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Coeliac disease associated risk variants in TNFAIP3 and REL implicate altered NF-κB signalling
  1. Gosia Trynka (g.trynka{at}medgen.umcg.nl)
  1. Genetics Department, University Medical Center and Groningen University, Groningen, Netherlands
    1. Alexandra Zhernakova (a.zhernakova{at}umcutrecht.nl)
    1. Complex Genetics Section, DBG-Dept Biomedical Genetics, University Medical Center Utrecht, Utrecht, Netherlands
      1. Jihane Romanos (j.romanos{at}medgen.umcg.nl)
      1. Genetics Department, University Medical Center and Groningen University, Groningen, Netherlands
        1. Lude Franke (lude{at}ludesign.nl)
        1. Genetics Department, University Medical Center and Groningen University, Groningen, Netherlands
          1. Karen Hunt (k.a.hunt{at}qmul.ac.uk)
          1. Institute of Cell and Molecular Science, Barts and The London School of Medicine and Dentistry, United Kingdom
            1. Graham Turner (gturner{at}tcd.ie)
            1. Departments of Clinical Medicine, Institute of Molecular Medicine, Trinity College Dublin, Dublin, Republic of Ireland
              1. Mathieu Platteel (m.platteel{at}medgen.umcg.nl)
              1. Genetics Department, University Medical Center and Groningen University, Groningen, Netherlands
                1. Anthony W Ryan (aryan12{at}tcd.ie)
                1. Departments of Clinical Medicine, Institute of Molecular Medicine, Trinity College Dublin, Dublin, Republic of Ireland
                  1. Carolien de Kovel (c.dekovel{at}umcutrecht.nl)
                  1. Complex Genetics Section, DBG-Dept Biomedical Genetics, University Medical Center Utrecht, Utrecht, Netherlands
                    1. Donatella Barisani (donatella.barisani{at}unimib.it)
                    1. Department of Experimental Medicine, Faculty of Medicine University of Milano-Bicocca, Monza, Italy
                      1. Maria T Bardella (mariateresa.bardella{at}unimi.it)
                      1. Fondazione IRCCS Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena, Milan, Italy
                        1. Ross McManus (rmcmanus{at}tcd.ie)
                        1. Departments of Clinical Medicine, Institute of Molecular Medicine, Trinity College Dublin, Dublin, Republic of Ireland
                          1. David A Van Heel (d.vanheel{at}qmul.ac.uk)
                          1. Institute of Cell and Molecular Science, Barts and The London School of Medicine and Dentistry, United Kingdom
                            1. Cisca Wijmenga (c.wijmenga{at}umcutrecht.nl)
                            1. Genetics Department, University Medical Center and Groningen University, Groningen, Netherlands

                              Abstract

                              Objective: Our previous coeliac disease genome-wide association study (GWAS) implicated risk variants in the HLA region and eight novel risk regions. To identify more coeliac disease loci, we selected 458 SNPs that showed more modest association in the GWAS for genotyping and analysis in four independent cohorts.

                              Design: 458 SNPs were assayed in 1682 cases and 3258 controls from three populations (UK, Irish and Dutch). We combined the results with the original GWAS cohort (767 UK cases and 1422 controls); six SNPs showed association with p < 1x10-04 and were then genotyped in an independent Italian coeliac cohort (538 cases and 593 controls).

                              Results: We identified two novel coeliac disease risk regions: 6q23.3 (OLIG3-TNFAIP3) and 2p16.1 (REL), both of which reached genome-wide significance in the combined analysis of all 2987 cases and 5273 controls (rs2327832 p = 1.3x10-08, and rs842647 p = 5.2x10-07). We investigated the expression of these genes in the RNA isolated from biopsies and from whole blood RNA. We did not observe any changes in gene expression, nor in the correlation of genotype with gene expression.

                              Conclusions: Both TNFAIP3 (A20, at the protein level) and REL are key mediators in the NF-κB inflammatory signalling pathway. We identify for the first time a role for primary heritable variation in this important biological pathway predisposing to coeliac disease. Currently, the HLA- and the ten established non-HLA risk factors explain ~40% of the heritability of coeliac disease.

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