Background: Patients with Crohn’s Disease (CD) have defects in intestinal epithelial permeability that are inadequately explained by known IBD susceptibility genes. E-cadherin (CDH1) plays a vital role in maintaining the integrity of the intestinal barrier and its cellular localization is disrupted in CD patients.
Aim: To determine if polymorphisms in the CDH1 gene are associated with CD and to determine the function associated with these polymorphisms.
Methods: The hypothesis was tested using a candidate gene approach using 20 Tag SNPs derived from the HapMap and CD trios. Functional studies were carried out using HapMap cell lines and polarized cell lines (MDCK-1).
Results: Here we show that CDH1 is associated with CD in 327 trios (rs10431923 excess transmission of 'TT' genotype; p=0.0020) and is replicated in the Wellcome Trust Case Control Consortium CD data set (TT risk allele; OR 1.2, p=0.005). Patients with the CD risk haplotype (rs12597188, rs10431923, and rs9935563; GTC allelic frequency 21%; p = 0.000016) exhibited increased E-cadherin cytoplasmic accumulation in their intestinal epithelium that may be explained by the presence of a novel truncated form of E-cadherin. Accordingly, expression of this truncated E-cadherin in cultured polarized epithelial cells resulted in abnormal intracellular accumulation of both E-cadherin and β-catenin.
Conclusion: The mis-localization of E-cadherin and β-catenin may explain the increased permeability seen in some patients with CD. Thus, the polymorphisms identified in CDH1 are important for understanding the pathogenesis of CD and point to a defect in barrier defense.