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

<div><h3>Background</h3><p>Genome-wide association studies identified <em>PTPN2</em> (protein tyrosine phosphatase, non-receptor type 2) as susceptibility gene for inflammatory bowel diseases (IBD). However, the exact role of <em>PTPN2</em> 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 <em>PTPN2</em> gene variants.</p> <h3>Methodology/Principal Findings</h3><p>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 <em>PTPN2</em> region (rs2542151, rs7234029) for which associations with IBD were found in previous studies in other cohorts. Our analysis revealed a significant association of <em>PTPN2</em> 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, <em>PTPN2</em> 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 <em>PTPN2</em> SNP rs7234029 with a stricturing disease phenotype (B2) in CD patients (p = 6.62×10⁻³). Epistasis analysis showed weak epistasis between the <em>ATG16L1</em> SNP rs2241879 and <em>PTPN2</em> SNP rs2542151 (p = 0.024) in CD and between <em>ATG16L1</em> SNP rs4663396 and <em>PTPN2</em> SNP rs7234029 (p = 4.68×10⁻³) in UC. There was no evidence of epistasis between <em>PTPN2</em> and <em>NOD2</em> and <em>PTPN2</em> and <em>IL23R</em>. <em>In silico</em> 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.</p> <h3>Conclusions/Significance</h3><p>Our data confirm the association of <em>PTPN2</em> variants with susceptibility to both CD and UC, suggesting a common disease pathomechanism for these diseases. Given recent evidence that <em>PTPN2</em> regulates autophagosome formation in intestinal epithelial cells, the potential link between <em>PTPN2</em> and <em>ATG16L1</em> should be further investigated.</p>