title: Effect of inflammatory bowel disease classification changes on NOD2 genotype-phenotype associations in a population-based cohort.
abstract: BACKGROUND
  NOD2 mutations are associated with Crohn's disease (CD) in Caucasian clinic-based cohorts. Data from population-based cohorts are limited. Clinic-based studies may overestimate this association. Genotype-phenotype relationships are yet to be assessed using the Montreal classification. We hypothesized that the NOD2-CD association would be weaker in a population-based cohort, and that the Montreal classification would strengthen genotype-phenotype associations.
  
  
  METHODS
  A population-based case-control study was performed including 91% of all people in Canterbury, New Zealand, with inflammatory bowel disease (IBD); NOD2 genotyping was performed and patients were phenotyped according to the Vienna and Montreal classification systems.
  
  
  RESULTS
  The NOD2 genotype was available on 684 CD, 643 ulcerative colitis (UC), 36 indeterminate colitis/IBDU (IBD unclassified) patients, and 201 controls. Control frequencies for the 702W, 908R, and 1007fs alleles were 0.030, 0.012, and 0.010, respectively, compared with 0.074, 0.027, and 0.040 for CD. The 702W (P = 0.001) and 1007fs (P = 0.002) alleles were significantly associated with CD. Younger age of diagnosis (<17 years) was associated with 1 (odds ratio (OR) 1.9 [95% confidence intervals 0.98-3.6]) or 2 (OR 6.5 [2.3-18.6]) NOD2 mutations compared with diagnosis >40 years. Ileal disease was most strongly associated with NOD2 mutations (1 mutation OR 3.9 [2.4-6.3], 2 mutations OR 6.7 [2.4-18.5]). Penetrating disease was associated with NOD2 mutations using the Montreal but not the Vienna classification.
  
  
  CONCLUSIONS
  The association between NOD2 mutations and CD was found to be weaker in our population-based cohort than in previous studies that used referral-based cohorts. Application of the Montreal classification led to a strengthening of the NOD2 genotype-phenotype association.
authors.affiliation: Department of Gastroenterology, Christchurch School of Medicine and Christchurch Hospital, Christchurch 8140, New Zealand. richard.gearry@cdhb.govt.nz
authors.forename: Richard B
authors.initials: RB
authors.lastname: Gearry
authors.forename: Rebecca L
authors.initials: RL
authors.lastname: Roberts
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Burt
authors.forename: Chris M A
authors.initials: CM
authors.lastname: Frampton
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Chapman
authors.forename: Judith A
authors.initials: JA
authors.lastname: Collett
authors.forename: Philippa
authors.initials: P
authors.lastname: Shirley
authors.forename: Melanie D E
authors.initials: MD
authors.lastname: Allington
authors.forename: Martin A
authors.initials: MA
authors.lastname: Kennedy
authors.forename: Murray L
authors.initials: ML
authors.lastname: Barclay
mesh_terms: D000328:Adult; D015331:Cohort Studies; D004247:DNA / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000145:classification* / Q000453:epidemiology / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009520:New Zealand / Q000453:epidemiology; D053473:Nod2 Signaling Adaptor Protein / Q000235:genetics*; D016017:Odds Ratio; D010641:Phenotype; D015995:Prevalence; D012189:Retrospective Studies; D012307:Risk Factors
chemical_list: C429018:NOD2 protein, human; D053473:Nod2 Signaling Adaptor Protein; D004247:DNA