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

[Guest guest]



http://www.ingentaconnect.com/content/bsc/ajg/2008/00000103/00000003/art00027;jsessionid=1sik168bpt5cs.alexandra

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, Silke1; Dambacher, 1; Seiderer, 1; Schroff, Frieder2; Wetzke, ; Roeske, Darina3; Török, Helga-a1; Tonenchi, Laurian2; Pfennig, Simone1; Haller, Dirk4; Griga, 5; Klein, Wolfram6; Epplen, Jörg T.6; Folwaczny, Christian7; Lohse, 8; Göke, Burkhard1; Ochsenkühn, 1; Mussack, 7; Folwaczny, Matthias2; Müller-Myhsok, Bertram3; Brand, Stephan1

Source: The American Journal of Gastroenterology, Volume 103, Number 3, March 2008 , pp. 682-691(10)

Publisher: Blackwell Publishing

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. (Am J Gastroenterol 2008;103:682-691)

Document Type: Research article

DOI: 10.1111/j.1572-0241.2007.01694.x

Affiliations: 1: Department of Medicine II - Grosshadern, University of Munich, Germany 2: Department of Preventive Dentistry and Periodontology, University of Munich, Germany 3: Max-Planck Institute of Psychiatry, Munich, Germany 4: Nutrition and Food Research Center, Experimental Nutritional Medicine, Technical University Munich-Weihenstephan, Germany 5: Department of Internal Medicine, Knappschaftskrankenhaus Dortmund, Germany 6: Department of Human Genetics, Ruhr-University Bochum, Germany 7: Department of Surgery (Campus Innenstadt), University of Munich, Germany 8: Institute of Clinical Chemistry - Grosshadern, University of Munich, Germany