Genetic variants in the region harbouring IL2/IL21 associated with ulcerative colitis
- E A M Festen1,
- P Goyette2,
- R Scott3,
- V Annese4,
- A Zhernakova5,
- J Lian2,
- C Lefèbvre2,
- S R Brant6,
- J H Cho7,
- M S Silverberg8,
- K D Taylor9,
- D J de Jong10,
- P C Stokkers11,
- D Mcgovern11,
- O Palmieri4,
- J-P Achkar12,
- R J Xavier13,
- M J Daly14,
- R H Duerr3,
- C Wijmenga2,
- R K Weersma1,
- J D Rioux2
- 1Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
- 2Laboratory in Genetics and Genomic Medicine of Inflammation, Montreal Heart Institute, Université de Montréal, Montreal, Canada
- 3Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
- 4UU.OO. Gastroenterologia ed Endoscopia Digestiva, Ospedale “Casa Sollievo della Sofferenza”, IRCCS, San Giovanni Rotondo, Italy
- 5Complex Genetics Section, Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands
- 6Harvey M and Lyn P Meyerhoff Inflammatory Bowel Disease Center, Department of Medicine, Johns Hopkins University, Baltimore, Maryland, USA
- 7Departments of Medicine and Genetics, Division of Gastroenterology, Inflammatory Bowel Disease (IBD) Center, Yale University, New Haven, Connecticut, USA
- 8Mount Sinai Hospital IBD Centre, University of Toronto, Toronto, Ontario, Canada
- 9Medical Genetics Institute and Inflammatory Bowel Disease (IBD) Center, Cedars-Sinai Medical Center, Los Angeles, California, USA
- 10Department of Gastroenterology and Hepatology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
- 11Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands
- 12Center for Inflammatory Bowel Disease, Department of Gastroenterology & Hepatology, Cleveland Clinic, Cleveland, Ohio, USA
- 13Center for Computational and Integrative Biology and Gastrointestinal Unit, Massachusetts General Hospital, Harvard Medical School, Massachusetts, USA
- 14Center for Human Genetic Research, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
- Dr J D Rioux, Université de Montréal and the Montreal Heart Institute, Research Center, 5000 Bélanger Street, Montreal, Quebec H1T 1C8, Canada;
- Revised 15 January 2009
- Accepted 20 January 2009
- Published Online First 6 February 2009
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.
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.