The ATG16L1 Gene Variants rs2241879 and rs2241880 (T300A) Are Strongly Associated With Susceptibility to Crohn's Disease in the German Population View Full Text


Ontology type: schema:ScholarlyArticle     


Article Info

DATE

2008-03

AUTHORS

Jürgen Glas, Astrid Konrad, Silke Schmechel, Julia Dambacher, Julia Seiderer, Frieder Schroff, Martin Wetzke, Darina Roeske, Helga-Paula Török, Laurian Tonenchi, Simone Pfennig, Dirk Haller, Thomas Griga, Wolfram Klein, Jörg T Epplen, Christian Folwaczny, Peter Lohse, Burkhard Göke, Thomas Ochsenkühn, Thomas Mussack, Matthias Folwaczny, Bertram Müller-Myhsok, Stephan Brand

ABSTRACT

OBJECTIVES: We analyzed ATG16L1, a recently identified Crohn's disease (CD) susceptibility gene, in a large cohort with inflammatory bowel disease (IBD) including potential interactions with other IBD genes as well as factors regulating its gene expression. METHODS: Genomic DNA from 2,890 Caucasians including 768 patients with CD, 507 patients with ulcerative colitis (UC), and 1,615 healthy controls was analyzed for 9 different ATG16L1 single nucleotide polymorphisms (SNPs). Genotyping included CARD15/NOD2 variants p.Arg702Trp, p.Gly908Arg, and p.Leu1007fsX1008 and polymorphisms in SLC22A4/OCTN1 (1672 C-->T) and SLC22A5/OCTN2 (-207 G-->C) as well as 10 CD-associated IL23R variants. The transcriptional regulation of ATG16L1 was studied in intestinal epithelial cells following stimulation with Toll-like receptor (TLR) ligands and proinflammatory cytokines and in a murine ileitis model and CD biopsies. RESULTS: All nine ATG16L1 gene variants analyzed displayed highly significant associations with CD demonstrating a CD-protective effect for the minor allele. The strongest associations were found for rs2241879 and the coding SNP rs2241880 (T300A); P= 3.6 x 10(-6) and 3.7 x 10(-6), respectively (OR 0.74, 95% CI 0.65-0.84 for both variants). The genotype-phenotype analysis revealed no significant associations. In UC, only rs6431660 was weakly disease-associated. There was no evidence for epistasis between the ATG16L1 gene and other susceptibility genes (IL23R, CARD15, SLC22A4/5). ATG16L1 mRNA expression was not upregulated in CD and murine ileitis, and was less than threefold increased in cells stimulated with proinflammatory cytokines and TLR ligands. CONCLUSION: ATG16L1 is a CD susceptibility gene without epistatic interaction with other CD susceptibility genes and is not upregulated in intestinal inflammation. More... »

PAGES

ajg200850135

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  • Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1111/j.1572-0241.2007.01694.x

    DOI

    http://dx.doi.org/10.1111/j.1572-0241.2007.01694.x

    DIMENSIONS

    https://app.dimensions.ai/details/publication/pub.1030434838

    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/18162085


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