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

被引：91

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

共 54 条

[1] Nod2 in normal and abnormal intestinal immune function [J].

Abreu, MT .

GASTROENTEROLOGY, 2005, 129 (04) :1302-1304

[2] Chemokine expression in IBD. Mucosal chemokine expression is unselectively increased in both ulcerative colitis and Crohn's disease [J].

Banks, C ;

Bateman, A ;

Payne, R ;

Johnson, P ;

Sheron, N .

JOURNAL OF PATHOLOGY, 2003, 199 (01) :28-35

[3] Cell differentiation dependent expressed CCR6 mediates ERK-1/2, SAPK/JNK, and Akt signaling resulting in proliferation and migration of colorectal cancer cells [J].

Brand, S ;

Olszak, T ;

Beigel, F ;

Diebold, J ;

Otte, JM ;

Eichhorst, ST ;

Göke, B ;

Dambacher, J .

JOURNAL OF CELLULAR BIOCHEMISTRY, 2006, 97 (04) :709-723

[4] IL-22 is increased in active Crohn's disease and promotes proinflammatory gene expression and intestinal epithelial cell migration [J].

Brand, S ;

Beigel, F ;

Olszak, T ;

Zitzmann, K ;

Eichhorst, ST ;

Otte, JM ;

Diepolder, H ;

Marquardt, A ;

Jagla, W ;

Popp, A ;

Leclair, S ;

Herrmann, K ;

Seiderer, J ;

Ochsenkühn, T ;

Göke, B ;

Auernhammer, CJ ;

Dambacher, J .

AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY, 2006, 290 (04) :G827-G838

[5] Increased expression of the chemokine fractalkine in Crohn's disease and association of the fractalkine receptor T280M polymorphism with a fibrostenosing disease phenotype [J].

Brand, S ;

Hofbauer, K ;

Dambacher, J ;

Schnitzler, F ;

Staudinger, T ;

Pfennig, S ;

Seiderer, J ;

Tillack, C ;

Konrad, A ;

Göke, B ;

Ochsenkühn, T ;

Lohse, P .

AMERICAN JOURNAL OF GASTROENTEROLOGY, 2006, 101 (01) :99-106

[6] IL-28A and IL-29 mediate antiproliferative and antiviral signals in intestinal epithelial cells and murine CMV infection increases colonic IL-28A expression [J].

Brand, S ;

Beigel, F ;

Olszak, T ;

Zitzmann, K ;

Eichhorst, ST ;

Otte, JM ;

Diebold, J ;

Diepolder, H ;

Adler, B ;

Auernhammer, CJ ;

Göke, B ;

Dambacher, J .

AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY, 2005, 289 (05) :G960-G968

[7] The role of Toll-like receptor 4 Asp299Gly and Thr399Ile polymorphisms and CARD15/NOD2 mutations in the susceptibility and phenotype of Crohn's disease [J].

Brand, S ;

Staudinger, T ;

Schnitzler, F ;

Pfennig, S ;

Hofbauer, K ;

Dambacher, J ;

Seiderer, J ;

Tillack, C ;

Konrad, A ;

Crispin, A ;

Göke, B ;

Lohse, P ;

Ochsenkühn, T .

INFLAMMATORY BOWEL DISEASES, 2005, 11 (07) :645-652

[8] CXCR4 and CXCL12 are inversely expressed in colorectal cancer cells and modulate cancer cell migration, invasion and MMP-9 activation [J].

Brand, S ;

Dambacher, J ;

Beigel, F ;

Olszak, T ;

Diebold, J ;

Otte, JM ;

Göke, B ;

Eichhorst, ST .

EXPERIMENTAL CELL RESEARCH, 2005, 310 (01) :117-130

[9] Gender-stratified analysis of DLG5 R30Q in 4707 patients with Crohn disease and 4973 controls from 12 Caucasian cohorts [J].

Browning, B. L. ;

Annese, V. ;

Barclay, M. L. ;

Bingham, S. A. ;

Brand, S. ;

Buening, C. ;

Castro, M. ;

Cucchiara, S. ;

Dallapiccola, B. ;

Drummond, H. ;

Ferguson, L. R. ;

Ferraris, A. ;

Fisher, S. A. ;

Gearry, R. B. ;

Glas, J. ;

Henckaerts, L. ;

Huebner, C. ;

Knafelz, D. ;

Lakatos, L. ;

Lakatos, P. L. ;

Latiano, A. ;

Liu, X. ;

Mathew, C. ;

Mueller-Myhsok, B. ;

Newman, W. G. ;

Nimmo, E. R. ;

Noble, C. L. ;

Palmieri, O. ;

Parkes, M. ;

Petermann, I. ;

Rutgeerts, P. ;

Satsangi, J. ;

Shelling, A. N. ;

Siminovitch, K. A. ;

Toeroek, H.-P. ;

Tremelling, M. ;

Vermeire, S. ;

Valvano, M. R. ;

Witt, H. .

JOURNAL OF MEDICAL GENETICS, 2008, 45 (01) :36-42

[10] Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls [J].

Burton, Paul R. ;

Clayton, David G. ;

Cardon, Lon R. ;

Craddock, Nick ;

Deloukas, Panos ;

Duncanson, Audrey ;

Kwiatkowski, Dominic P. ;

McCarthy, Mark I. ;

Ouwehand, Willem H. ;

Samani, Nilesh J. ;

Todd, John A. ;

Donnelly, Peter ;

Barrett, Jeffrey C. ;

Davison, Dan ;

Easton, Doug ;

Evans, David ;

Leung, Hin-Tak ;

Marchini, Jonathan L. ;

Morris, Andrew P. ;

Spencer, Chris C. A. ;

Tobin, Martin D. ;

Attwood, Antony P. ;

Boorman, James P. ;

Cant, Barbara ;

Everson, Ursula ;

Hussey, Judith M. ;

Jolley, Jennifer D. ;

Knight, Alexandra S. ;

Koch, Kerstin ;

Meech, Elizabeth ;

Nutland, Sarah ;

Prowse, Christopher V. ;

Stevens, Helen E. ;

Taylor, Niall C. ;

Walters, Graham R. ;

Walker, Neil M. ;

Watkins, Nicholas A. ;

Winzer, Thilo ;

Jones, Richard W. ;

McArdle, Wendy L. ;

Ring, Susan M. ;

Strachan, David P. ;

Pembrey, Marcus ;

Breen, Gerome ;

St Clair, David ;

Caesar, Sian ;

Gordon-Smith, Katherine ;

Jones, Lisa ;

Fraser, Christine ;

Green, Elain K. .

NATURE, 2007, 447 (7145) :661-678

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