title: NOD2/CARD15 mutations in Croatian patients with Crohn's disease: prevalence and genotype-phenotype relationship.
abstract: BACKGROUND
  Crohn's disease (CD) is a chronic inflammatory disorder of the gastrointestinal tract with variations in localization and behaviour. Mutations in the NOD2/CARD15 gene on chromosome 16q have been implicated in the pathogenesis of the disease and three main sequence variants, all single nucleotide polymorphisms (SNPs), have been identified in North American and European populations.
  
  
  OBJECTIVE
  As no data exist in the Croatian population, we consecutively collected a cohort of 136 CD patients and 91 healthy controls to determine the prevalence of NOD2/CARD15 mutations and their association with phenotypic expression of the disease. All patients and controls were genotyped for Arg702Trp (Hugot SNP8), Gly908Arg (Hugot SNP12), and Leu1007fsinsC (Hugot SNP13) and allele frequencies were compared between the Crohn's patients and controls. The correlation of NOD2/CARD15 genotypes with the phenotypic expression of Crohn's disease was further assessed by logistic regression analysis.
  
  
  RESULTS
  NOD2/CARD15 variants were found in 38/136 CD patients (27.9%) compared to 10/91 (10.9%) healthy controls (P = 0.0022). Allele frequencies in patients with CD were 13.97%, 4.4% and 11.76%, respectively, for SNP8, 12 and 13, compared to 5.49%, 1.12% and 4.40% in controls (P = 0.041, P = 0.162, P = 0.055). Six CD patients carried double mutations and, remarkably, we identified two homozygous mutants amongst the healthy control group. Surgery over the course of the disease and a younger age at onset of the disease were significantly more frequent in patients who were carriers of NOD2/CARD15 mutations.
  
  
  CONCLUSIONS
  This report on NOD2/CARD15 mutations in Croatian patients with CD demonstrates that this gene is also implicated in susceptibility to CD in the Croatian population. Phenotypic association showed a younger age at diagnosis and a higher need for surgery in patients carrying NOD2/CARD15 mutations. However, the prevalence is somewhat lower compared to other reports, likely due to a more prominent colonic inflammation.
authors.affiliation: Division of Gastroenterology dDepartment of Pathology, University Hospital Rebro, Zagreb, Croatia. silvija.cukovic@gmail.com
authors.forename: Silvija
authors.initials: S
authors.lastname: Cukovic-Cavka
authors.forename: Severine
authors.initials: S
authors.lastname: Vermeire
authors.forename: Irena
authors.initials: I
authors.lastname: Hrstic
authors.forename: Greet
authors.initials: G
authors.lastname: Claessens
authors.forename: Sanja
authors.initials: S
authors.lastname: Kolacek
authors.forename: Jasminka
authors.initials: J
authors.lastname: Jakic-Razumovic
authors.forename: Zeljko
authors.initials: Z
authors.lastname: Krznaric
authors.forename: Katja
authors.initials: K
authors.lastname: Grubelic
authors.forename: Davor
authors.initials: D
authors.lastname: Radic
authors.forename: Zrinjka
authors.initials: Z
authors.lastname: Misak
authors.forename: Oleg
authors.initials: O
authors.lastname: Jadresin
authors.forename: Paul
authors.initials: P
authors.lastname: Rutgeerts
authors.forename: Boris
authors.initials: B
authors.lastname: Vucelic
mesh_terms: D000293:Adolescent; D000328:Adult; D016022:Case-Control Studies; D015331:Cohort Studies; D017523:Croatia / Q000208:ethnology; D003424:Crohn Disease / Q000208:ethnology* / Q000235:genetics*; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D053473:Nod2 Signaling Adaptor Protein / Q000235:genetics*; D010641:Phenotype; D015995:Prevalence
chemical_list: C429018:NOD2 protein, human; D053473:Nod2 Signaling Adaptor Protein