title: Genetic variation in DLG5 is associated with inflammatory bowel disease.
abstract: Crohn disease and ulcerative colitis are two subphenotypes of inflammatory bowel disease (IBD), a complex disorder resulting from gene-environment interaction. We refined our previously defined linkage region for IBD on chromosome 10q23 and used positional cloning to identify genetic variants in DLG5 associated with IBD. DLG5 encodes a scaffolding protein involved in the maintenance of epithelial integrity. We identified two distinct haplotypes with a replicable distortion in transmission (P = 0.000023 and P = 0.004 for association with IBD, P = 0.00012 and P = 0.04 for association with Crohn disease). One of the risk-associated DLG5 haplotypes is distinguished from the common haplotype by a nonsynonymous single-nucleotide polymorphism 113G-->A, resulting in the amino acid substitution R30Q in the DUF622 domain of DLG5. This mutation probably impedes scaffolding of DLG5. We stratified the study sample according to the presence of risk-associated CARD15 variants to study potential gene-gene interaction. We found a significant difference in association of the 113A DLG5 variant with Crohn disease in affected individuals carrying the risk-associated CARD15 alleles versus those carrying non-risk-associated CARD15 alleles. This is suggestive of a complex pattern of gene-gene interaction between DLG5 and CARD15, reflecting the complex nature of polygenic diseases. Further functional studies will evaluate the biological significance of DLG5 variants.
authors.affiliation: First Department of Medicine, University Hospital Schleswig-Holstein, Schittenhelmstr. 12, 24105 Kiel, Germany.
authors.forename: Monika
authors.initials: M
authors.lastname: Stoll
authors.forename: Brit
authors.initials: B
authors.lastname: Corneliussen
authors.forename: Christine M
authors.initials: CM
authors.lastname: Costello
authors.forename: Georg H
authors.initials: GH
authors.lastname: Waetzig
authors.forename: Bjorn
authors.initials: B
authors.lastname: Mellgard
authors.forename: W Andreas
authors.initials: WA
authors.lastname: Koch
authors.forename: Philip
authors.initials: P
authors.lastname: Rosenstiel
authors.forename: Mario
authors.initials: M
authors.lastname: Albrecht
authors.forename: Peter J P
authors.initials: PJ
authors.lastname: Croucher
authors.forename: Dirk
authors.initials: D
authors.lastname: Seegert
authors.forename: Susanna
authors.initials: S
authors.lastname: Nikolaus
authors.forename: Jochen
authors.initials: J
authors.lastname: Hampe
authors.forename: Thomas
authors.initials: T
authors.lastname: Lengauer
authors.forename: Stefan
authors.initials: S
authors.lastname: Pierrou
authors.forename: Ulrich R
authors.initials: UR
authors.lastname: Foelsch
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Mathew
authors.forename: Maria
authors.initials: M
authors.lastname: Lagerstrom-Fermer
authors.forename: Stefan
authors.initials: S
authors.lastname: Schreiber
mesh_terms: D000483:Alleles; D019943:Amino Acid Substitution; D002352:Carrier Proteins / Q000235:genetics; D016022:Case-Control Studies; D002648:Child; D002874:Chromosome Mapping; D002879:Chromosomes, Human, Pair 10 / Q000235:genetics*; D003001:Cloning, Molecular; D015331:Cohort Studies; D003093:Colitis, Ulcerative / Q000453:epidemiology / Q000235:genetics*; D003424:Crohn Disease / Q000453:epidemiology / Q000235:genetics*; D005060:Europe / Q000453:epidemiology; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D053473:Nod2 Signaling Adaptor Protein; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D025521:Tumor Suppressor Proteins / Q000235:genetics*
chemical_list: D002352:Carrier Proteins; C114461:DLG5 protein, human; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C429018:NOD2 protein, human; D053473:Nod2 Signaling Adaptor Protein; D025521:Tumor Suppressor Proteins