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dc.contributor.authorDiegelmann, Juliaen_US
dc.contributor.authorCzamara, Darinaen_US
dc.contributor.authorLe Bras, Emmanuelleen_US
dc.contributor.authorZimmermann, Evaen_US
dc.contributor.authorOlszak, Torstenen_US
dc.contributor.authorBedynek, Andreaen_US
dc.contributor.authorGöke, Burkharden_US
dc.contributor.authorFranke, Andreen_US
dc.contributor.authorGlas, Jürgenen_US
dc.contributor.authorBrand, Stephanen_US
dc.date.accessioned2014-03-11T02:49:54Z
dc.date.issued2013en_US
dc.identifier.citationDiegelmann, Julia, Darina Czamara, Emmanuelle Le Bras, Eva Zimmermann, Torsten Olszak, Andrea Bedynek, Burkhard Göke, Andre Franke, Jürgen Glas, and Stephan Brand. 2013. “Intestinal DMBT1 Expression Is Modulated by Crohn’s Disease-Associated IL23R Variants and by a DMBT1 Variant Which Influences Binding of the Transcription Factors CREB1 and ATF-2.” PLoS ONE 8 (11): e77773. doi:10.1371/journal.pone.0077773. http://dx.doi.org/10.1371/journal.pone.0077773.en
dc.identifier.issn1932-6203en
dc.identifier.urihttp://nrs.harvard.edu/urn-3:HUL.InstRepos:11879185
dc.description.abstractObjectives: DMBT is an antibacterial pattern recognition and scavenger receptor. In this study, we analyzed the role of DMBT1 single nucleotide polymorphisms (SNPs) regarding inflammatory bowel disease (IBD) susceptibility and examined their functional impact on transcription factor binding and downstream gene expression. Methods: Seven SNPs in the DMBT1 gene region were analyzed in 2073 individuals including 818 Crohn’s disease (CD) patients and 972 healthy controls in two independent case-control panels. Comprehensive epistasis analyses for the known CD susceptibility genes NOD2, IL23R and IL27 were performed. The influence of IL23R variants on DMBT1 expression was analyzed. Functional analysis included siRNA transfection, quantitative PCR, western blot, electrophoretic mobility shift and luciferase assays. Results: IL-22 induces DMBT1 protein expression in intestinal epithelial cells dependent on STAT3, ATF-2 and CREB1. IL-22 expression-modulating, CD risk-associated IL23R variants influence DMBT1 expression in CD patients and DMBT1 levels are increased in the inflamed intestinal mucosa of CD patients. Several DMBT1 SNPs were associated with CD susceptibility. SNP rs2981804 was most strongly associated with CD in the combined panel (p = 3.0×10−7, OR 1.42; 95% CI 1.24–1.63). All haplotype groups tested showed highly significant associations with CD (including omnibus P-values as low as 6.1×10−18). The most strongly CD risk-associated, non-coding DMBT1 SNP rs2981804 modifies the DNA binding sites for the transcription factors CREB1 and ATF-2 and the respective genomic region comprising rs2981804 is able to act as a transcriptional regulator in vitro. Intestinal DMBT1 expression is decreased in CD patients carrying the rs2981804 CD risk allele. Conclusion: We identified novel associations of DMBT1 variants with CD susceptibility and discovered a novel functional role of rs2981804 in regulating DMBT1 expression. Our data suggest an important role of DMBT1 in CD pathogenesis.en
dc.language.isoen_USen
dc.publisherPublic Library of Scienceen
dc.relation.isversionofdoi:10.1371/journal.pone.0077773en
dc.relation.hasversionhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC3818382/pdf/en
dash.licenseLAAen_US
dc.titleIntestinal DMBT1 Expression Is Modulated by Crohn’s Disease-Associated IL23R Variants and by a DMBT1 Variant Which Influences Binding of the Transcription Factors CREB1 and ATF-2en
dc.typeJournal Articleen_US
dc.description.versionVersion of Recorden
dc.relation.journalPLoS ONEen
dc.date.available2014-03-11T02:49:54Z
dc.identifier.doi10.1371/journal.pone.0077773*


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