title: Polymorphisms in E-cadherin (CDH1) result in a mis-localised cytoplasmic protein that is associated with Crohn's disease.
abstract: 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.
  
  
  OBJECTIVE
  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 beta-catenin.
  
  
  CONCLUSIONS
  The mis-localisation of E-cadherin and beta-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.
authors.affiliation: Department of Pediatrics, Division of Gastroenterology, Hepatology, and Nutrition, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
authors.forename: A M
authors.initials: AM
authors.lastname: Muise
authors.forename: T D
authors.initials: TD
authors.lastname: Walters
authors.forename: W K
authors.initials: WK
authors.lastname: Glowacka
authors.forename: A M
authors.initials: AM
authors.lastname: Griffiths
authors.forename: B-Y
authors.initials: BY
authors.lastname: Ngan
authors.forename: H
authors.initials: H
authors.lastname: Lan
authors.forename: W
authors.initials: W
authors.lastname: Xu
authors.forename: M S
authors.initials: MS
authors.lastname: Silverberg
authors.forename: D
authors.initials: D
authors.lastname: Rotin
mesh_terms: D000293:Adolescent; D015820:Cadherins / Q000235:genetics* / Q000378:metabolism; D002460:Cell Line; D002648:Child; D003424:Crohn Disease / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D003593:Cytoplasm / Q000378:metabolism*; D004847:Epithelial Cells / Q000378:metabolism; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism; D015810:Linkage Disequilibrium; D008297:Male; D018613:Microscopy, Confocal; D020641:Polymorphism, Single Nucleotide
chemical_list: D015820:Cadherins