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

被引：92

作者：

Glas, Jurgen ^{[1
,2
]}

Konrad, Astrid ^{[1
]}

Schmechel, Silke ^{[1
]}

Dambacher, Julia ^{[1
]}

Seiderer, Julia ^{[1
]}

Schroff, Frieder ^{[2
]}

Wetzke, Martin ^{[1
,2
]}

Roeske, Darina ^{[3
]}

Toeroek, Helga-Paula ^{[1
]}

Tonenchi, Laurian ^{[2
]}

Pfennig, Simone ^{[1
]}

Haller, Dirk ^{[4
]}

Griga, Thomas ^{[5
]}

Klein, Wolfram ^{[6
]}

Epplen, Joerg T. ^{[6
]}

Folwaczny, Christian ^{[7
]}

Lohse, Peter ^{[8
]}

Goeke, Burkhard ^{[1
]}

Ochsenkuehn, Thomas ^{[1
]}

Mussack, Thomas ^{[7
]}

Folwaczny, Matthias ^{[2
]}

Mueller-Myhsok, Bertram ^{[3
]}

Brand, Stephan ^{[1
]}

机构：

[1] Univ Munich, Dept Med 2 Grosshadern, D-81377 Munich, Germany

[2] Univ Munich, Dept Prevent Dent & Periodontol, D-81377 Munich, Germany

[3] Max Planck Inst Psychiat, D-80804 Munich, Germany

[4] Tech Univ Munich Weihenstephan, Nutr & Food Res Ctr, Munich, Germany

[5] Knappschaftskrankenhaus Dortmund, Dept Internal Med, Dortmund, Germany

[6] Ruhr Univ Bochum, Dept Human Genet, Bochum, Germany

[7] Univ Munich, Dept Surg Campus Innenstadt, D-81377 Munich, Germany

[8] Univ Munich, Inst Clin Chem Grosshadern, D-81377 Munich, Germany

来源：

AMERICAN JOURNAL OF GASTROENTEROLOGY | 2008年 / 103卷 / 03期

关键词：

D O I：

10.1111/j.1572-0241.2007.01694.x

中图分类号：

R57 [消化系及腹部疾病];

学科分类号：

摘要：

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

引用

页码：682 / 691

页数：10

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