title: Molecular prediction of disease risk and severity in a large Dutch Crohn's disease cohort.
abstract: BACKGROUND
  Crohn's disease and ulcerative colitis have a complex genetic background. We assessed the risk for both the development and severity of the disease by combining information from genetic variants associated with inflammatory bowel disease (IBD).
  
  
  METHODS
  We studied 2804 patients (1684 with Crohn's disease and 1120 with ulcerative colitis) and 1350 controls from seven university hospitals. Details of the phenotype were available for 1600 patients with Crohn's disease and for 800 with ulcerative colitis. Genetic association for disease susceptibility was tested for the nucleotide-binding and oligomerisation domain 2 gene (NOD2), the IBD5 locus, the Drosophila discs large homologue 5 and autophagy-related 16-like 1 genes (DLG5 and ATG16L1) and the interleukin 23 receptor gene (IL23R). Interaction analysis was performed for Crohn's disease using the most associated single nucleotide polymorphism (SNP) for each locus. Odds ratios were calculated in an ordinal regression analysis with the number of risk alleles as an independent variable to analyse disease development and severity.
  
  
  RESULTS
  Association with Crohn's disease was confirmed for NOD2, IBD5, DLG5, ATG16L1 and IL23R. Patients with Crohn's disease carry more risk alleles than controls (p = 3.85 x 10(-22)). Individuals carrying an increasing number of risk alleles have an increasing risk for Crohn's disease, consistent with an independent effects multiplicative model (trend analysis p = 4.25 x 10(-23)). Patients with Crohn's disease 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 behaviour (p = 0.0008), no operations (p = 0.02) or age of onset above 40 years (p = 0.028).
  
  
  CONCLUSIONS
  Crohn's disease is a multigenic disorder. An increase in the number of risk alleles is associated with an increased risk for the development of Crohn's disease 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.
authors.affiliation: Department of Gastroenterology and Hepatology, University Medical Center Groningen and University of Groningen, P.O. Box 30001, 9700 RB Groningen, The Netherlands. R.K.Weersma@int.umcg.nl
authors.forename: R K
authors.initials: RK
authors.lastname: Weersma
authors.forename: P C F
authors.initials: PC
authors.lastname: Stokkers
authors.forename: A A
authors.initials: AA
authors.lastname: van Bodegraven
authors.forename: R A
authors.initials: RA
authors.lastname: van Hogezand
authors.forename: H W
authors.initials: HW
authors.lastname: Verspaget
authors.forename: D J
authors.initials: DJ
authors.lastname: de Jong
authors.forename: C J
authors.initials: CJ
authors.lastname: van der Woude
authors.forename: B
authors.initials: B
authors.lastname: Oldenburg
authors.forename: R K
authors.initials: RK
authors.lastname: Linskens
authors.forename: E A M
authors.initials: EA
authors.lastname: Festen
authors.forename: G
authors.initials: G
authors.lastname: van der Steege
authors.forename: D W
authors.initials: DW
authors.lastname: Hommes
authors.forename: J B A
authors.initials: JB
authors.lastname: Crusius
authors.forename: C
authors.initials: C
authors.lastname: Wijmenga
authors.forename: I M
authors.initials: IM
authors.lastname: Nolte
authors.forename: G
authors.initials: G
authors.lastname: Dijkstra
mesh_terms: D000328:Adult; D000483:Alleles; D003093:Colitis, Ulcerative / Q000453:epidemiology / Q000235:genetics*; D003424:Crohn Disease / Q000453:epidemiology / Q000235:genetics*; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000453:epidemiology / Q000235:genetics*; D005838:Genotype; D006801:Humans; D008297:Male; D008967:Molecular Biology; D009426:Netherlands / Q000453:epidemiology; D053473:Nod2 Signaling Adaptor Protein / Q000235:genetics*; D016017:Odds Ratio; D011110:Polymorphism, Genetic / Q000235:genetics; D018123:Receptors, Interleukin / Q000235:genetics*; D018570:Risk Assessment
chemical_list: C515500:IL23R protein, human; D053473:Nod2 Signaling Adaptor Protein; D018123:Receptors, Interleukin