NEOPICS: interNational Early Onset Pediatric IBD Cohort Study www.NEOPICS.org; see Supporting Material for details.
IL-10R polymorphisms are associated with very-early-onset ulcerative colitis
Version of Record online: 1 MAY 2012
Copyright © 2012 Crohn's & Colitis Foundation of America, Inc.
Inflammatory Bowel Diseases
How to Cite
Moran, C. J., Walters, T. D., Guo, C.-H., Kugathasan, S., Klein, C., Turner, D., Wolters, V. M., Bandsma, R. H., Mouzaki, M., Zachos, M., NEOPICS, Langer, J. C., Cutz, E., Benseler, S. M., Roifman, C. M., Silverberg, M. S., Griffiths, A. M., Snapper, S. B. and Muise, A. M. (2012), IL-10R polymorphisms are associated with very-early-onset ulcerative colitis. Inflamm Bowel Dis. doi: 10.1002/ibd.22974
- Version of Record online: 1 MAY 2012
- Manuscript Accepted: 14 MAR 2012
- Manuscript Received: 25 FEB 2012
- Crohn's and Colitis Foundation of America (CCFA)
- Crohn's and Colitis Foundation of Canada (CCFC)
- Canadian Association of Gastroenterology (CAG)
- Canadian Institute for Health Research (CIHR)
- Canadian Child Health Clinician Scientist Program (Strategic Training Initiatives in Health Research Program – CIHR) award
- Early Researcher Award from the Ontario Ministry of Research and Innovation and a CDHNF/NASPGHAN George Ferry Young Investigator Development Award
- Canadian Institute of Health Research – Operating Grant (MOP119457)
- Gale and Graham Wright Research Chair in Digestive Diseases
- NIDDK grant DK
- Wolpow Chair in IBD Research and Treatment
- Harvard Digestive Disease Center P30 DK034854
- IL-10 receptor;
- inflammatory bowel disease;
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).
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.
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 × 10−4; and OR 2.93, P = 6 × 10−4, respectively).
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. (Inflamm Bowel Dis 2012;)