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Polymorphisms in E-cadherin (CDH1) result in a mis-localised cytoplasmic protein that is associated with Crohn’s disease
  1. A M Muise1,2,
  2. T D Walters1,
  3. W K Glowacka2,
  4. A M Griffiths1,
  5. B-Y Ngan3,
  6. H Lan4,
  7. W Xu5,
  8. M S Silverberg6,
  9. D Rotin2
  1. 1
    Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Hospital for Sick Children, University of Toronto, Canada
  2. 2
    Program in Cell Biology and Research Institute, Hospital for Sick Children, University of Toronto, Canada
  3. 3
    Department of Pathology, Hospital for Sick Children, University of Toronto, Canada
  4. 4
    Department of Computer Science, University of Toronto, Canada
  5. 5
    Public Health Sciences, Princess Margaret Hospital, University of Toronto, Canada
  6. 6
    Mount Sinai Hospital, Inflammatory Bowel Disease Group, University of Toronto, Canada
  1. Dr D Rotin, Program in Cell Biology, Hospital for Sick Children, 555 University Ave, Toronto, Ontario M5G 1X8, Canada; drotin{at} or Dr M Silverberg, Mount Sinai Hospital Inflammatory Bowel Disease Group, University of Toronto, 600 University Ave, Toronto, Canada M5G 1X8; msilverberg{at}


Background: Patients with Crohn’s disease have defects in intestinal epithelial permeability that are inadequately explained by known inflammatory bowel disease (IBD) susceptibility genes. E-cadherin (CDH1) plays a vital role in maintaining the integrity of the intestinal barrier and its cellular localisation is disrupted in patients with Crohn’s disease.

Aim: To determine if polymorphisms in the CDH1 gene are associated with Crohn’s disease 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 Crohn’s disease trios. Functional studies were carried out using HapMap cell lines and polarised epithelial cell lines (MDCK-1 and Caco2).

Results: Here we show that CDH1 is associated with Crohn’s disease 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 Crohn’s disease risk haplotype (rs12597188, rs10431923 and rs9935563; GTC allelic frequency 21%; p = 0.000016) exhibited increased E-cadherin cytoplasmic accumulation in their intestinal epithelium which may be explained by the presence of a novel truncated form of E-cadherin. Accordingly, expression of this truncated E-cadherin in cultured polarised epithelial cells resulted in abnormal intracellular accumulation and impaired plasma membrane localisation of both E-cadherin and β-catenin.

Conclusion: The mis-localisation of E-cadherin and β-catenin may explain the increased permeability seen in some patients with Crohn’s disease. Thus, the polymorphisms identified in CDH1 are important for understanding the pathogenesis of Crohn’s disease and point to a defect in barrier defence.

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  • Competing interests: None.

  • Funding: This work was supported by the Canadian Institute of Health Research (CIHR, grant no MOP-86496) to DR, NIDDK Grant (DK-06-504) to MS, the Crohn’s Colitis Foundation of Canada (CCFC) to AMG and DR, and a Thrasher Research Fund New Investigators Grant to AMM. AMM is supported by a transition award from the CCFC/CAG/CIHR and a Canadian Child Health Clinician Scientist Program (Strategic Training Initiatives in Health Research Program – CIHR) award. TW is supported by CCFC and AstraZenca Partnered fellowships from the CAG/CIHR. MSS is supported by the Gale and Graham Wright Research Chair in Digestive Diseases at Mount Sinai Hospital. DR holds a Canada Research Chair (Tier I) from the CFI/CIHR.

  • Ethics approval: Study subject phenotypic information and DNA samples were obtained with institutional review board approval for IBD genetic studies at the Hospital for Sick Children and Mount Sinai Hospital in Toronto. Written informed consent was obtained from all participants.

  • ▸ Two supplementary figures and two supplementary tables are published online only at