A genome-wide association study identifies IL23R as an inflammatory bowel disease gene

被引：2430

作者：

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.

机构：

[1] Yale Univ, IBD Ctr, Sect Digest Dis, Dept Med, New Haven, CT 06519 USA

[2] Univ Pittsburgh, Med Ctr, Sch Med,Dept Med, Div Gastroenterol Hepatol & Nutr, Pittsburgh, PA 15213 USA

[3] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Human Genet, Pittsburgh, PA 15261 USA

[4] Cedars Sinai Med Ctr, Inst Med Genet, Los Angeles, CA 90048 USA

[5] Cedars Sinai Med Ctr, Div Gastroenterol, IBD Ctr, Los Angeles, CA 90048 USA

[6] Johns Hopkins Univ, Sch Med, Dept Med, Harvey M & Lyn P Meyerhoff Inflammatory Bowel Dis, Baltimore, MD 21231 USA

[7] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD 21205 USA

[8] Univ Montreal, Montreal, PQ H1T 1C8, Canada

[9] Montreal Heart Inst, Montreal, PQ H1T 1C8, Canada

[10] MIT, Broad Inst, Med & Populat Genet Program, Cambridge, MA 02142 USA

[11] Harvard Univ, Cambridge, MA 02142 USA

[12] Univ Toronto, Mt Sinai Hosp, IBD Ctr, Toronto, ON M5G 1X5, Canada

[13] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA 02114 USA

[14] Univ Chicago, Dept Med, Chicago, IL 60637 USA

[15] Hosp Sick Children, Dept Pediat, Toronto, ON M5G 1X8, Canada

[16] McGill Univ, Royal Victoria Hosp, Ctr Hlth, Montreal, PQ H3A 1A1, Canada

[17] Cedars Sinai Med Ctr, Immunobiol Res Inst, Los Angeles, CA 90048 USA

[18] Univ Chicago, Dept Hlth Studies, Chicago, IL 60637 USA

[19] Feinstein Inst Med Res, Manhasset, NY 11030 USA

[20] Univ Chicago, Dept Stat, Chicago, IL 60637 USA

[21] Yale Univ, IBD Ctr, Sect Digest Dis, Dept Genet, New Haven, CT 06519 USA

来源：

SCIENCE | 2006年 / 314卷 / 5804期

关键词：

D O I：

10.1126/science.1135245

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 [理学]; 0710 [生物学]; 09 [农学];

摘要：

The inflammatory bowel diseases Crohn's disease and ulcerative colitis are common, chronic disorders that cause abdominal pain, diarrhea, and gastrointestinal bleeding. To identify genetic factors that might contribute to these disorders, we performed a genome-wide association study. We found a highly significant association between Crohn's disease and the IL23R gene on chromosome 1p31, which encodes a subunit of the receptor for the proinflammatory cytokine interleukin-23. An uncommon coding variant (rs11209026, c. 1142G> A, p. Arg381Gln) confers strong protection against Crohn's disease, and additional noncoding IL23R variants are independently associated. Replication studies confirmed IL23R associations in independent cohorts of patients with Crohn's disease or ulcerative colitis. These results and previous studies on the proinflammatory role of IL-23 prioritize this signaling pathway as a therapeutic target in inflammatory bowel disease.

引用

页码：1461 / 1463

页数：3

共 28 条

[1]

Interleukin-23 promotes a distinct CD4 T cell activation state characterized by the production of interleukin-17 [J].

Aggarwal, S ;

Ghilardi, N ;

Xie, MH ;

de Sauvage, FJ ;

Gurney, AL .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2003, 278 (03) :1910-1914

[2]

Constitutive p40 promoter activation and IL-23 production in the terminal ileum mediated by dendritic cells [J].

Becker, C ;

Wirtz, S ;

Blessing, M ;

Pirhonen, J ;

Strand, D ;

Bechthold, O ;

Frick, J ;

Galle, PR ;

Autenrieth, I ;

Neurath, MF .

JOURNAL OF CLINICAL INVESTIGATION, 2003, 112 (05) :693-706

[3]

Cutting edge: IL-23 cross-regulates IL-12 production in T cell-dependent experimental colitis [J].

Becker, Christoph ;

Dornhoff, Heike ;

Neufert, Clemens ;

Fantini, Massimo C. ;

Wirtz, Stefan ;

Huebner, Sabine ;

Nikolaev, Alexei ;

Lehr, Hans-Anton ;

Murphy, Andrew J. ;

Valenzuela, David M. ;

Yancopoulos, George D. ;

Galle, Peter R. ;

Karow, Margaret ;

Neurath, Markus F. .

JOURNAL OF IMMUNOLOGY, 2006, 177 (05) :2760-2764

[4]

Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells [J].

Bettelli, E ;

Carrier, YJ ;

Gao, WD ;

Korn, T ;

Strom, TB ;

Oukka, M ;

Weiner, HL ;

Kuchroo, VK .

NATURE, 2006, 441 (7090) :235-238

[5]

Mice lacking bioactive IL-12 can generate protective, antigen-specific cellular responses to mycobacterial infection only if the IL-12 p40 subunit is present [J].

Cooper, AM ;

Kipnis, A ;

Turner, J ;

Magram, J ;

Ferrante, J ;

Orme, IM .

JOURNAL OF IMMUNOLOGY, 2002, 168 (03) :1322-1327

[6]

Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain [J].

Cua, DJ ;

Sherlock, J ;

Chen, Y ;

Murphy, CA ;

Joyce, B ;

Seymour, B ;

Lucian, L ;

To, W ;

Kwan, S ;

Churakova, T ;

Zurawski, S ;

Wiekowski, M ;

Lira, SA ;

Gorman, D ;

Kastelein, RA ;

Sedgwick, JD .

NATURE, 2003, 421 (6924) :744-748

[7]

Increased expression of interleukin 17 in inflammatory bowel disease [J].

Fujino, S ;

Andoh, A ;

Bamba, S ;

Ogawa, A ;

Hata, K ;

Araki, Y ;

Bamba, T ;

Fujiyama, Y .

GUT, 2003, 52 (01) :65-70

[8]

Both IL-12p70 and IL-23 are synthesized during active Crohn's disease and are down-regulated by treatment with anti-IL-12 p40 monoclonal antibody [J].

Fuss, IJ ;

Becker, C ;

Yang, ZQ ;

Groden, C ;

Hornung, RL ;

Heller, F ;

Neurath, MF ;

Strober, W ;

Mannon, PJ .

INFLAMMATORY BOWEL DISEASES, 2006, 12 (01) :9-15

[9]

Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn's disease [J].

Hugot, JP ;

Chamaillard, M ;

Zouali, H ;

Lesage, S ;

Cézard, JP ;

Belaiche, J ;

Almer, S ;

Tysk, C ;

O'Morain, CA ;

Gassull, M ;

Binder, V ;

Finkel, Y ;

Cortot, A ;

Modigliani, R ;

Laurent-Puig, P ;

Gower-Rousseau, C ;

Macry, J ;

Colombel, JF ;

Sahbatou, M ;

Thomas, G .

NATURE, 2001, 411 (6837) :599-603

[10]

IL-23 drives a pathogenic T cell population that induces autoimmune inflammation [J].

Langrish, CL ;

Chen, Y ;

Blumenschein, WM ;

Mattson, J ;

Basham, B ;

Sedgwick, JD ;

McClanahan, T ;

Kastelein, RA ;

Cua, DJ .

JOURNAL OF EXPERIMENTAL MEDICINE, 2005, 201 (02) :233-240

← 1 2 3 →