Inflammatory bowel disease

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

¹ Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
² Laboratory in Genetics and Genomic Medicine of Inflammation, Montreal Heart Institute, Université de Montréal, Montreal, Canada
³ Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
⁴ UU.OO. Gastroenterologia ed Endoscopia Digestiva, Ospedale "Casa Sollievo della Sofferenza", IRCCS, San Giovanni Rotondo, Italy
⁵ Complex Genetics Section, Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands
⁶ Harvey M and Lyn P Meyerhoff Inflammatory Bowel Disease Center, Department of Medicine, Johns Hopkins University, Baltimore, Maryland, USA
⁷ Departments of Medicine and Genetics, Division of Gastroenterology, Inflammatory Bowel Disease (IBD) Center, Yale University, New Haven, Connecticut, USA
⁸ Mount Sinai Hospital IBD Centre, University of Toronto, Toronto, Ontario, Canada
⁹ Medical Genetics Institute and Inflammatory Bowel Disease (IBD) Center, Cedars-Sinai Medical Center, Los Angeles, California, USA
¹⁰ Department of Gastroenterology and Hepatology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
¹¹ Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands
¹² Center for Inflammatory Bowel Disease, Department of Gastroenterology & Hepatology, Cleveland Clinic, Cleveland, Ohio, USA
¹³ Center for Computational and Integrative Biology and Gastrointestinal Unit, Massachusetts General Hospital, Harvard Medical School, Massachusetts, USA
¹⁴ Center 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; john.david.rioux{at}umontreal.ca

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 = 1.35x10^–10, rs13119723 p = 8.60x10^–8, rs6840978 p = 3.07x10^–8, rs6822844 p = 2.77x10^–9). A moderate association with CD was also found in the pooled analysis (p value range 0.0016–9.86x10^–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.

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