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

Authors

  • Christopher J. Moran MD,

    1. Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, MassGeneral Hospital for Children, Boston, Massachusetts
    2. Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Children's Hospital Boston, Boston, Massachusetts
    3. Department of Pediatrics, Harvard Medical School, Boston, Massachusetts
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  • Thomas D. Walters MD,

    1. Division of Gastroenterology, Hepatology, and Nutrition, Department of Paediatrics, Hospital for Sick Children, Toronto, Ontario, Canada
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  • Cong-Hui Guo MD,

    1. Program in Cell Biology at University of Toronto, Toronto, Ontario, Canada
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  • Subra Kugathasan MD,

    1. Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia
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  • Christoph Klein MD, PhD,

    1. Department of Pediatrics, Dr. von Hauner Children's Hospital, Ludwig-Maximilians University, Munich, Germany
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  • Dan Turner MD, PhD,

    1. Pediatric Gastroenterology Unit, Shaare Zedek Medical Center, Hebrew University of Jerusalem, Jerusalem, Israel
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  • Victorien M. Wolters MD, PhD,

    1. Division of Gastroenterology, Hepatology, and Nutrition, Department of Paediatrics, Hospital for Sick Children, Toronto, Ontario, Canada
    2. Program in Cell Biology at University of Toronto, Toronto, Ontario, Canada
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  • Robert H. Bandsma MD, PhD,

    1. Division of Gastroenterology, Hepatology, and Nutrition, Department of Paediatrics, Hospital for Sick Children, Toronto, Ontario, Canada
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  • Marialena Mouzaki MD,

    1. Division of Gastroenterology, Hepatology, and Nutrition, Department of Paediatrics, Hospital for Sick Children, Toronto, Ontario, Canada
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  • Mary Zachos MD,

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

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

  • Jacob C. Langer MD,

    1. Department of Surgery, Hospital for Sick Children, Toronto, Ontario, Canada
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  • Ernest Cutz MD,

    1. Department of Pathology, Hospital for Sick Children, Toronto, Ontario, Canada
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  • Susanne M. Benseler MD,

    1. Division of Rheumatology, Hospital for Sick Children, Toronto, Ontario, Canada
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  • Chaim M. Roifman MD,

    1. Division of Immunology and Allergy, Hospital for Sick Children, Toronto, Ontario, Canada
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  • Mark S. Silverberg MD,

    1. Division of Gastroenterology, Mount Sinai Hospital, Toronto, Ontario, Canada
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  • Anne M. Griffiths MD,

    1. Division of Gastroenterology, Hepatology, and Nutrition, Department of Paediatrics, Hospital for Sick Children, Toronto, Ontario, Canada
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  • Scott B. Snapper MD, PhD,

    Corresponding author
    1. Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Children's Hospital Boston, Boston, Massachusetts
    2. Department of Pediatrics, Harvard Medical School, Boston, Massachusetts
    3. Division of Gastroenterology and Hepatology, Brigham & Women's Hospital, Boston, Massachusetts
    4. Department of Medicine, Harvard Medical School, Boston, Massachusetts
    • Center for Inflammatory Bowel Disease Treatment and Research, Division of Gastroenterology & Nutrition, Children's Hospital Boston, 300 Longwood Ave., Boston, MA 02115
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    • Snapper and Muise contributed equally to this article.

  • Aleixo M. Muise MD, PhD

    Corresponding author
    1. Division of Gastroenterology, Hepatology, and Nutrition, Department of Paediatrics, Hospital for Sick Children, Toronto, Ontario, Canada
    2. Program in Cell Biology at University of Toronto, Toronto, Ontario, Canada
    • Division of Gastroenterology, Program in Cell Biology, Department of Pediatrics, Hospital for Sick Children, 555 University Ave., Toronto, Ontario M5G 1X8, Canada
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    • Snapper and Muise contributed equally to this article.


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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