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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.    Methodology/Principal Findings  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/Significance  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.

PTPN2 Gene Variants Are Associated with Susceptibility to Both Crohn's Disease and Ulcerative Colitis Supporting a Common Genetic Disease Background