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IL-10R Polymorphisms Are Associated with Very-early-onset Ulcerative Colitis

Moran, Christopher J. MD1,2,3; Walters, Thomas D. MD4; Guo, Cong-Hui MD5; Kugathasan, Subra MD6; Klein, Christoph MD, PhD7; Turner, Dan MD, PhD8; Wolters, Victorien M. MD, PhD4,5; Bandsma, Robert H. MD, PhD4; Mouzaki, Marialena MD4; Zachos, Mary MD4; Langer, Jacob C. MD9; Cutz, Ernest MD10; Benseler, Susanne M. MD11; Roifman, Chaim M. MD12; Silverberg, Mark S. MD13; Griffiths, Anne M. MD4; Snapper, Scott B. MD, PhD2,3,14,15; Muise, Aleixo M. MD, PhD4,5

doi: 10.1002/ibd.22974
Original Basic Science Articles

Background: Interleukin-10 (IL-10) signaling genes are attractive inflammatory bowel disease (IBD) candidate genes as IL-10 restricts intestinal inflammation, IL-10 polymorphisms have been associated with IBD in genome-wide association studies, and mutations in IL-10 and IL-10 receptor (IL-10R) genes have been reported in immunodeficient children with severe infantile-onset IBD. Our objective was to determine if IL-10R polymorphisms were associated with early-onset IBD (EO-IBD) and very-early-onset IBD (VEO-IBD).

Methods: Candidate-gene analysis of IL10RA and IL10RB was performed after initial sequencing of an infantile onset-IBD patient identified a novel homozygous mutation. The discovery cohort included 188 EO-IBD subjects and 188 healthy subjects. Polymorphisms associated with IBD in the discovery cohort were genotyped in an independent validation cohort of 422 EO-IBD subjects and 480 healthy subjects.

Results: We identified a homozygous, splice-site point mutation in IL10RA in an infantile-onset IBD patient causing a premature stop codon (P206X) and IL-10 insensitivity. IL10RA and IL10RB sequencing in the discovery cohort identified five IL10RA polymorphisms associated with ulcerative colitis (UC) and two IL10RB polymorphisms associated with Crohn's disease (CD). Of these polymorphisms, two IL10RA single nucleotide polymorphisms, rs2228054 and rs2228055, were associated with VEO-UC in the discovery cohort and replicated in an independent validation cohort (odds ratio [OR] 3.08, combined P = 2 x 10−4; and OR 2.93, P = 6 x 10−4, respectively).

Conclusions: We identified IL10RA polymorphisms that confer risk for developing VEO-UC. Additionally, we identified the first splice site mutation in IL10RA resulting in infantile-onset IBD. This study expands the phenotype of IL10RA polymorphisms to include both severe arthritis and VEO-UC.

Supplemental Digital Content is Available in the Text.Article first published online 1 May 2012

1Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, MassGeneral Hospital for Children, Boston, Massachusetts

2Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Children's Hospital Boston, Boston, Massachusetts

3Department of Pediatrics, Harvard Medical School, Boston, Massachusetts

4Division of Gastroenterology, Hepatology, and Nutrition, Department of Paediatrics, Hospital for Sick Children, Toronto, Ontario, Canada

5Program in Cell Biology at University of Toronto, Toronto, Ontario, Canada

6Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia

7Department of Pediatrics, Dr. von Hauner Children's Hospital, Ludwig-Maximilians University, Munich, Germany

8Pediatric Gastroenterology Unit, Shaare Zedek Medical Center, Hebrew University of Jerusalem, Jerusalem, Israel

9Department of Surgery, Hospital for Sick Children, Toronto, Ontario, Canada

10Department of Pathology, Hospital for Sick Children, Toronto, Ontario, Canada

11Division of Rheumatology, Hospital for Sick Children, Toronto, Ontario, Canada

12Division of Immunology and Allergy, Hospital for Sick Children, Toronto, Ontario, Canada

13Division of Gastroenterology, Mount Sinai Hospital, Toronto, Ontario, Canada

14Division of Gastroenterology and Hepatology, Brigham & Women's Hospital, Boston, Massachusetts

15Department of Medicine, Harvard Medical School, Boston, Massachusetts.

Reprints: Scott B. Snapper, MD, PhD, Center for Inflammatory Bowel Disease Treatment and Research, Division of Gastroenterology & Nutrition, Children's Hospital Boston, 300 Longwood Ave., Boston, MA 02115 (e-mail: or Aleixo M. Muise, Division of Gastroenterology, Program in Cell Biology, Department of Pediatrics, Hospital for Sick Children, 555 University Ave., Toronto, Ontario M5G 1X8, Canada (e-mail:

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal\x{2019}s Web site (

Snapper and Muise contributed equally to this article.

C.J.M. is supported by an award from the Crohn's and Colitis Foundation of America (CCFA). A.M.M. is supported by a transition award from the Crohn's and Colitis Foundation of Canada (CCFC) / Canadian Association of Gastroenterology (CAG) / Canadian Institute for Health Research (CIHR), a Canadian Child Health Clinician Scientist Program (Strategic Training Initiatives in Health Research Program - CIHR) award, and an Early Researcher Award from the Ontario Ministry of Research and Innovation and a CDHNF/NASPGHAN George Ferry Young Investigator Development Award and funded by a Canadian Institute of Health Research – Operating Grant (MOP119457). M.S.S. is supported in part by the Gale and Graham Wright Research Chair in Digestive Diseases. Partial funding to recruit subjects and collect samples was provided by M.S.S. through NIDDK grant DK. This work was funded in part by funding to Dr. Snapper through the Wolpow Chair in IBD Research and Treatment as well as through funding made possible from the Harvard Digestive Disease Center P30 DK034854.

* NEOPICS: interNational Early Onset Pediatric IBD Cohort Study; see Supplemental Digital Content for details.

Received February 25, 2012

Accepted March 14, 2012

© Crohn's & Colitis Foundation of America, Inc.
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