title: CARD15/NOD2 gene variants are associated with familially occurring and complicated forms of Crohn's disease.
abstract: BACKGROUND
  Variants of the caspase activating recruitment domain 15/nucleotide oligomerisation domain 2 (CARD15/NOD2) gene have been associated with susceptibility to Crohn's disease (CD).
  
  
  OBJECTIVE
  Our aim was to evaluate the allele frequencies of the CARD15 variants R702W, G908R, and 1007fs in Finnish inflammatory bowel disease (IBD) patients and to search for possible associations between CARD15 variants and occurrence of familial forms of IBD or complicated forms of CD.
  
  
  METHODS
  We investigated 198 sporadic CD patients, 46 probands with familial CD, 27 CD probands from mixed IBD families, 99 unrelated patients with ulcerative colitis (UC), and 300 control individuals for the occurrence of the CARD15 gene variants R702W, G908R, and 1007fs.
  
  
  RESULTS
  In CD patients, the allele frequencies for the rare variants of these polymorphisms were 3.3%, 0.6%, and 4.8% (total 8.7%), and the corresponding frequencies in healthy controls were 1.8%, 0%, and 1.7% (total 3.5%) (8.7% v 3.5%; p<0.01). In UC patients allele frequencies were comparable with those in controls. The frequency of the 1007fs polymorphism variant allele was significantly higher among all CD patients than in controls (4.8% v 1.7%; p<0.01) but there was no significant difference in allele frequencies between the CD and UC groups. The 1007fs allele frequency was higher in familial CD than in non-familial cases with CD (10.9% v 3.5%; p<0.01). There were no significant differences in the allele frequencies of the R702W and G908R polymorphisms between CD patients, UC patients, and controls. We found that 15.5% of CD patients, 9.1% of UC patients, and 6.7% of controls carried at least one of the CARD15 variants. In CD patients carrying at least one of the three NOD2 variants, the ileum was affected more often than in non-carrier CD patients (90% v 73%; p<0.05), they had stricturing or penetrating disease more often than non-carriers (88% v 56%; p<0.01), and they had an increased need for bowel surgery.
  
  
  CONCLUSIONS
  The frequency of NOD2 gene variants was lower in genetically homogenous Finns than in other populations. The 1007fs variant was associated with CD. The occurrence of CARD15 variants predicted ileal location as well as stricturing and penetrating forms of CD.
authors.affiliation: Department of Medicine, Helsinki University Hospital, Helsinki, Finland. tiina.helio@hus.fi
authors.forename: T
authors.initials: T
authors.lastname: Heliö
authors.forename: L
authors.initials: L
authors.lastname: Halme
authors.forename: M
authors.initials: M
authors.lastname: Lappalainen
authors.forename: H
authors.initials: H
authors.lastname: Fodstad
authors.forename: P
authors.initials: P
authors.lastname: Paavola-Sakki
authors.forename: U
authors.initials: U
authors.lastname: Turunen
authors.forename: M
authors.initials: M
authors.lastname: Färkkilä
authors.forename: T
authors.initials: T
authors.lastname: Krusius
authors.forename: K
authors.initials: K
authors.lastname: Kontula
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000368:Aged; D002352:Carrier Proteins / Q000235:genetics*; D002648:Child; D003093:Colitis, Ulcerative / Q000235:genetics; D003424:Crohn Disease / Q000150:complications / Q000235:genetics* / Q000473:pathology; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D008875:Middle Aged; D053473:Nod2 Signaling Adaptor Protein; D010641:Phenotype; D012189:Retrospective Studies
chemical_list: D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; C429018:NOD2 protein, human; D053473:Nod2 Signaling Adaptor Protein