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Published Online October 26, 2006
Science DOI: 10.1126/science.1135245

Reports

Submitted on September 18, 2006
Accepted on October 18, 2006

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

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

1 Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, School of Medicine, University of Pittsburgh, UPMC-PUH, Mezzanine Level, C-Wing, 200 Lothrop Street, Pittsburgh, PA 15213, USA; Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Crabtree A300, 130 Desoto Street, Pittsburgh, PA 15261, USA.
2 Medical Genetics Institute, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, CA 90048, USA; IBD Center, Division of Gastroenterology, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, CA 90048, USA.
3 Harvey M. and Lyn P. Meyerhoff Inflammatory Bowel Disease Center, B136, 1503 East Jefferson Street, Baltimore, MD 21231, USA; Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, 615 North Wolfe Street, Baltimore, MD 21205, USA.
4 Université de Montréal and the Montreal Heart Institute, S-6400, 5000 Belanger Street, Montreal, Quebec H1T 1C8, Canada; Medical and Population Genetics Program, Broad Institute of MIT and Harvard, 7 Cambridge Center, Cambridge, MA 02142, USA.
5 Mount Sinai Hospital IBD Centre, University of Toronto, 441-600 University Avenue, Toronto, Ontario M5G 1X5, Canada.
6 Medical and Population Genetics Program, Broad Institute of MIT and Harvard, 7 Cambridge Center, Cambridge, MA 02142, USA; Massachusetts General Hospital, Harvard Medical School, 185 Cambridge Street, Boston, MA 02114, USA.
7 Department of Medicine, University of Chicago, 5841 South Maryland Avenue, Chicago, IL 60637, USA.
8 Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, School of Medicine, University of Pittsburgh, UPMC-PUH, Mezzanine Level, C-Wing, 200 Lothrop Street, Pittsburgh, PA 15213, USA.
9 Department of Pediatrics, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario M5G 1X8, Canada.
10 Harvey M. and Lyn P. Meyerhoff Inflammatory Bowel Disease Center, B136, 1503 East Jefferson Street, Baltimore, MD 21231, USA.
11 Royal Victoria Hospital, McGill University Health Centre, 687 Pine Avenue West, Montreal, Quebec H3A 1A1, Canada.
12 IBD Center, Division of Gastroenterology, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, CA 90048, USA; Immunobiology Research Institute, Cedars-Sinai Medical Center, Davis 4063, 8700 Beverly Boulevard, Los Angeles, CA 90048, USA.
13 Department of Health Studies, University of Chicago, 5841 South Maryland Avenue, Chicago, IL 60637, USA.
14 The Feinstein Institute for Medical Research, 350 Community Drive, Manhasset, NY 11030, USA.
15 Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Crabtree A300, 130 Desoto Street, Pittsburgh, PA 15261, USA.
16 Department of Medicine, University of Chicago, 5841 South Maryland Avenue, Chicago, IL 60637, USA; Department of Statistics, University of Chicago, 5734 South University Avenue, Chicago, IL 60637, USA.
17 IBD Center, Division of Gastroenterology, Departments of Medicine and Genetics, Yale University, S155A, 300 Cedar Street, New Haven, CT 06519, USA.

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

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 pro-inflammatory cytokine interleukin-23. An uncommon coding variant (rs11209026, c.1142G>A, p.Arg381Gln) confers strong protection against Crohn's disease, and additional non-coding 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 pro-inflammatory role of IL-23 prioritize this signaling pathway as a therapeutic target in inflammatory bowel disease.


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From the Cover: Genome-wide association study for Crohn's disease in the Quebec Founder Population identifies multiple validated disease loci.
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Risk Alleles for Multiple Sclerosis Identified by a Genomewide Study.
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Primary Immunodeficiencies: A Field in Its Infancy.
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