title: The NOD2 p.Leu1007fsX1008 mutation (rs2066847) is a stronger predictor of the clinical course of Crohn's disease than the FOXO3A intron variant rs12212067.
abstract: BACKGROUND
  Very recently, a sub-analysis of genome-wide association scans revealed that the non-coding single nucleotide polymorphism (SNP) rs12212067 in the FOXO3A gene is associated with a milder course of Crohn's disease (CD) (Cell 2013;155:57-69). The aim of our study was to evaluate the clinical value of the SNP rs12212067 in predicting the severity of CD by correlating CD patient genotype status with the most relevant complications of CD such as stenoses, fistulas, and CD-related surgery.
  
  
  RESULTS
  We genotyped 550 CD patients for rs12212067 (FOXO3A) and the three common CD-associated NOD2 mutations rs2066844, rs2066847, and rs2066847 and performed genotype-phenotype analyses.
  
  
  RESULTS
  No significant phenotypic differences were found between the wild-type genotype TT of the FOXO3A SNP rs12212067 and the minor genotypes TG and GG independently from NOD2 variants. The allele frequency of the minor G allele was 12.7%. Age at diagnosis, disease duration, body mass index, surgery rate, stenoses, fistula, need for immunosuppressive therapy, and disease course were not significantly different. In contrast, the NOD2 mutant p.Leu1007fsX1008 (rs2066847) was highly associated with penetrating CD (p = 0.01), the development of fistulas (p = 0.01) and stenoses (p = 0.01), and ileal disease localization (p = 0.03). Importantly, the NOD2 SNP rs2066847 was a strong separator between an aggressive and a mild course of CD (p = 2.99×10(-5)), while the FOXO3A SNP rs12212067 did not separate between mild and aggressive CD behavior in our cohort (p = 0.35). 96.2% of the homozygous NOD2 p.Leu1007fsX1008 carriers had an aggressive disease behavior compared to 69.3% of the patients with the NOD2 wild-type genotype (p = 0.007).
  
  
  CONCLUSIONS
  In clinical practice, the NOD2 variant p.Leu1007fsX1008 (rs2066847), in particular in homozygous form, is a much stronger marker for a severe clinical phenotype than the FOXO3A rs12212067 SNP for a mild disease course on an individual patient level despite its important impact on the inflammatory response of monocytes.
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, 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: 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: Florian
authors.initials: F
authors.lastname: Beigel
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: Johannes
authors.initials: J
authors.lastname: Stallhofer
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: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D002648:Child; D003424:Crohn Disease / Q000175:diagnosis* / Q000235:genetics*; D005260:Female; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000235:genetics*; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006720:Homozygote; D006801:Humans; D007438:Introns; D008297:Male; D008875:Middle Aged; D009154:Mutation; D053473:Nod2 Signaling Adaptor Protein / Q000235:genetics*; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D012720:Severity of Illness Index; D055815:Young Adult
chemical_list: C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D053473:Nod2 Signaling Adaptor Protein