Dense genotyping of immune-related loci implicates host responses to microbial exposure in Behçet's disease susceptibility.

Autor: Takeuchi M; Inflammatory Disease Section, National Human Genome Research Institute, US National Institutes of Health, Bethesda, Maryland, USA.; Department of Ophthalmology and Visual Science, Yokohama City University Graduate School of Medicine, Yokohama, Japan., Mizuki N; Department of Ophthalmology and Visual Science, Yokohama City University Graduate School of Medicine, Yokohama, Japan., Meguro A; Department of Ophthalmology and Visual Science, Yokohama City University Graduate School of Medicine, Yokohama, Japan., Ombrello MJ; Translational Genetics and Genomics Unit, National Institute of Arthritis and Musculoskeletal and Skin Diseases, US National Institutes of Health, Bethesda, Maryland, USA., Kirino Y; Department of Stem Cell and Immune Regulation, Yokohama City University Graduate School of Medicine, Yokohama, Japan., Satorius C; Inflammatory Disease Section, National Human Genome Research Institute, US National Institutes of Health, Bethesda, Maryland, USA., Le J; Inflammatory Disease Section, National Human Genome Research Institute, US National Institutes of Health, Bethesda, Maryland, USA., Blake M; Translational Immunology Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases, US National Institutes of Health, Bethesda, Maryland, USA., Erer B; Inflammatory Disease Section, National Human Genome Research Institute, US National Institutes of Health, Bethesda, Maryland, USA., Kawagoe T; Department of Ophthalmology and Visual Science, Yokohama City University Graduate School of Medicine, Yokohama, Japan., Ustek D; Department of Genetics, Institute for Experimental Medicine, Istanbul University, Istanbul, Turkey., Tugal-Tutkun I; Department of Ophthalmology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey., Seyahi E; Department of Internal Medicine, Division of Rheumatology, Cerrahpasş a Faculty of Medicine, Istanbul University, Istanbul, Turkey., Ozyazgan Y; Department of Ophthalmology, Cerrahpaşa Faculty of Medicine, Istanbul University, Istanbul, Turkey., Sousa I; Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal.; Instituto Gulbenkian de Ciência, Oeiras, Portugal., Davatchi F; Rheumatology Research Center, Tehran University of Medical Sciences, Tehran, Iran., Francisco V; Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal.; Instituto Gulbenkian de Ciência, Oeiras, Portugal., Shahram F; Rheumatology Research Center, Tehran University of Medical Sciences, Tehran, Iran., Abdollahi BS; Rheumatology Research Center, Tehran University of Medical Sciences, Tehran, Iran., Nadji A; Rheumatology Research Center, Tehran University of Medical Sciences, Tehran, Iran., Shafiee NM; Rheumatology Research Center, Tehran University of Medical Sciences, Tehran, Iran., Ghaderibarmi F; Rheumatology Research Center, Tehran University of Medical Sciences, Tehran, Iran., Ohno S; Department of Ophthalmology, Hokkaido University Graduate School of Medicine, Sapporo, Japan., Ueda A; Department of Stem Cell and Immune Regulation, Yokohama City University Graduate School of Medicine, Yokohama, Japan., Ishigatsubo Y; Department of Stem Cell and Immune Regulation, Yokohama City University Graduate School of Medicine, Yokohama, Japan., Gadina M; Translational Immunology Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases, US National Institutes of Health, Bethesda, Maryland, USA., Oliveira SA; Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal.; Instituto Gulbenkian de Ciência, Oeiras, Portugal., Gül A; Department of Internal Medicine, Division of Rheumatology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey., Kastner DL; Inflammatory Disease Section, National Human Genome Research Institute, US National Institutes of Health, Bethesda, Maryland, USA., Remmers EF; Inflammatory Disease Section, National Human Genome Research Institute, US National Institutes of Health, Bethesda, Maryland, USA.
Jazyk: angličtina
Zdroj: Nature genetics [Nat Genet] 2017 Mar; Vol. 49 (3), pp. 438-443. Date of Electronic Publication: 2017 Feb 06.
DOI: 10.1038/ng.3786
Abstrakt: We analyzed 1,900 Turkish Behçet's disease cases and 1,779 controls genotyped with the Immunochip. The most significantly associated SNP was rs1050502, a tag SNP for HLA-B*51. In the Turkish discovery set, we identified three new risk loci, IL1A-IL1B, IRF8, and CEBPB-PTPN1, with genome-wide significance (P < 5 × 10 -8 ) by direct genotyping and ADO-EGR2 by imputation. We replicated the ADO-EGR2, IRF8, and CEBPB-PTPN1 loci by genotyping 969 Iranian cases and 826 controls. Imputed data in 608 Japanese cases and 737 controls further replicated ADO-EGR2 and IRF8, and meta-analysis additionally identified RIPK2 and LACC1. The disease-associated allele of rs4402765, the lead marker at IL1A-IL1B, was associated with both decreased IL-1α and increased IL-1β production. ABO non-secretor genotypes for two ancestry-specific FUT2 SNPs showed strong disease association (P = 5.89 × 10 -15 ). Our findings extend the list of susceptibility genes shared with Crohn's disease and leprosy and implicate mucosal factors and the innate immune response to microbial exposure in Behçet's disease susceptibility.
Databáze: MEDLINE
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