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Gut 58:799-804 doi:10.1136/gut.2008.166918
  • Inflammatory bowel disease

Genetic variants in the region harbouring IL2/IL21 associated with ulcerative colitis

  1. E A M Festen1,
  2. P Goyette2,
  3. R Scott3,
  4. V Annese4,
  5. A Zhernakova5,
  6. J Lian2,
  7. C Lefèbvre2,
  8. S R Brant6,
  9. J H Cho7,
  10. M S Silverberg8,
  11. K D Taylor9,
  12. D J de Jong10,
  13. P C Stokkers11,
  14. D Mcgovern11,
  15. O Palmieri4,
  16. J-P Achkar12,
  17. R J Xavier13,
  18. M J Daly14,
  19. R H Duerr3,
  20. C Wijmenga2,
  21. R K Weersma1,
  22. J D Rioux2
  1. 1
    Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
  2. 2
    Laboratory in Genetics and Genomic Medicine of Inflammation, Montreal Heart Institute, Université de Montréal, Montreal, Canada
  3. 3
    Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
  4. 4
    UU.OO. Gastroenterologia ed Endoscopia Digestiva, Ospedale “Casa Sollievo della Sofferenza”, IRCCS, San Giovanni Rotondo, Italy
  5. 5
    Complex Genetics Section, Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands
  6. 6
    Harvey M and Lyn P Meyerhoff Inflammatory Bowel Disease Center, Department of Medicine, Johns Hopkins University, Baltimore, Maryland, USA
  7. 7
    Departments of Medicine and Genetics, Division of Gastroenterology, Inflammatory Bowel Disease (IBD) Center, Yale University, New Haven, Connecticut, USA
  8. 8
    Mount Sinai Hospital IBD Centre, University of Toronto, Toronto, Ontario, Canada
  9. 9
    Medical Genetics Institute and Inflammatory Bowel Disease (IBD) Center, Cedars-Sinai Medical Center, Los Angeles, California, USA
  10. 10
    Department of Gastroenterology and Hepatology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
  11. 11
    Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands
  12. 12
    Center for Inflammatory Bowel Disease, Department of Gastroenterology & Hepatology, Cleveland Clinic, Cleveland, Ohio, USA
  13. 13
    Center for Computational and Integrative Biology and Gastrointestinal Unit, Massachusetts General Hospital, Harvard Medical School, Massachusetts, USA
  14. 14
    Center for Human Genetic Research, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
  1. Dr J D Rioux, Université de Montréal and the Montreal Heart Institute, Research Center, 5000 Bélanger Street, Montreal, Quebec H1T 1C8, Canada; john.david.rioux{at}umontreal.ca
  • Revised 15 January 2009
  • Accepted 20 January 2009
  • Published Online First 6 February 2009

Abstract

Objectives: Genetic susceptibility is known to play a large part in the predisposition to the inflammatory bowel diseases (IBDs) known as Crohn’s disease (CD) and ulcerative colitis (UC). The IL2/IL21 locus on 4q27 is known to be a common risk locus for inflammatory disease (shown in coeliac disease, type 1 diabetes, rheumatoid arthritis, systemic lupus erythematosus and psoriasis), while the roles that interleukin 2 (IL2) and IL21 play in the immune response also make them attractive candidates for IBD. The objective of this study was to test for association between the IL2/IL21 locus and the IBDs.

Methods: The four single nucleotide polymorphisms (SNPs) in the IL2/IL21 locus most associated with coeliac disease were genotyped in 1590 subjects with IBD and 929 controls from The Netherlands, and then replicated in a North American cohort (2387 cases and 1266 controls) and an Italian cohort (805 cases and 421 controls), yielding a total of 4782 cases (3194 UC, 1588 CD) and 2616 controls. Allelic association testing and a pooled analysis using a Cochran–Mantel–Haenszel test were performed.

Results: All four SNPs were strongly associated with UC in all three cohorts and reached genome-wide significance in the pooled analysis (rs13151961 p = 1.35×10−10, rs13119723 p = 8.60×10−8, rs6840978 p = 3.07×10−8, rs6822844 p = 2.77×10−9). A moderate association with CD was also found in the pooled analysis (p value range 0.0016–9.86×10−5).

Conclusions: A strong association for the IL2/IL21 locus with UC was found, which also confirms it as a general susceptibility locus for inflammatory disease.

Footnotes

  • Competing interests: None.

  • Funding: This study was made possible by a VICI grant from the Netherlands Organization for Scientific Research (918.66.620) to CW, and an AGIKO-grant from the Netherlands Organization for Scientific Research to EF.

  • ▸ Additional tables are published online only at http://gut.bmj.com/content/vol58/issue6

  • Patient consent: Informed consent was obtained using protocols approved by the local institutional review board in all participating institutions.