title: The contribution of NOD2 gene mutations to the risk and site of disease in inflammatory bowel disease.
abstract: OBJECTIVE
  Mutations in the NOD2 gene are strongly associated with susceptibility to Crohn's disease (CD). We analyzed a large cohort of European patients with inflammatory bowel disease to determine which mutations confer susceptibility, the degree of risk conferred, their prevalence in familial and sporadic forms of the disease, and whether they are associated with site of disease.
  
  
  METHODS
  Individuals were genotyped for 4 NOD2 mutations: P268S, R702W, G908R, and 3020insC. Allelic transmission distortion to 531 CD- and 337 ulcerative colitis-affected offspring was assessed by the transmission disequilibrium test. Association was also tested in an independent cohort of 995 patients with inflammatory bowel disease and 290 controls. Cases were stratified by disease site and compared across NOD2 genotypes.
  
  
  RESULTS
  R702W, G908R, and 3020insC were strongly associated with CD but not with ulcerative colitis. Linkage disequilibrium was observed between P268S and the other mutations, forming 3 independent disease haplotypes. Genotype relative risks were 3.0 for mutation heterozygotes and 23.4 for homozygotes or compound heterozygotes. The frequency of NOD2 mutations was higher in cases from families affected only with CD and was significantly increased in ileal-specific disease cases compared with colon-specific disease (26.9% vs. 12.7%, P = 0.0004).
  
  
  CONCLUSIONS
  The R702W, G908R, and 3020insC mutations are strong independent risk factors for CD and are associated particularly with ileal disease.
authors.affiliation: Division of Medical and Molecular Genetics, Guy's, King's, and St Thomas' School of Medicine, London, England, United Kingdom.
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Cuthbert
authors.forename: Sheila A
authors.initials: SA
authors.lastname: Fisher
authors.forename: Muddassar M
authors.initials: MM
authors.lastname: Mirza
authors.forename: Kathy
authors.initials: K
authors.lastname: King
authors.forename: Jochen
authors.initials: J
authors.lastname: Hampe
authors.forename: Peter J P
authors.initials: PJ
authors.lastname: Croucher
authors.forename: Silvia
authors.initials: S
authors.lastname: Mascheretti
authors.forename: Jeremy
authors.initials: J
authors.lastname: Sanderson
authors.forename: Alastair
authors.initials: A
authors.lastname: Forbes
authors.forename: John
authors.initials: J
authors.lastname: Mansfield
authors.forename: Stefan
authors.initials: S
authors.lastname: Schreiber
authors.forename: Cathryn M
authors.initials: CM
authors.lastname: Lewis
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Mathew
mesh_terms: D002352:Carrier Proteins; D015331:Cohort Studies; D003106:Colon / Q000473:pathology; D003424:Crohn Disease / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology; D005192:Family Health; D005260:Female; D016368:Frameshift Mutation; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D006801:Humans; D007082:Ileum / Q000473:pathology; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D020125:Mutation, Missense; D053473:Nod2 Signaling Adaptor Protein; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011506:Proteins / Q000235:genetics*; D012307:Risk Factors
chemical_list: D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; C429018:NOD2 protein, human; D053473:Nod2 Signaling Adaptor Protein; D011506:Proteins