title: The ATG16L1 gene variants rs2241879 and rs2241880 (T300A) are strongly associated with susceptibility to Crohn's disease in the German population.
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  ATG16L1 is a CD susceptibility gene without epistatic interaction with other CD susceptibility genes and is not upregulated in intestinal inflammation.
authors.affiliation: Department of Medicine II-Grosshadern, University of Munich, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Glas
authors.forename: Astrid
authors.initials: A
authors.lastname: Konrad
authors.forename: Silke
authors.initials: S
authors.lastname: Schmechel
authors.forename: Julia
authors.initials: J
authors.lastname: Dambacher
authors.forename: Julia
authors.initials: J
authors.lastname: Seiderer
authors.forename: Frieder
authors.initials: F
authors.lastname: Schroff
authors.forename: Martin
authors.initials: M
authors.lastname: Wetzke
authors.forename: Darina
authors.initials: D
authors.lastname: Roeske
authors.forename: Helga-Paula
authors.initials: HP
authors.lastname: Török
authors.forename: Laurian
authors.initials: L
authors.lastname: Tonenchi
authors.forename: Simone
authors.initials: S
authors.lastname: Pfennig
authors.forename: Dirk
authors.initials: D
authors.lastname: Haller
authors.forename: Thomas
authors.initials: T
authors.lastname: Griga
authors.forename: Wolfram
authors.initials: W
authors.lastname: Klein
authors.forename: Jörg T
authors.initials: JT
authors.lastname: Epplen
authors.forename: Christian
authors.initials: C
authors.lastname: Folwaczny
authors.forename: Peter
authors.initials: P
authors.lastname: Lohse
authors.forename: Burkhard
authors.initials: B
authors.lastname: Göke
authors.forename: Thomas
authors.initials: T
authors.lastname: Ochsenkühn
authors.forename: Thomas
authors.initials: T
authors.lastname: Mussack
authors.forename: Matthias
authors.initials: M
authors.lastname: Folwaczny
authors.forename: Bertram
authors.initials: B
authors.lastname: Müller-Myhsok
authors.forename: Stephan
authors.initials: S
authors.lastname: Brand
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D002648:Child; D003093:Colitis, Ulcerative / Q000235:genetics; D003424:Crohn Disease / Q000235:genetics* / Q000473:pathology; D004843:Epistasis, Genetic; D005260:Female; D015870:Gene Expression; D020022:Genetic Predisposition to Disease; D005838:Genotype; D005858:Germany; D006801:Humans; D007079:Ileitis / Q000235:genetics; D008297:Male; D051379:Mice; D008875:Middle Aged; D053473:Nod2 Signaling Adaptor Protein / Q000235:genetics*; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide
chemical_list: D053473:Nod2 Signaling Adaptor Protein