Nature Genetics
36, 476 - 480 (2004)
Published online: 11 April 2004; | doi:10.1038/ng1345
Genetic variation in DLG5 is associated with inflammatory bowel diseaseMonika Stoll1, 7, Brit Corneliussen2, Christine M Costello1, Georg H Waetzig3, Bjorn Mellgard2, W Andreas Koch1, Philip Rosenstiel1, Mario Albrecht4, Peter J P Croucher1, Dirk Seegert3, Susanna Nikolaus1, Jochen Hampe1, 5, Thomas Lengauer4, Stefan Pierrou2, Ulrich R Foelsch1, Christopher G Mathew6, Maria Lagerstrom-Fermer2
& Stefan Schreiber1, 51
First Department of Medicine, University Hospital Schleswig-Holstein, Schittenhelmstr. 12, 24105
Kiel, Germany. 2
AstraZeneca, Experimental Medicine and Department of Molecular Sciences, R&D Molndal, Sweden. 3
Conaris Research Institute AG, Kiel, Germany. 4
Max-Planck-Institute for Informatics, Saarbrücken, Germany. 5
Institute for Clinical Molecular Biology, Christian-Albrechts-University, Kiel, Germany. 6
Guy's, King's and St. Thomas' School of Medicine, London, UK. 7
Present address: Genetic Epidemiology of Vascular Disorders, Institute for Arteriosclerosis Research, Muenster, Germany.
Correspondence should be addressed to Stefan Schreiber s.schreiber@mucosa.deCrohn 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.
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