Genetic variation in DLG5 is associated with inflammatory bowel disease

• Published in: Nature genetics Vol. 36; no. 5; pp. 476 - 480
• Main Authors: Lagerstrom-Fermer, Maria, Hampe, Jochen, Rosenstiel, Philip, Stoll, Monika, Albrecht, Mario, Corneliussen, Brit, Foelsch, Ulrich R, Schreiber, Stefan, Croucher, Peter J P, Waetzig, Georg H, Lengauer, Thomas, Costello, Christine M, Mellgard, Bjorn, Seegert, Dirk, Mathew, Christopher G, Nikolaus, Susanna, Koch, W Andreas, Pierrou, Stefan
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group 01.05.2004
• Subjects: Alleles; Amino Acid Substitution; Amino acids; Biological and medical sciences; Carrier Proteins - genetics; Case-Control Studies; Child; Chromosome Mapping; Chromosomes, Human, Pair 10 - genetics; Classical genetics, quantitative genetics, hybrids; Cloning; Cloning, Molecular; Cohort Studies; Colitis, Ulcerative - epidemiology; Colitis, Ulcerative - genetics; Crohn Disease - epidemiology; Crohn Disease - genetics; Europe - epidemiology; Female; Fundamental and applied biological sciences. Psychology; Gastroenterology. Liver. Pancreas. Abdomen; Genetic aspects; Genetic diversity; Genetic variance; Genetic Variation; Genetics of eukaryotes. Biological and molecular evolution; Genotype; Genotype-environment interactions; Haplotypes; Human; Humans; Inflammatory bowel diseases; Intracellular Signaling Peptides and Proteins; Male; Medical sciences; Membrane Proteins - genetics; Mutation; Nod2 Signaling Adaptor Protein; Other diseases. Semiology; Pedigree; Polymorphism, Single Nucleotide; Risk Factors; Stomach. Duodenum. Small intestine. Colon. Rectum. Anus; Tumor Suppressor Proteins - genetics; Europe; United Kingdom; Germany; Human; Crohn disease; Gene interaction; Genetic variant; Digestive diseases; Intestinal disease; Haplotype; Inflammatory disease; Ulcerative colitis
• ISSN: 1061-4036; 1546-1718
• DOI: 10.1038/ng1345

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.