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- Title
Genetic variation in DLG5 is associated with inflammatory bowel disease.
- Authors
Stoll, Monika; Corneliussen, Brit; Costello, Christine M; Waetzig, Georg H; Mellgard, Bjorn; Koch, W Andreas; Rosenstiel, Philip; Albrecht, Mario; Croucher, Peter J P; Seegert, Dirk; Nikolaus, Susanna; Hampe, Jochen; Lengauer, Thomas; Pierrou, Stefan; Foelsch, Ulrich R; Mathew, Christopher G; Lagerstrom-Fermer, Maria; Schreiber, Stefan
- 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 DLGS associated with IBD. DLGS 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 DLGS haplotypes is distinguished from the common haplotype by a nonsynonymous single-nucleotide polymorphism 113G→A, resulting in the amino acid substitution R3OQ in the DUF622 domain of DL.G5. This mutation probably impedes scaffolding of DL.G5. 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 C4RD15 alleles versus those carrying non-risk-associated C4RD15 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 DL.G5 variants.
- Subjects
HUMAN genetic variation; INTESTINAL diseases; CROHN'S disease; ULCERATIVE colitis; AMINO acids; GENES
- Publication
Nature Genetics, 2004, Vol 36, Issue 5, p476
- ISSN
1061-4036
- Publication type
Article
- DOI
10.1038/ng1345