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Molecular prediction of disease risk and severity in a large Dutch Crohn's disease cohort
  1. Rinse K. Weersma (r.k.weersma{at}int.umcg.nl)
  1. University Medical Center Groningen, Netherlands
    1. Pieter C. F. Stokkers (p.stokkers{at}amc.nl)
    1. Academic Medical Center Amsterdam, Netherlands
      1. Ad A van Bodegraven (v.bodegraven{at}vumc.nl)
      1. VU University Medical Centre, Netherlands
        1. Ruud A. van Hogezand (r.a.van_hogezand.mdlz{at}lumc.nl)
        1. Leiden University Medical Center, Netherlands
          1. Hein W. Verspaget (h.w.verspaget{at}lumc.nl)
          1. Leiden University Medical Center, Netherlands
            1. Dirk J. de Jong (d.dejong{at}mdl.umcn.nl)
            1. University Medical Center Nijmegen, Netherlands
              1. C J van der Woude (c.vanderwoude{at}erasmusmc.nl)
              1. Erasmus Medical Centre Rotterdam, Netherlands
                1. Bas Oldenburg (boldenburg{at}umcutrecht.nl)
                1. University Medical Centre Utrecht, Netherlands
                  1. Ronald Linskens (r.linskens{at}st-anna.nl)
                  1. St-Anna Zorrgroep Hospital Geldrop, Netherlands
                    1. Gerrit van der Steege (g.van.der.steege{at}medgen.umcg.nl)
                    1. University Medical Center Groningen, Netherlands
                      1. Eleanora a Festen (e.a.m.festen{at}medgen.umcg.nl)
                      1. University Medical Center Groningen, Netherlands
                        1. Daan W Hommes (d.w.hommes{at}lumc.nl)
                        1. Leiden University Medical Center, Netherlands
                          1. J. B. A. Crusius (b.crusius{at}vumc.nl)
                          1. VU University Medical Centre, Netherlands
                            1. Cisca Wijmenga (c.wijmenga{at}umcutrecht.nl)
                            1. University Medical Center Groningen, Netherlands
                              1. Ilja M. Nolte (i.m.nolte{at}epi.umcg.nl)
                              1. University Medical Center Groningen, Netherlands
                                1. Gerard Dijkstra (g.dijkstra{at}int.umcg.nl)
                                1. University Medical Center Groningen, Netherlands

                                  Abstract

                                  Background: Crohn's disease (CD) and ulcerative colitis (UC) have a complex genetic background. We assessed the risk for both disease development and severity by combining information from IBD-associated genetic variants.

                                  Methods: We studied 2804 patients (1684 CD, 1120 UC) and 1350 controls from seven university hospitals. Phenotypic details were available for 1600 CD and 800 UC patients. Genetic association for disease susceptibility was tested for NOD2, the IBD5 locus, DLG5, ATG16L1 and IL23R.Interaction analysis was performed for CD using the most associated SNP for each locus. Odds ratios were calculated in an ordinal regression analysis with the number of risk alleles as an independent variable to analyze disease development and severity.

                                  Results: Association with CD was confirmed for NOD2, IBD5, DLG5, ATG16L1 and IL23R. CD patients carry more risk alleles than controls (p=3.85x10-22). Individuals carrying an increasing number of risk alleles have an increasing risk for CD, consistent with an independent effects multiplicative model (Trend analysis p=4.25x10-23). CD patients with a more severe disease course, operations or an age of onset below 40 years have more risk alleles compared to non-stricturing, non-penetrating behavior (p = 0.0008), no operations (p=0.02) or age of onset above 40 yrs (p=0.028).

                                  Conclusion: CD is a multigenic disorder. An increase in the number of risk alleles is associated with an increased risk for CD development and with a more severe disease course. Combining information from the known common risk polymorphisms may enable clinicians to predict the course of Crohn's disease

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