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Genetic Variants in the Region Harbouring IL2/IL21 Associated to Ulcerative Colitis
  1. Eleonora A M Festen (e.a.m.festen{at}medgen.umcg.nl)
  1. University Medical Center Groningen, University of Groningen, Netherlands
    1. Philippe Goyette (philippe.goyette{at}inflammgen.org)
    1. Institut de Cardiologie de Montréal / Montreal Heart Institute, Université de Montréal, Canada
      1. Regan Scott (scottr{at}dom.pitt.edu)
      1. University of Pittsburgh School of Medicine, United States
        1. Vito Annese (v.annese{at}operapadrepio.it)
        1. Ospedale, Italy
          1. Alexandra Zhernakova (a.zhernakova{at}umcutrecht.nl)
          1. University Medical Center Utrecht, Netherlands
            1. Steven R Brant (sbrant{at}jhmi.edu)
            1. Johns Hopkins University, Baltimore, United States
              1. Judy H Cho (judy.cho{at}yale.edu)
              1. Yale University, United States
                1. Mark S Silverberg (msilverberg{at}mtsinai.on.ca)
                1. University of Toronto, United States
                  1. Kent D Taylor (kent.taylor{at}cshs.org)
                  1. Cedars-Sinai Medical Center, United States
                    1. Dirk J de Jong (d.dejong{at}mdl.umcn.nl)
                    1. Radboud University Nijmegen Medical Centre, Netherlands
                      1. Pieter C Stokkers (p.stokkers{at}amc.uva.nl)
                      1. Academic Medical Center, Amsterdam, Netherlands
                        1. Dermot McGovern (mcgovernd{at}cshs.org)
                        1. Cedars-Sinai Medical Center, United States
                          1. Orazio Palmieri (o.palmieri{at}operapadrepio.it)
                          1. Ospedale, Italy
                            1. Jean-Paul Achkar (achkarj{at}ccf.org)
                            1. Cleveland Clinic, United States
                              1. Ramnik J Xavier (xavier{at}molbio.mgh.harvard.edu)
                              1. Massachusetts General Hospital, Harvard Medical School, United States
                                1. Richard H Duerr (duerr{at}pitt.edu)
                                1. University of Pittsburgh, School of Medicine, United States
                                  1. Mark J Daly (mjdaly{at}chgr.mgh.harvard.edu)
                                  1. Massachusetts General Hospital, Harvard Medical School, United States
                                    1. Cisca Wijmenga (c.wijmenga{at}medgen.umcg.nl)
                                    1. University Medical Center Groningen, University of Groningen, Netherlands
                                      1. Rinse K Weersma (r.k.weersma{at}int.umcg.nl)
                                      1. University Medical Center Groningen, University of Groningen, Netherlands
                                        1. John D Rioux (rioux{at}broad.mit.edu)
                                        1. Montreal Heart Institute, Université de Montréal, Canada

                                          Abstract

                                          Objectives: Genetic susceptibility is known to play a large part in the predisposition to the inflammatory bowel diseases (IBD) 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 celiac disease, type 1 diabetes, rheumatoid arthritis, systemic lupus erythematosus and psoriasis), while the roles that IL2 and IL21 play in the immune response also make them attractive candidates for inflammatory bowel disease. Our objective was to test for association between the IL2/IL21 locus and the inflammatory bowel diseases.

                                          Methods: The four single nucleotide polymorphisms (SNPs) in the IL2/IL21 locus most associated to celiac disease were genotyped in 1590 IBD cases 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). We also found a moderate association with CD in the pooled analysis (p value range 0.0016-9.86x10-5).

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

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