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      Genome-wide association analysis identifies new susceptibility loci for Behçet's disease and epistasis between HLA-B* 51 and ERAP1

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          Abstract

          Patients with Behçet's disease (BD) suffer from episodic inflammation often affecting the orogenital mucosa, skin, and eyes. To discover new BD-susceptibility loci, we performed a genome-wide association study (GWAS) of 779,465 SNPs with imputed genotypes in 1,209 Turkish BD patients and 1,278 controls. We identified novel associations at CCR1, STAT4, and KLRC4. Additionally, two SNPs in ERAP1, encoding ERAP1 p.Asp575Asn and p.Arg725Gln, recessively conferred disease risk. These findings replicated in 1,468 independent Turkish and/or 1,352 Japanese samples (combined meta-analysis p < 2 × 10 −9). We also found evidence for interaction between HLA-B*51 and ERAP1 (p = 9 × 10 −4). The CCR1 and STAT4 variants were associated with gene expression differences. Three risk loci shared with ankylosing spondylitis and psoriasis ( MHC-I, ERAP1, and IL23R, and the MHC-I-ERAP1 interaction), as well as two loci shared with inflammatory bowel disease ( IL23R and IL10) implicate shared pathogenic pathways in the spondyloarthritides and BD.

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          Most cited references24

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          Activation of NK cells and T cells by NKG2D, a receptor for stress-inducible MICA.

          Stress-inducible MICA, a distant homolog of major histocompatibility complex (MHC) class I, functions as an antigen for gammadelta T cells and is frequently expressed in epithelial tumors. A receptor for MICA was detected on most gammadelta T cells, CD8+ alphabeta T cells, and natural killer (NK) cells and was identified as NKG2D. Effector cells from all these subsets could be stimulated by ligation of NKG2D. Engagement of NKG2D activated cytolytic responses of gammadelta T cells and NK cells against transfectants and epithelial tumor cells expressing MICA. These results define an activating immunoreceptor-MHC ligand interaction that may promote antitumor NK and T cell responses.
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            Behçet's disease.

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              Roles of the NKG2D immunoreceptor and its ligands.

              According to present concepts, innate immunity is regulated by receptors that determine danger levels by responding to molecules that are associated with infection or cellular distress. NKG2D is, perhaps, the best characterized receptor that is associated with responses to cellular distress, defined as transformation, infection or cell stress. This review summarizes recent findings that concern NKG2D, its ligands, its signalling properties and its role in disease, and provides a framework for considering how the induction of immune responses can be regulated by cellular responses to injury.
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                Author and article information

                Contributors
                Journal
                9216904
                2419
                Nat Genet
                Nat. Genet.
                Nature genetics
                1061-4036
                1546-1718
                15 July 2013
                06 January 2013
                February 2013
                29 October 2013
                : 45
                : 2
                : 10.1038/ng.2520
                Affiliations
                [1 ]Inflammatory Disease Section, Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA
                [2 ]Department of Internal Medicine and Clinical Immunology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
                [3 ]Rheumatology, Clinical Immunology, and Allergy, Faculty of Medicine, University of Crete, Iraklion, Greece
                [4 ]Department of Ophthalmology and Visual Science, Yokohama City University Graduate School of Medicine, Yokohama, Japan
                [5 ]Istanbul Faculty of Medicine, Department of Ophthalmology, Istanbul University, Istanbul, Turkey
                [6 ]Cerrahpaşa Faculty of Medicine, Department of Internal Medicine, Division of Rheumatology, Istanbul University, Istanbul, Turkey
                [7 ]Cerrahpaşa Faculty of Medicine, Department of Ophthalmology, Istanbul University, Istanbul, Turkey
                [8 ]Istanbul Faculty of Medicine, Department of Internal Medicine, Division of Rheumatology, Istanbul University, Istanbul, Turkey
                [9 ]Department of Molecular Life Science, Division of Molecular Medical Science and Molecular Medicine, Tokai University School of Medicine, Isehara, Kanagawa, Japan
                [10 ]Department of Genetics, Institute for Experimental Medicine, Istanbul University, Istanbul, Turkey
                [11 ]Genometrics Section, Inherited Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Baltimore, Maryland, USA
                Author notes
                [*]

                These authors made equal contributions to the study.

                [†]

                These authors jointly directed this work.

                Article
                NIHMS474675
                10.1038/ng.2520
                3810947
                23291587
                cdcb6f6e-d2a0-4d28-b399-69588e247997

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                History
                Funding
                Funded by: National Human Genome Research Institute : NHGRI
                Award ID: Z99 HG999999 || HG
                Categories
                Article

                Genetics
                Genetics

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