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- Title
The ATG16L1 Gene Variants rs2241879 and rs2241880 (T300A) Are Strongly Associated With Susceptibility to Crohn's Disease in the German Population.
- Authors
Glas, Jürgen; Konrad, Astrid; Schmechel, Silke; Dambacher, Julia; Seiderer, Julia; Schroff, Frieder; Wetzke, Martin; Roeske, Darina; Török, Helga-Paula; Tonenchi, Laurian; Pfennig, Simone; Haller, Dirk; Griga, Thomas; Klein, Wolfram; Epplen, Jörg T.; Folwaczny, Christian; Lohse, Peter; Göke, Burkhard; Ochsenkühn, Thomas; Mussack, Thomas
- 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 × 10−6 and 3.7 × 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.
- Subjects
INFLAMMATORY bowel diseases; CROHN'S disease; INTESTINAL diseases; IMMUNOREGULATION; COLON diseases; GENETIC research
- Publication
American Journal of Gastroenterology (Springer Nature), 2008, Vol 103, Issue 3, p682
- ISSN
0002-9270
- Publication type
Article
- DOI
10.1111/j.1572-0241.2007.01694.x