title: NOD2/CARD15 gene polymorphisms in Crohn's disease: a genotype- phenotype analysis.
abstract: OBJECTIVE
  Three recently identified NOD2/CARD15 mutations have been described associated with an increased susceptibility Crohn's disease (CD). Our aim was to examine the potential association of these NOD2 mutations with CD and different subsets of CD phenotypes in our population.
  
  
  METHODS
  Two hundred and five well-defined CD patients from north-western France and 95 ethnically matched healthy controls were genotyped for mutations R702W, G908R and Leu1007insC by DNA sequencing. Allele and genotype frequencies of NOD2 variants were examined in the whole series of CD and in different subgroups of CD phenotypes defined by the clinical characteristics of the Vienna classification (age at diagnosis, location and behaviour) or by histological features (granuloma).
  
  
  RESULTS
  Carriers of at least one NOD2/CARD15 variant were significantly more frequent in CD than in controls (38.0% versus 20.0%, P < 0.002), and the R702W allele was the most significant contributor to this NOD2 association with CD. Homozygotes and compound heterozygotes combined had a higher risk of CD (odds ratio = 12.0, P < 0.0026) than simple heterozygotes for any variant (odds ratio = 2.2, P < 0.013) compared with subjects with no variant. Univariate analysis revealed that carriage of at least one NOD2 mutation was significantly associated with ileal involvement (P < 0.03), and stricturing evolution (P < 0.0015). Granuloma was associated with an excess of the R702W allele (16.1% versus 8.0%, Pc < 0.035), and was correlated with a young age at diagnosis, whatever the NOD2/CARD15 genotype. Multivariate analysis demonstrated that carriage of NOD2/CARD15 mutants, especially R702W, was primarily and independently associated both with stricturing evolution of CD and the presence of granuloma.
  
  
  CONCLUSIONS
  In our population, all NOD2/CARD15 mutant genotypes, especially compound heterozygosity, were found to increase the risk of CD, but R702W was the sole allele showing a significant association with CD. In addition, we confirm the positive and independent association of the R702W mutation with stricturing behaviour and describe a second one with the presence of granuloma.
authors.affiliation: Gastroenterology Department, CHU Pontchaillou and CEMDR, Rennes, France. denis.heresbach@chu-rennes.fr
authors.forename: Denis
authors.initials: D
authors.lastname: Heresbach
authors.forename: Véronique
authors.initials: V
authors.lastname: Gicquel-Douabin
authors.forename: Brigitte
authors.initials: B
authors.lastname: Birebent
authors.forename: Pierre-Nicolas
authors.initials: PN
authors.lastname: D'halluin
authors.forename: Nathalie
authors.initials: N
authors.lastname: Heresbach-Le Berre
authors.forename: Stéphane
authors.initials: S
authors.lastname: Dreano
authors.forename: Laurent
authors.initials: L
authors.lastname: Siproudhis
authors.forename: Alain
authors.initials: A
authors.lastname: Dabadie
authors.forename: Michel
authors.initials: M
authors.lastname: Gosselin
authors.forename: Jean
authors.initials: J
authors.lastname: Mosser
authors.forename: Gilbert
authors.initials: G
authors.lastname: Semana
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Bretagne
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Yaouanq
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000704:Analysis of Variance; D002352:Carrier Proteins / Q000235:genetics*; D002648:Child; D003424:Crohn Disease / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006099:Granuloma / Q000235:genetics; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D053473:Nod2 Signaling Adaptor Protein; D011110:Polymorphism, Genetic / Q000235:genetics*
chemical_list: D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; C429018:NOD2 protein, human; D053473:Nod2 Signaling Adaptor Protein