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

[11] Delivering new disease genes [J].

Cardon, Lon R. .

SCIENCE, 2006, 314 (5804) :1403-+

[12] Haplotype structure and association to Crohn's disease of CARD15 mutations in two ethnically divergent populations [J].

Croucher, PJP ;

Mascheretti, S ;

Hampe, J ;

Huse, K ;

Frenzel, H ;

Stoll, M ;

Lu, T ;

Nikolaus, S ;

Yang, SK ;

Krawczak, M ;

Kim, WH ;

Schreiber, S .

EUROPEAN JOURNAL OF HUMAN GENETICS, 2003, 11 (01) :6-16

[13] Confirmation of the role of ATG16L1 as a Crohn's disease susceptibility gene [J].

Cummings, J. R. Fraser ;

Cooney, Rachel ;

Pathan, Saad ;

Anderson, Carl A. ;

Barrett, Jeffrey C. ;

Beckly, John ;

Geremia, Alessandra ;

Hancock, Laura ;

Guo, Changcun ;

Ahmad, Tariq ;

Cardon, Lon R. ;

Jeweil, Derek P. .

INFLAMMATORY BOWEL DISEASES, 2007, 13 (08) :941-946

[14] The role of the Toll receptor pathway in susceptibility to inflammatory bowel diseases [J].

De Jager, P. L. ;

Franchimont, D. ;

Waliszewska, A. ;

Bitton, A. ;

Cohen, A. ;

Langelier, D. ;

Belaiche, J. ;

Vermeire, S. ;

Farwell, L. ;

Goris, A. ;

Libioulle, C. ;

Jani, N. ;

Dassopoulos, T. ;

Bromfield, G. P. ;

Dubois, B. ;

Cho, J. H. ;

Brant, S. R. ;

Duerr, R. H. ;

Yang, H. ;

Rotter, J. I. ;

Silverberg, M. S. ;

Steinhart, A. H. ;

Daly, M. J. ;

Podolsky, D. K. ;

Louis, E. ;

Hafler, D. A. ;

Rioux, J. D. .

GENES AND IMMUNITY, 2007, 8 (05) :387-397

[15] A genome-wide association study identifies IL23R as an inflammatory bowel disease gene [J].

Duerr, Richard H. ;

Taylor, Kent D. ;

Brant, Steven R. ;

Rioux, John D. ;

Silverberg, Mark S. ;

Daly, Mark J. ;

Steinhart, A. Hillary ;

Abraham, Clara ;

Regueiro, Miguel ;

Griffiths, Anne ;

Dassopoulos, Themistocles ;

Bitton, Alain ;

Yang, Huiying ;

Targan, Stephan ;

Datta, Lisa Wu ;

Kistner, Emily O. ;

Schumm, L. Philip ;

Lee, Annette T. ;

Gregersen, Peter K. ;

Barmada, M. Michael ;

Rotter, Jerome I. ;

Nicolae, Dan L. ;

Cho, Judy H. .

SCIENCE, 2006, 314 (5804) :1461-1463

[16] rs1004819 Is the Main Disease-Associated IL23R Variant in German Crohn's Disease Patients: Combined Analysis of IL23R, CARD15, and OCTN1/2 Variants [J].

Glas, Juergen ;

Seiderer, Julia ;

Wetzke, Martin ;

Konrad, Astrid ;

Toeroek, Helga-Paula ;

Schmechel, Silke ;

Tonenchi, Laurian ;

Grassl, Christine ;

Dambacher, Julia ;

Pfennig, Simone ;

Maier, Kerstin ;

Griga, Thomas ;

Klein, Wolfram ;

Epplen, Joerg T. ;

Schiemann, Uwe ;

Folwaczny, Christian ;

Lohse, Peter ;

Goeke, Burkhard ;

Ochsenkuehn, Thomas ;

Mueller-Myhsok, Bertram ;

Folwaczny, Matthias ;

Mussack, Thomas ;

Brand, Stephan .

PLOS ONE, 2007, 2 (09)

[17]

Guo QS, 2004, WORLD J GASTROENTERO, V10, P1069

[18] Association between insertion mutation in NOD2 gene and Crohn's disease in German and British populations [J].

Hampe, J ;

Cuthbert, A ;

Croucher, PJP ;

Mirza, MM ;

Mascheretti, S ;

Fisher, S ;

Frenzel, H ;

King, K ;

Hasselmeyer, A ;

MacPherson, AJS ;

Bridger, S ;

van Deventer, S ;

Forbes, A ;

Nikolaus, S ;

Lennard-Jones, JE ;

Foelsch, UR ;

Krawczak, M ;

Lewis, C ;

Schreiber, S ;

Mathew, CG .

LANCET, 2001, 357 (9272) :1925-1928

[19] A genome-wide association scan of nonsynonymous SNPs identifies a susceptibility variant for Crohn disease in ATG16L1 [J].

Hampe, Jochen ;

Franke, Andre ;

Rosenstiel, Philip ;

Till, Andreas ;

Teuber, Markus ;

Huse, Klaus ;

Albrecht, Mario ;

Mayr, Gabriele ;

De La Vega, Francisco M. ;

Briggs, Jason ;

Guenther, Simone ;

Prescott, Natalie J. ;

Onnie, Clive M. ;

Haesler, Robert ;

Sipos, Bence ;

Foelsch, Ulrich R. ;

Lengauer, Thomas ;

Platzer, Matthias ;

Mathew, Christopher G. ;

Krawczak, Michael ;

Schreiber, Stefan .

NATURE GENETICS, 2007, 39 (02) :207-211

[20] Inflammatory bowel disease: Epidemiology, pathogenesis, and therapeutic opportunities [J].

Hanauer, SB .

INFLAMMATORY BOWEL DISEASES, 2006, 12 :S3-S9

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