Variants in TRIM22 That Affect NOD2 Signaling Are Associated With Very-Early-Onset Inflammatory Bowel Disease.
Autor: | Li Q; SickKids Inflammatory Bowel Disease Center and Cell Biology Program, Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada; Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, University of Toronto, Hospital for Sick Children, Toronto, Ontario, Canada., Lee CH; Gastroenterology Department, The Children's Hospital at Westmead, Westmead, New South Wales, Australia; The James Fairfax Institute of Paediatric Nutrition, University of Sydney, New South Wales, Australia., Peters LA; Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, New York; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai and the Icahn Institute for Genomics and Multiscale Biology, New York, New York., Mastropaolo LA; Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, University of Toronto, Hospital for Sick Children, Toronto, Ontario, Canada., Thoeni C; SickKids Inflammatory Bowel Disease Center and Cell Biology Program, Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada; Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, University of Toronto, Hospital for Sick Children, Toronto, Ontario, Canada., Elkadri A; SickKids Inflammatory Bowel Disease Center and Cell Biology Program, Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada; Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, University of Toronto, Hospital for Sick Children, Toronto, Ontario, Canada; Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada., Schwerd T; Translational Gastroenterology Unit, Nuffield Department of Clinical Medicine, Experimental Medicine Division, University of Oxford and Department of Pediatrics, John Radcliffe Hospital, Oxford, UK., Zhu J; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai and the Icahn Institute for Genomics and Multiscale Biology, New York, New York., Zhang B; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai and the Icahn Institute for Genomics and Multiscale Biology, New York, New York., Zhao Y; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai and the Icahn Institute for Genomics and Multiscale Biology, New York, New York., Hao K; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai and the Icahn Institute for Genomics and Multiscale Biology, New York, New York., Dinarzo A; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai and the Icahn Institute for Genomics and Multiscale Biology, New York, New York., Hoffman G; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai and the Icahn Institute for Genomics and Multiscale Biology, New York, New York., Kidd BA; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai and the Icahn Institute for Genomics and Multiscale Biology, New York, New York., Murchie R; SickKids Inflammatory Bowel Disease Center and Cell Biology Program, Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada; Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, University of Toronto, Hospital for Sick Children, Toronto, Ontario, Canada., Al Adham Z; SickKids Inflammatory Bowel Disease Center and Cell Biology Program, Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada; Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, University of Toronto, Hospital for Sick Children, Toronto, Ontario, Canada; Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada., Guo C; Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, University of Toronto, Hospital for Sick Children, Toronto, Ontario, Canada., Kotlarz D; Department of Pediatrics, Dr. von Hauner Children's Hospital, Ludwig-Maximilians-University, Munich, Germany., Cutz E; Division of Pathology, The Hospital for Sick Children, Toronto, Ontario, Canada., Walters TD; SickKids Inflammatory Bowel Disease Center and Cell Biology Program, Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada; Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, University of Toronto, Hospital for Sick Children, Toronto, Ontario, Canada., Shouval DS; Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts., Curran M; Janssen R&D, LLC, Spring House, Pennsylvania., Dobrin R; Janssen R&D, LLC, Spring House, Pennsylvania., Brodmerkel C; Janssen R&D, LLC, Spring House, Pennsylvania., Snapper SB; Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts; Division of Gastroenterology and Hepatology, Brigham & Women's Hospital, Department of Medicine, Boston, Massachusetts., Klein C; Department of Pediatrics, Dr. von Hauner Children's Hospital, Ludwig-Maximilians-University, Munich, Germany., Brumell JH; SickKids Inflammatory Bowel Disease Center and Cell Biology Program, Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada; Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada; Molecular Genetics, University of Toronto, Toronto, Ontario, Canada., Hu M; Gastroenterology Department, The Children's Hospital at Westmead, Westmead, New South Wales, Australia; The James Fairfax Institute of Paediatric Nutrition, University of Sydney, New South Wales, Australia., Nanan R; Gastroenterology Department, The Children's Hospital at Westmead, Westmead, New South Wales, Australia; The James Fairfax Institute of Paediatric Nutrition, University of Sydney, New South Wales, Australia., Snanter-Nanan B; Gastroenterology Department, The Children's Hospital at Westmead, Westmead, New South Wales, Australia; The James Fairfax Institute of Paediatric Nutrition, University of Sydney, New South Wales, Australia., Wong M; Immunology Department, The Children's Hospital at Westmead, Westmead, New South Wales, Australia., Le Deist F; Department of Microbiology and Immunology, CHU Sainte Justine and Department of Microbiology, Infectiology and Immunology, University of Montreal, Quebec, Canada., Haddad E; Department of Pediatrics, CHU Sainte-Justine, Department of Microbiology, Infectiology and Immunology, University of Montreal, Quebec, Canada., Roifman CM; Division of Immunology, Department of Pediatrics, University of Toronto, The Hospital for Sick Children, Toronto, Canada., Deslandres C; Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, CHU Sainte-Justine, Montreal, Quebec, Canada., Griffiths AM; SickKids Inflammatory Bowel Disease Center and Cell Biology Program, Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada; Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, University of Toronto, Hospital for Sick Children, Toronto, Ontario, Canada., Gaskin KJ; Gastroenterology Department, The Children's Hospital at Westmead, Westmead, New South Wales, Australia; The James Fairfax Institute of Paediatric Nutrition, University of Sydney, New South Wales, Australia., Uhlig HH; Translational Gastroenterology Unit, Nuffield Department of Clinical Medicine, Experimental Medicine Division, University of Oxford and Department of Pediatrics, John Radcliffe Hospital, Oxford, UK., Schadt EE; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai and the Icahn Institute for Genomics and Multiscale Biology, New York, New York., Muise AM; SickKids Inflammatory Bowel Disease Center and Cell Biology Program, Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada; Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, University of Toronto, Hospital for Sick Children, Toronto, Ontario, Canada; Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada. Electronic address: aleixo.muise@utoronto.ca. |
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Jazyk: | angličtina |
Zdroj: | Gastroenterology [Gastroenterology] 2016 May; Vol. 150 (5), pp. 1196-1207. Date of Electronic Publication: 2016 Feb 04. |
DOI: | 10.1053/j.gastro.2016.01.031 |
Abstrakt: | Background & Aims: Severe forms of inflammatory bowel disease (IBD) that develop in very young children can be caused by variants in a single gene. We performed whole-exome sequence (WES) analysis to identify genetic factors that might cause granulomatous colitis and severe perianal disease, with recurrent bacterial and viral infections, in an infant of consanguineous parents. Methods: We performed targeted WES analysis of DNA collected from the patient and her parents. We validated our findings by a similar analysis of DNA from 150 patients with very-early-onset IBD not associated with known genetic factors analyzed in Toronto, Oxford, and Munich. We compared gene expression signatures in inflamed vs noninflamed intestinal and rectal tissues collected from patients with treatment-resistant Crohn's disease who participated in a trial of ustekinumab. We performed functional studies of identified variants in primary cells from patients and cell culture. Results: We identified a homozygous variant in the tripartite motif containing 22 gene (TRIM22) of the patient, as well as in 2 patients with a disease similar phenotype. Functional studies showed that the variant disrupted the ability of TRIM22 to regulate nucleotide binding oligomerization domain containing 2 (NOD2)-dependent activation of interferon-beta signaling and nuclear factor-κB. Computational studies demonstrated a correlation between the TRIM22-NOD2 network and signaling pathways and genetic factors associated very early onset and adult-onset IBD. TRIM22 is also associated with antiviral and mycobacterial effectors and markers of inflammation, such as fecal calprotectin, C-reactive protein, and Crohn's disease activity index scores. Conclusions: In WES and targeted exome sequence analyses of an infant with severe IBD characterized by granulomatous colitis and severe perianal disease, we identified a homozygous variant of TRIM22 that affects the ability of its product to regulate NOD2. Combined computational and functional studies showed that the TRIM22-NOD2 network regulates antiviral and antibacterial signaling pathways that contribute to inflammation. Further study of this network could lead to new disease markers and therapeutic targets for patients with very early and adult-onset IBD. (Copyright © 2016 AGA Institute. Published by Elsevier Inc. All rights reserved.) |
Databáze: | MEDLINE |
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