title: PTPN2 gene variants are associated with susceptibility to both Crohn's disease and ulcerative colitis supporting a common genetic disease background.
abstract: BACKGROUND
  Genome-wide association studies identified PTPN2 (protein tyrosine phosphatase, non-receptor type 2) as susceptibility gene for inflammatory bowel diseases (IBD). However, the exact role of PTPN2 in Crohn's disease (CD) and ulcerative colitis (UC) and its phenotypic effect are unclear. We therefore performed a detailed genotype-phenotype and epistasis analysis of PTPN2 gene variants.
  
  
  RESULTS
  Genomic DNA from 2131 individuals of Caucasian origin (905 patients with CD, 318 patients with UC, and 908 healthy, unrelated controls) was analyzed for two SNPs in the PTPN2 region (rs2542151, rs7234029) for which associations with IBD were found in previous studies in other cohorts. Our analysis revealed a significant association of PTPN2 SNP rs2542151 with both susceptibility to CD (p = 1.95×10⁻⁵; OR 1.49 [1.34-1.79]) and UC (p = 3.87×10⁻², OR 1.31 [1.02-1.68]). Moreover, PTPN2 SNP rs7234029 demonstrated a significant association with susceptibility to CD (p = 1.30×10⁻³; OR 1.35 [1.13-1.62]) and a trend towards association with UC (p = 7.53×10⁻²; OR 1.26 [0.98-1.62]). Genotype-phenotype analysis revealed an association of PTPN2 SNP rs7234029 with a stricturing disease phenotype (B2) in CD patients (p = 6.62×10⁻³). Epistasis analysis showed weak epistasis between the ATG16L1 SNP rs2241879 and PTPN2 SNP rs2542151 (p = 0.024) in CD and between ATG16L1 SNP rs4663396 and PTPN2 SNP rs7234029 (p = 4.68×10⁻³) in UC. There was no evidence of epistasis between PTPN2 and NOD2 and PTPN2 and IL23R. In silico analysis revealed that the SNP rs7234029 modulates potentially the binding sites of several transcription factors involved in inflammation including GATA-3, NF-κB, C/EBP, and E4BP4.
  
  
  CONCLUSIONS
  Our data confirm the association of PTPN2 variants with susceptibility to both CD and UC, suggesting a common disease pathomechanism for these diseases. Given recent evidence that PTPN2 regulates autophagosome formation in intestinal epithelial cells, the potential link between PTPN2 and ATG16L1 should be further investigated.
authors.affiliation: Department of Medicine II-Grosshadern, Ludwig-Maximilians-University, Munich, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Glas
authors.forename: Johanna
authors.initials: J
authors.lastname: Wagner
authors.forename: Julia
authors.initials: J
authors.lastname: Seiderer
authors.forename: Torsten
authors.initials: T
authors.lastname: Olszak
authors.forename: Martin
authors.initials: M
authors.lastname: Wetzke
authors.forename: Florian
authors.initials: F
authors.lastname: Beigel
authors.forename: Cornelia
authors.initials: C
authors.lastname: Tillack
authors.forename: Johannes
authors.initials: J
authors.lastname: Stallhofer
authors.forename: Matthias
authors.initials: M
authors.lastname: Friedrich
authors.forename: Christian
authors.initials: C
authors.lastname: Steib
authors.forename: Burkhard
authors.initials: B
authors.lastname: Göke
authors.forename: Thomas
authors.initials: T
authors.lastname: Ochsenkühn
authors.forename: Nazanin
authors.initials: N
authors.lastname: Karbalai
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; D003093:Colitis, Ulcerative / Q000235:genetics*; D003424:Crohn Disease / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D054578:Protein Tyrosine Phosphatase, Non-Receptor Type 2 / Q000235:genetics*; D055815:Young Adult
chemical_list: C516649:PTPN2 protein, human; D054578:Protein Tyrosine Phosphatase, Non-Receptor Type 2