title: The NOD2 single nucleotide polymorphisms rs2066843 and rs2076756 are novel and common Crohn's disease susceptibility gene variants.
abstract: BACKGROUND
  The aims were to analyze two novel NOD2 variants (rs2066843 and rs2076756) in a large cohort of patients with inflammatory bowel disease and to elucidate phenotypic consequences.
  
  
  RESULTS
  Genomic DNA from 2700 Caucasians including 812 patients with Crohn's disease (CD), 442 patients with ulcerative colitis (UC), and 1446 healthy controls was analyzed for the NOD2 SNPs rs2066843 and rs2076756 and the three main CD-associated NOD2 variants p.Arg702Trp (rs2066844), p.Gly908Arg (rs2066847), and p.Leu1007fsX1008 (rs2066847). Haplotype and genotype-phenotype analyses were performed. The SNPs rs2066843 (p = 3.01×10(-5), OR 1.48, [95% CI 1.23-1.78]) and rs2076756 (p = 4.01×10(-6); OR 1.54, [95% CI 1.28-1.86]) were significantly associated with CD but not with UC susceptibility. Haplotype analysis revealed a number of significant associations with CD susceptibility with omnibus p values <10(-10). The SNPs rs2066843 and rs2076756 were in linkage disequilibrium with each other and with the three main CD-associated NOD2 mutations (D'>0.9). However, in CD, SNPs rs2066843 and rs2076756 were more frequently observed than the other three common NOD2 mutations (minor allele frequencies for rs2066843 and rs2076756: 0.390 and 0.380, respectively). In CD patients homozygous for these novel NOD2 variants, genotype-phenotype analysis revealed higher rates of a penetrating phenotype (rs2076756: p = 0.015) and fistulas (rs2076756: p = 0.015) and significant associations with CD-related surgery (rs2076756: p = 0.003; rs2066843: p = 0.015). However, in multivariate analysis only disease localization (p<2×10(-16)) and behaviour (p = 0.02) were significantly associated with the need for surgery.
  
  
  CONCLUSIONS
  The NOD2 variants rs2066843 and rs2076756 are novel and common CD susceptibility gene variants.
authors.affiliation: Department of Medicine II--Grosshadern, Ludwig-Maximilians-University, Munich, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Glas
authors.forename: Julia
authors.initials: J
authors.lastname: Seiderer
authors.forename: Cornelia
authors.initials: C
authors.lastname: Tillack
authors.forename: Simone
authors.initials: S
authors.lastname: Pfennig
authors.forename: Florian
authors.initials: F
authors.lastname: Beigel
authors.forename: Matthias
authors.initials: M
authors.lastname: Jürgens
authors.forename: Torsten
authors.initials: T
authors.lastname: Olszak
authors.forename: Rüdiger P
authors.initials: RP
authors.lastname: Laubender
authors.forename: Maria
authors.initials: M
authors.lastname: Weidinger
authors.forename: Bertram
authors.initials: B
authors.lastname: Müller-Myhsok
authors.forename: Burkhard
authors.initials: B
authors.lastname: Göke
authors.forename: Thomas
authors.initials: T
authors.lastname: Ochsenkühn
authors.forename: Peter
authors.initials: P
authors.lastname: Lohse
authors.forename: Julia
authors.initials: J
authors.lastname: Diegelmann
authors.forename: Darina
authors.initials: D
authors.lastname: Czamara
authors.forename: Stephan
authors.initials: S
authors.lastname: Brand
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002648:Child; D015331:Cohort Studies; D003424:Crohn Disease / Q000235:genetics*; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000235:genetics; D008875:Middle Aged; D053473:Nod2 Signaling Adaptor Protein / Q000235:genetics*; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide
chemical_list: C429018:NOD2 protein, human; D053473:Nod2 Signaling Adaptor Protein