycobacterium tuberculosis has long been proposed. Observations made through early candidate gene studies of constituents of the IFN-γ pathway have identified moderately associated variants associated with resistance or susceptibility to tuberculosis (TB). By analysing 20 major genes whose proteins contribute to IFN-γ signalling we have assessed a large fraction of the variability in genes that might contribute to susceptibility to TB. Genetic variants were identified by sequencing the promoter regions and all exons of IFNG, IFNGR1, IFNGR2, IRF1, IL12A, IL12B, IL12RB1, IL12RB2, IL23A, IL23R, IL27, EBI3, IL27RA, IL6ST, SOCS1, STAT1, STAT4, JAK2, TYK2 and TBX21 in 69 DNA samples from Ghana. In addition, we screened all exons of IFNGR1 in a Ghanaian study group comprising 1999 TB cases and 2589 controls by high-resolution melting point analysis. The fine-mapping approach allows for a detailed screening of all variants, common and rare. Statistical comparisons of cases and controls, however, did not yield significant results after correction for multiple testing with any of the 246 variants selected for genotyping in this investigation. Gene-wise haplotype tests and analysis of rare variants did not reveal any significant association with susceptibility to TB in our investigation as well. Although this analysis was applied on a plausible set of IFN-γ pathway genes in the largest African TB cohort available so far, the lack of significant results challenges the view that genetic marker of the IFN-γ pathway have an important impact on susceptibility to TB.
authors.affiliation: Department of Molecular Medicine, Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany.
authors.forename: Christian G
authors.initials: CG
authors.lastname: Meyer
authors.affiliation: Department of Molecular Medicine, Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany.
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Intemann
authors.affiliation: Department of Molecular Medicine, Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany.
authors.forename: Birgit
authors.initials: B
authors.lastname: Förster
authors.affiliation: Kumasi Centre for Collaborative Research in Tropical Medicine, Kumasi, Ghana.|Department of Community Health, College of Health Sciences, Kwame Nkrumah University of Science and Technology, Kumasi, Ghana.
authors.forename: Ellis
authors.initials: E
authors.lastname: Owusu-Dabo
authors.affiliation: Institute of Clinical Molecular Biology, Christian-Albrechts University Kiel, Kiel, Germany.
authors.forename: Andre
authors.initials: A
authors.lastname: Franke
authors.affiliation: Department of Molecular Medicine, Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany.
authors.forename: Rolf D
authors.initials: RD
authors.lastname: Horstmann
authors.affiliation: Department of Molecular Medicine, Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Thye
mesh_terms: D016022:Case-Control Studies; D005091:Exons; D056426:Genetic Loci; D005869:Ghana; D006801:Humans; D007371:Interferon-gamma / Q000235:genetics* / Q000378:metabolism; D007378:Interleukins / Q000235:genetics / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D017471:Receptors, Interferon / Q000235:genetics*; D050791:STAT Transcription Factors / Q000235:genetics / Q000378:metabolism; D014376:Tuberculosis / Q000235:genetics*; D000096743:Interferon gamma Receptor
chemical_list: D007371:Interferon-gamma; D007378:Interleukins; D017471:Receptors, Interferon; D050791:STAT Transcription Factors; D000096743:Interferon gamma Receptor