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      Meta-analysis identifies 29 additional ulcerative colitis risk loci, increasing the number of confirmed associations to 47

      research-article
      1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 2 , 3 , 9 , 10 , 2 , 3 , 11 , 12 , 1 , 11 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 5 , 23 , 1 , 24 , 25 , 23 , 26 , 16 , 27 , 28 , 29 , 30 , 31 , 2 , 32 , 20 , 33 , 34 , 35 , 36 , 36 , 7 , 29 , 37 , 30 , 1 , 38 , 39 , 40 , 41 , 42 , 43 , 10 , 44 , 45 , 38 , 46 , 47 , 14 , 48 , 49 , 50 , 51 , 52 , 53 , 47 , 30 , 54 , 55 , 56 , 7 , 57 , 58 , 59 , 60 , 23 , 48 , 61 , 23 , 39 , 40 , 30 , 62 , 63 , 64 , 65 , 65 , 58 , 66 , 66 , 67 , 68 , 56 , 69 , 29 , 46 , 60 , 14 , 70 , 15 , 71 , 4 , 47 , 72 , 5 , 73 , 74 , 1 , 8 , 10 , 37 , 13 , 75 , 76 , 11 , 77 ,   49 , 78 , 2 , 3
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          Abstract

          Genome-wide association studies (GWAS) and candidate gene studies in ulcerative colitis (UC) have identified 18 susceptibility loci. We conducted a meta-analysis of 6 UC GWAS, comprising 6,687 cases and 19,718 controls, and followed-up the top association signals in 9,628 cases and 12,917 controls. We identified 29 additional risk loci (P<5×10 -8), increasing the number of UC associated loci to 47. After annotating associated regions using GRAIL, eQTL data and correlations with non-synonymous SNPs, we identified many candidate genes providing potentially important insights into disease pathogenesis, including IL1R2, IL8RA/B, IL7R, IL12B, DAP, PRDM1, JAK2, IRF5, GNA12 and LSP1. The total number of confirmed inflammatory bowel disease (IBD) risk loci is now 99, including a minimum of 28 shared association signals between Crohn’s disease (CD) and UC.

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          Most cited references28

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          Interleukin-7 mediates the homeostasis of naïve and memory CD8 T cells in vivo.

          The naïve and memory T lymphocyte pools are maintained through poorly understood homeostatic mechanisms that may include signaling via cytokine receptors. We show that interleukin-7 (IL-7) plays multiple roles in regulating homeostasis of CD8+ T cells. We found that IL-7 was required for homeostatic expansion of naïve CD8+ and CD4+ T cells in lymphopenic hosts and for CD8+ T cell survival in normal hosts. In contrast, IL-7 was not necessary for growth of CD8+ T cells in response to a virus infection but was critical for generating T cell memory. Up-regulation of Bcl-2 in the absence of IL-7 signaling was impaired after activation in vivo. Homeostatic proliferation of memory cells was also partially dependent on IL-7. These results point to IL-7 as a pivotal cytokine in T cell homeostasis.
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            Induction and effector functions of T(H)17 cells.

            T helper (T(H)) cells constitute an important arm of the adaptive immune system because they coordinate defence against specific pathogens, and their unique cytokines and effector functions mediate different types of tissue inflammation. The recently discovered T(H)17 cells, the third subset of effector T helper cells, have been the subject of intense research aimed at understanding their role in immunity and disease. Here we review emerging data suggesting that T(H)17 cells have an important role in host defence against specific pathogens and are potent inducers of autoimmunity and tissue inflammation. In addition, the differentiation factors responsible for their generation have revealed an interesting reciprocal relationship with regulatory T (T(reg)) cells, which prevent tissue inflammation and mediate self-tolerance.
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              Genome-wide association identifies multiple ulcerative colitis susceptibility loci.

              Ulcerative colitis is a chronic, relapsing inflammatory condition of the gastrointestinal tract with a complex genetic and environmental etiology. In an effort to identify genetic variation underlying ulcerative colitis risk, we present two distinct genome-wide association studies of ulcerative colitis and their joint analysis with a previously published scan, comprising, in aggregate, 2,693 individuals with ulcerative colitis and 6,791 control subjects. Fifty-nine SNPs from 14 independent loci attained an association significance of P < 10(-5). Seven of these loci exceeded genome-wide significance (P < 5 x 10(-8)). After testing an independent cohort of 2,009 cases of ulcerative colitis and 1,580 controls, we identified 13 loci that were significantly associated with ulcerative colitis (P < 5 x 10(-8)), including the immunoglobulin receptor gene FCGR2A, 5p15, 2p16 and ORMDL3 (orosomucoid1-like 3). We confirmed association with 14 previously identified ulcerative colitis susceptibility loci, and an analysis of acknowledged Crohn's disease loci showed that roughly half of the known Crohn's disease associations are shared with ulcerative colitis. These data implicate approximately 30 loci in ulcerative colitis, thereby providing insight into disease pathogenesis.
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                Author and article information

                Journal
                9216904
                2419
                Nat Genet
                Nat. Genet.
                Nature genetics
                1061-4036
                1546-1718
                5 April 2011
                06 February 2011
                March 2011
                01 September 2011
                : 43
                : 3
                : 246-252
                Affiliations
                [1 ]Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK
                [2 ]Université de Montréal, Medicine, Montréal, Québec, Canada
                [3 ]Montreal Heart Institute, Research Center, Montréal, Québec, Canada
                [4 ]University of Edinburgh, Western General Hospital, Gastrointestinal Unit, Molecular Medicine Centre, Edinburgh, UK
                [5 ]Christian-Albrechts-University Kiel, Institute of Clinical Molecular Biology, Kiel, Germany
                [6 ]Karolinska Institute, Department of Biosciences and Nutrition, Stockholm, Sweden
                [7 ]Cedars-Sinai Medical Center, Inflammatory Bowel and Immunobiology Research Institute, Los Angeles, California, USA
                [8 ]Addenbrooke’s Hospital, University of Cambridge, Gastroenterology Research Unit, Cambridge, UK
                [9 ]The Children’s Hospital of Philadelphia, Center for Applied Genomics, Philadelphia, Pennsylvania, USA
                [10 ]IRCCS-CSS Hospital, Unit of Gastroenterology, San Giovanni Rotondo, Italy
                [11 ]University of Pittsburgh School of Medicine, Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, Pittsburgh, Pennsylvania, USA
                [12 ]Erasmus Hospital, Free University of Brussels, Department of Gastroenterology, Brussels, Belgium
                [13 ]The Children’s Hospital of Philadelphia, Department of Pediatrics, Center for Pediatric Inflammatory Bowel Disease, Philadelphia, Pennsylvania, USA
                [14 ]University of Otago, Department of Medicine, Christchurch, New Zealand
                [15 ]Johns Hopkins University School of Medicine, Meyeroff Inflammatory Bowel Disease Center, Dept. of Medicine, Baltimore, Maryland, USA
                [16 ]University Hospital Munich, Department of Medicine II, Munich, Germany
                [17 ]Universitätsmedizin Berlin, Department of Gastroenterology, Charité, Campus Mitte, Berlin, Germany
                [18 ]Université de Lille Department of Hepato-Gastroenterology, Lille, France
                [19 ]Cincinnati Children’s Hospital Medical Center, Pediatric Gastroenterology, Cincinnati, Ohio, USA
                [20 ]Ghent University Hospital, Department of Hepatology and Gastroenterology, Ghent, Belgium
                [21 ]Cedars-Sinai Medical Center, Department of Pediatrics, Los Angeles, California, USA
                [22 ]Torbay Hospital, Department of Gastroenterology, Torbay, Devon, UK
                [23 ]University Medical Center Groningen, Department of Genetics, Groningen, the Netherlands
                [24 ]Mater Health Services, Department of Gastroenterology, Brisbane, Australia
                [25 ]Erasmus Hospital, Free University of Brussels, Department of Gastroenterology, Brussels, Belgium
                [26 ]University of Liège, Department of Genetics, Faculty of Veterinary Medicine, Liège, Belgium
                [27 ]University of Washington, Cardiovascular Health Research Unit, Department of Internal Medicine, Seattle, Washington, USA
                [28 ]University of Utah School of Medicine, Department of Pediatrics, Salt Lake City, Utah, USA
                [29 ]Cedars-Sinai Medical Center, Medical Genetics Institute, Los Angeles, California, USA
                [30 ]Queensland Institute of Medical Research, Genetic Epidemiology, Brisbane, Australia
                [31 ]Université Paris Diderot & INSERM & Hopital Robert Debre APHP, Gastroenterology, Paris, France
                [32 ]Hôpital Maisonneuve-Rosemont, Dept of Gastroenterology, Montréal, Québec, Canada
                [33 ]The University of Western Australia, School of Medicine and Pharmacology, Fremantle, Australia
                [34 ]Université Paris Diderot, GETAID group, Paris, France
                [35 ]Tel Aviv University, Pediatric Gastroenterology Unit, Wolfson Medical Center and Sackler School of Medicine, Tel Aviv, Israel
                [36 ]Centre Hospitalier Universitaire Université de Liège, Division of Gastroenterology, Liège, Belgium
                [37 ]AOU Careggi, Unit of Gastroenterology SOD2, Florence, Italy
                [38 ]Ninewells Hospital and Medical School, Dept of Medicine, Dundee, UK
                [39 ]Massachusetts General Hospital, Harvard Medical School, Gastroenterology Unit Boston, Massachusetts, USA
                [40 ]Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, Massachusetts, USA
                [41 ]University of Manchester Department of Medical Genetics, Manchester, UK
                [42 ]University Medical Center Utrecht, Department of Medical Genetics, Utrecht, Netherlands
                [43 ]University of Florence, Institute of Human Genetics, Florence, Italy
                [44 ]University Hospital of Nancy, Department of Hepato-Gastroenterology, Vandoeuvre-lès-Nancy, France
                [45 ]Hospital Clínic de Barcelona, IDIBAPS, CIBERehd, Department of Gastroenterology, Barcelona, Spain
                [46 ]King’s College London School of Medicine, Guy’s Hospital, Department of Medical and Molecular Genetics, London, UK
                [47 ]Yale University, Section of Digestive Diseases, Department of Medicine, New Haven, Connecticut, USA
                [48 ]Royal Hospital for Sick Children, Paediatric Gastroenterology and Nutrition, Glasgow, UK
                [49 ]University Hospital Gasthuisberg, Division of Gastroenterology, Leuven, Belgium
                [50 ]Guy’s & St Thomas’ NHS Foundation Trust, St Thomas’ Hospital, Dept Gastroenterology, London, UK
                [51 ]Hospital Clínic de Barcelona, IDIBAPS, CIBERehd, Department of Gastroenterology, Barcelona, Spain
                [52 ]University of Chicago, Department of Health Studies, Chicago, Illinois, USA
                [53 ]University of Bern, Division of Gastroenterology, Inselspital, Bern, Switzerland
                [54 ]Genome Institute of Singapore, Human Genetics, Singapore
                [55 ]Institute for Human Genetics, University of California San Fransisco, San Francisco, California, USA
                [56 ]University of Toronto, Mount Sinai Hospital Inflammatory Bowel Disease Centre, Toronto, Ontario, Canada
                [57 ]Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, Department of Neurology, Utrecht, the Netherlands
                [58 ]Rikshospitalet University Hospital, Medical Department, Oslo, Norway
                [59 ]Leiden University Medical Center, Experimental Gastroenterology, Leiden, the Netherlands
                [60 ]The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada
                [61 ]Child Life and Health, University of Edinburgh, Scotland
                [62 ]Academic Medical Center, Department of Gastroenterology, Amsterdam, the Netherlands
                [63 ]Viborg Regional Hospital, Medical Department, Viborg, Denmark
                [64 ]Karolinska Institutet, Department of Clinical Science Intervention and Technology, Stockholm, Sweden
                [65 ]University of Athens, Department of Biology, School of Medicine, Athens, Greece
                [66 ]Kaunas University of medicine, Department of Gastroenterology, Kaunas, Lithuania
                [67 ]Newcastle University, Institute of Human Genetics, Newcastle upon Tyne, UK
                [68 ]Emory School of Medicine, Department of Genetics and Department of Pediatrics, Atlanta, Georgia, USA
                [69 ]Örebro University Hospital, Department of Medicine, Örebro, Sweden
                [70 ]Peninsula College of Medicine and Dentistry, Barrack Road, Exeter, UK
                [71 ]Inserm, U1019, Lille, France
                [72 ]Yale University, Department of Genetics, Yale School of Medicine, New Haven CT
                [73 ]Department for General Internal Medicine, Christian-Albrechts-University, Kiel, Germany
                [74 ]Massachusetts General Hospital, Harvard Medical School, Center for Human Genetic Research, Boston, Massachusetts, USA
                [75 ]Center for Applied Genomics, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
                [76 ]Queensland Institute of Medical Research, IBD Research Group, Brisbane, Australia
                [77 ]University of Pittsburgh Graduate School of Public Health, 130 Desoto Street, Pittsburgh, PA, USA
                [78 ]University Medical Center Groningen, Department of Gastroenterology, Groningen, the Netherlands
                Author notes
                Correspondence should be addressed to C.A.A. ( carl.anderson@ 123456sanger.ac.uk )or J.D.R. ( john.david.rioux@ 123456umontreal.ca )
                [79]

                These authors contributed equally to this work.

                [80]

                These authors contributed equally to this work.

                Article
                nihpa265993
                10.1038/ng.764
                3084597
                21297633
                96bc1f35-14a4-4933-b149-a2dec7bf966c
                History
                Funding
                Funded by: National Institute of Diabetes and Digestive and Kidney Diseases : NIDDK
                Award ID: U01 DK062432-10 || DK
                Funded by: National Institute of Diabetes and Digestive and Kidney Diseases : NIDDK
                Award ID: U01 DK062432-09 || DK
                Funded by: National Institute of Diabetes and Digestive and Kidney Diseases : NIDDK
                Award ID: U01 DK062432-08 || DK
                Funded by: National Institute of Diabetes and Digestive and Kidney Diseases : NIDDK
                Award ID: U01 DK062432-07 || DK
                Funded by: National Institute of Diabetes and Digestive and Kidney Diseases : NIDDK
                Award ID: R01 DK064869-08 || DK
                Funded by: National Institute of Diabetes and Digestive and Kidney Diseases : NIDDK
                Award ID: R01 DK064869-07 || DK
                Funded by: National Institute of Diabetes and Digestive and Kidney Diseases : NIDDK
                Award ID: R01 DK064869-06A1 || DK
                Funded by: National Institute of Diabetes and Digestive and Kidney Diseases : NIDDK
                Award ID: R01 DK064869-05S1 || DK
                Funded by: National Institute of Diabetes and Digestive and Kidney Diseases : NIDDK
                Award ID: P30 DK040561-15 || DK
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                Genetics
                Genetics

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