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Science 314 (5804): 1461-1463

Copyright © 2006 by the American Association for the Advancement of Science

A Genome-Wide Association Study Identifies IL23R as an Inflammatory Bowel Disease Gene

Richard H. Duerr,1,2 Kent D. Taylor,3,4 Steven R. Brant,5,6 John D. Rioux,7,8 Mark S. Silverberg,9 Mark J. Daly,8,10 A. Hillary Steinhart,9 Clara Abraham,11 Miguel Regueiro,1 Anne Griffiths,12 Themistocles Dassopoulos,5 Alain Bitton,13 Huiying Yang,3,4 Stephan Targan,4,14 Lisa Wu Datta,5 Emily O. Kistner,15 L. Philip Schumm,15 Annette T. Lee,16 Peter K. Gregersen,16 M. Michael Barmada,2 Jerome I. Rotter,3,4 Dan L. Nicolae,11,17 Judy H. Cho18*

Abstract: The inflammatory bowel diseases Crohn's disease and ulcerative colitis are common, chronic disorders that cause abdominal pain, diarrhea, and gastrointestinal bleeding. To identify genetic factors that might contribute to these disorders, we performed a genome-wide association study. We found a highly significant association between Crohn's disease and the IL23R gene on chromosome 1p31, which encodes a subunit of the receptor for the proinflammatory cytokine interleukin-23. An uncommon coding variant (rs11209026, c.1142G>A, p.Arg381Gln) confers strong protection against Crohn's disease, and additional noncoding IL23R variants are independently associated. Replication studies confirmed IL23R associations in independent cohorts of patients with Crohn's disease or ulcerative colitis. These results and previous studies on the proinflammatory role of IL-23 prioritize this signaling pathway as a therapeutic target in inflammatory bowel disease.

1 Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, School of Medicine, University of Pittsburgh, University of Pittsburgh Medical Center Presbyterian, Mezzanine Level, C-Wing, 200 Lothrop Street, Pittsburgh, PA 15213, USA.
2 Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Crabtree A300, 130 Desoto Street, Pittsburgh, PA15261, USA.
3 Medical Genetics Institute, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, CA 90048, USA.
4 IBD Center, Division of Gastroenterology, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, CA 90048, USA.
5 Harvey M. and Lyn P. Meyerhoff Inflammatory Bowel Disease Center, Department of Medicine, Johns Hopkins University School of Medicine, B136, 1503 East Jefferson Street, Baltimore, MD 21231, USA.
6 Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, 615 North Wolfe Street, Baltimore, MD 21205, USA.
7 Université de Montréal and the Montreal Heart Institute, S-6400, 5000 Belanger Street, Montreal, Quebec H1T 1C8, Canada.
8 Medical and Population Genetics Program, Broad Institute of MIT and Harvard, 7 Cambridge Center, Cambridge, MA 02142, USA.
9 Mount Sinai Hospital IBD Centre, University of Toronto, 441–600 University Avenue, Toronto, Ontario M5G 1X5, Canada.
10 Massachusetts General Hospital, Harvard Medical School, 185 Cambridge Street, Boston, MA 02114, USA.
11 Department of Medicine, University of Chicago, 5841 South Maryland Avenue, Chicago, IL 60637, USA.
12 Department of Pediatrics, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario M5G 1X8, Canada.
13 Royal Victoria Hospital, McGill University Health Centre, 687 Pine Avenue West, Montreal, Quebec H3A 1A1, Canada.
14 Immunobiology Research Institute, Cedars-Sinai Medical Center, Davis 4063, 8700 Beverly Boulevard, Los Angeles, CA 90048, USA.
15 Department of Health Studies, University of Chicago, 5841 South Maryland Avenue, Chicago, IL 60637, USA.
16 The Feinstein Institute for Medical Research, 350 Community Drive, Manhasset, NY 11030, USA.
17 Department of Statistics, University of Chicago, 5734 South University Avenue, Chicago, IL 60637, USA.
18 IBD Center, Section of Digestive Diseases, Departments of Medicine and Genetics, Yale University, S155A, 300 Cedar Street, New Haven, CT 06519, USA.

* To whom correspondence should be addressed. E-mail: judy.cho{at}yale.edu


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