Original Article

IL-10R polymorphisms are associated with very-early-onset ulcerative colitis

  1. Christopher J. Moran MD1,2,3,
  2. Thomas D. Walters MD4,
  3. Cong-Hui Guo MD5,
  4. Subra Kugathasan MD6,
  5. Christoph Klein MD, PhD7,
  6. Dan Turner MD, PhD8,
  7. Victorien M. Wolters MD, PhD4,5,
  8. Robert H. Bandsma MD, PhD4,
  9. Marialena Mouzaki MD4,
  10. Mary Zachos MD4,
  11. NEOPICS†,
  12. Jacob C. Langer MD9,
  13. Ernest Cutz MD10,
  14. Susanne M. Benseler MD11,
  15. Chaim M. Roifman MD12,
  16. Mark S. Silverberg MD13,
  17. Anne M. Griffiths MD4,
  18. Scott B. Snapper MD, PhD2,3,14,15,‡,*,
  19. Aleixo M. Muise MD, PhD4,5,‡,*

Article first published online: 1 MAY 2012

DOI: 10.1002/ibd.22974

Additional Information

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

Author Information

  1. 1

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

  2. 2

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

  3. 3

    Department of Pediatrics, Harvard Medical School, Boston, Massachusetts

  4. 4

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

  5. 5

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

  6. 6

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

  7. 7

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

  8. 8

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

  9. 9

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

  10. 10

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

  11. 11

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

  12. 12

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

  13. 13

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

  14. 14

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

  15. 15

    Department of Medicine, Harvard Medical School, Boston, Massachusetts

  1. †

    NEOPICS: interNational Early Onset Pediatric IBD Cohort Study www.NEOPICS.org; see Supporting Material for details.

  2. ‡

    Snapper and Muise contributed equally to this article.

*Center for Inflammatory Bowel Disease Treatment and Research, Division of Gastroenterology & Nutrition, Children's Hospital Boston, 300 Longwood Ave., Boston, MA 02115

  1. †

    NEOPICS: interNational Early Onset Pediatric IBD Cohort Study www.NEOPICS.org; see Supporting Material for details.

  2. ‡

    Snapper and Muise contributed equally to this article.

Publication History

  1. Article first published online: 1 MAY 2012
  2. Manuscript Accepted: 14 MAR 2012
  3. Manuscript Received: 25 FEB 2012

Funded by

  • 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

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Keywords:

  • IL-10;
  • IL-10 receptor;
  • inflammatory bowel disease;
  • immunodeficiency

Abstract

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 × 10−4; and OR 2.93, P = 6 × 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. (Inflamm Bowel Dis 2012;)

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