title: Associations with tight junction genes PARD3 and MAGI2 in Dutch patients point to a common barrier defect for coeliac disease and ulcerative colitis.
abstract: BACKGROUND
  Coeliac disease (gluten-sensitive enteropathy; GSE) and inflammatory bowel disease (IBD) are common gastrointestinal disorders. Both display enhanced intestinal permeability, initiated by gluten exposure (GSE) or bacterial interactions (IBD). Previous studies showed the association of both diseases with variants in MYO9B, presumably involved in epithelial permeability.
  
  
  OBJECTIVE
  It was hypothesised that genetic variants in tight junction genes might affect epithelial barrier function, thus contributing to a shared pathogenesis of GSE and IBD.
  
  
  METHODS
  This hypothesis was tested with a comprehensive genetic association analysis of 41 genes from the tight junction pathway, represented by 197 tag single nucleotide polymorphism (SNP) markers.
  
  
  RESULTS
  Two genes, PARD3 (two SNPs) and MAGI2 (two SNPs), showed weak association with GSE in a Dutch cohort. Replication in a British GSE cohort yielded significance for one SNP in PARD3 and suggestive associations for two additional SNPs, one each in PARD3 and MAGI2. Joint analysis of the British and Dutch data further substantiated the association for both PARD3 (rs10763976, p = 6.4 x 10(-5); OR 1.23, 95% CI 1.11 to 1.37) and MAGI2 (rs6962966, p = 7.6 x 10(-4); OR 1.19, 95% CI 1.08 to 1.32). Association was also observed in Dutch ulcerative colitis patients with MAGI2 (rs6962966, p = 0.0036; OR 1.26, 95% CI 1.08 to 1.47), and suggestive association with PARD3 (rs4379776, p = 0.068).
  
  
  CONCLUSIONS
  These results suggest that coeliac disease and ulcerative colitis may share a common aetiology through tight junction-mediated barrier defects, although the observations need further replication.
authors.affiliation: Genetics Department, University Medical Center Groningen, PO Box 30001, 9700 RB Groningen, The Netherlands. m.c.wapenaar@medgen.umcg.nl
authors.forename: M C
authors.initials: MC
authors.lastname: Wapenaar
authors.forename: A J
authors.initials: AJ
authors.lastname: Monsuur
authors.forename: A A
authors.initials: AA
authors.lastname: van Bodegraven
authors.forename: R K
authors.initials: RK
authors.lastname: Weersma
authors.forename: M R
authors.initials: MR
authors.lastname: Bevova
authors.forename: R K
authors.initials: RK
authors.lastname: Linskens
authors.forename: P
authors.initials: P
authors.lastname: Howdle
authors.forename: G
authors.initials: G
authors.lastname: Holmes
authors.forename: C J
authors.initials: CJ
authors.lastname: Mulder
authors.forename: G
authors.initials: G
authors.lastname: Dijkstra
authors.forename: D A
authors.initials: DA
authors.lastname: van Heel
authors.forename: C
authors.initials: C
authors.lastname: Wijmenga
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D002446:Celiac Disease / Q000235:genetics* / Q000503:physiopathology; D018797:Cell Cycle Proteins / Q000235:genetics*; D015331:Cohort Studies; D003093:Colitis, Ulcerative / Q000235:genetics* / Q000503:physiopathology; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing / Q000379:methods; D005838:Genotype; D051528:Guanylate Kinases; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011506:Proteins / Q000235:genetics*; D019108:Tight Junctions / Q000235:genetics*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D008565:Membrane Proteins; C509689:PARD3 protein, human; D011506:Proteins; D051528:Guanylate Kinases; C485777:MAGI2 protein, human