title: The NOD2 Single Nucleotide Polymorphism rs72796353 (IVS4+10 A>C) Is a Predictor for Perianal Fistulas in Patients with Crohn's Disease in the Absence of Other NOD2 Mutations.
abstract: BACKGROUND
  A previous study suggested an association of the single nucleotide polymorphism (SNP) rs72796353 (IVS4+10 A>C) in the NOD2 gene with susceptibility to Crohn's disease (CD). However, this finding has not been confirmed. Given that NOD2 variants still represent the most important predictors for CD susceptibility and phenotype, we evaluated the association of rs72796353 with inflammatory bowel disease (IBD) susceptibility and the IBD phenotype.
  
  
  METHODS
  Genomic DNA from 2256 Caucasians, including 1073 CD patients, 464 patients with ulcerative colitis (UC), and 719 healthy controls, was genotyped for the NOD2 SNP rs72796353 and the three main CD-associated NOD2 mutations rs2066844, rs2066845, and rs2066847. Subsequently, IBD association and genotype-phenotype analyses were conducted.
  
  
  RESULTS
  In contrast to the strong associations of the NOD2 SNPs rs2066844 (p=3.51 x 10(-3)), rs2066845 (p=1.54 x 10(-2)), and rs2066847 (p=1.61 x 10(-20)) with CD susceptibility, no significant association of rs72796353 with CD or UC susceptibility was found. However, in CD patients without the three main CD-associated NOD2 mutations, rs72796353 was significantly associated with the development of perianal fistulas (p=2.78 x 10(-7), OR 5.27, [95% CI 2.75-10.12] vs. NOD2 wild-type carriers).
  
  
  CONCLUSIONS
  Currently, this study represents the largest genotype-phenotype analysis of the impact of the NOD2 variant rs72796353 on the disease phenotype in IBD. Our data demonstrate that in CD patients the IVS4+10 A>C variant is strongly associated with the development of perianal fistulas. This association is particularly pronounced in patients who are not carriers of the three main CD-associated NOD2 mutations, suggesting rs72796353 as additional genetic marker for the CD disease behaviour.
authors.affiliation: Department of Medicine II-Grosshadern, Ludwig-Maximilians-University (LMU), Munich, Germany.
authors.forename: Fabian
authors.initials: F
authors.lastname: Schnitzler
authors.affiliation: Department of Medicine II-Grosshadern, Ludwig-Maximilians-University (LMU), Munich, Germany; Department of Preventive Dentistry and Periodontology, LMU, Munich, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Friedrich
authors.affiliation: Max-Planck-Institute of Psychiatry, Biostatistics Group, Munich, Germany.
authors.forename: Christiane
authors.initials: C
authors.lastname: Wolf
authors.affiliation: Department of Medicine II-Grosshadern, Ludwig-Maximilians-University (LMU), Munich, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Stallhofer
authors.affiliation: Department of Medicine II-Grosshadern, Ludwig-Maximilians-University (LMU), Munich, Germany.
authors.forename: Marianne
authors.initials: M
authors.lastname: Angelberger
authors.affiliation: Department of Preventive Dentistry and Periodontology, LMU, Munich, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Diegelmann
authors.affiliation: Department of Medicine II-Grosshadern, Ludwig-Maximilians-University (LMU), Munich, Germany.
authors.forename: Torsten
authors.initials: T
authors.lastname: Olszak
authors.affiliation: Department of Medicine II-Grosshadern, Ludwig-Maximilians-University (LMU), Munich, Germany.
authors.forename: Cornelia
authors.initials: C
authors.lastname: Tillack
authors.affiliation: Department of Medicine II-Grosshadern, Ludwig-Maximilians-University (LMU), Munich, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Beigel
authors.affiliation: Department of Medicine II-Grosshadern, Ludwig-Maximilians-University (LMU), Munich, Germany.
authors.forename: Burkhard
authors.initials: B
authors.lastname: Göke
authors.affiliation: Department of Human Genetics, Rheinisch-Westfälische Technische Hochschule (RWTH) Aachen, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Glas
authors.affiliation: Department of Clinical Chemistry-Grosshadern, LMU, Munich, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Lohse
authors.affiliation: Department of Medicine II-Grosshadern, Ludwig-Maximilians-University (LMU), Munich, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Brand
mesh_terms: D000328:Adult; D016022:Case-Control Studies; D003424:Crohn Disease / Q000150:complications / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D053473:Nod2 Signaling Adaptor Protein / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D012003:Rectal Fistula / Q000150:complications / Q000235:genetics*
chemical_list: C429018:NOD2 protein, human; D053473:Nod2 Signaling Adaptor Protein