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Common variants at five new loci associated with early-onset inflammatory bowel disease.

ABSTRACT: The inflammatory bowel diseases (IBD) Crohn's disease and ulcerative colitis are common causes of morbidity in children and young adults in the western world. Here we report the results of a genome-wide association study in early-onset IBD involving 3,426 affected individuals and 11,963 genetically matched controls recruited through international collaborations in Europe and North America, thereby extending the results from a previous study of 1,011 individuals with early-onset IBD. We have identified five new regions associated with early-onset IBD susceptibility, including 16p11 near the cytokine gene IL27 (rs8049439, P = 2.41 x 10(-9)), 22q12 (rs2412973, P = 1.55 x 10(-9)), 10q22 (rs1250550, P = 5.63 x 10(-9)), 2q37 (rs4676410, P = 3.64 x 10(-8)) and 19q13.11 (rs10500264, P = 4.26 x 10(-10)). Our scan also detected associations at 23 of 32 loci previously implicated in adult-onset Crohn's disease and at 8 of 17 loci implicated in adult-onset ulcerative colitis, highlighting the close pathogenetic relationship between early- and adult-onset IBD.

SUBMITTER: Imielinski M

PROVIDER: S-EPMC3267927 | biostudies-literature | 2009 Dec

REPOSITORIES: biostudies-literature

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Common variants at five new loci associated with early-onset inflammatory bowel disease.

Imielinski Marcin M Baldassano Robert N RN Griffiths Anne A Russell Richard K RK Annese Vito V Dubinsky Marla M Kugathasan Subra S Bradfield Jonathan P JP Walters Thomas D TD Sleiman Patrick P Kim Cecilia E CE Muise Aleixo A Wang Kai K Glessner Joseph T JT Saeed Shehzad S Zhang Haitao H Frackelton Edward C EC Hou Cuiping C Flory James H JH Otieno George G Chiavacci Rosetta M RM Grundmeier Robert R Castro Massimo M Latiano Anna A Dallapiccola Bruno B Stempak Joanne J Abrams Debra J DJ Taylor Kent K McGovern Dermot D Silber Gary G Wrobel Iwona I Quiros Antonio A Barrett Jeffrey C JC Hansoul Sarah S Nicolae Dan L DL Cho Judy H JH Duerr Richard H RH Rioux John D JD Brant Steven R SR Silverberg Mark S MS Taylor Kent D KD Barmuda M Michael MM Bitton Alain A Dassopoulos Themistocles T Datta Lisa Wu LW Green Todd T Griffiths Anne M AM Kistner Emily O EO Murtha Michael T MT Regueiro Miguel D MD Rotter Jerome I JI Schumm L Philip LP Steinhart A Hillary AH Targan Stephen R SR Xavier Ramnik J RJ Libioulle Cécile C Sandor Cynthia C Lathrop Mark M Belaiche Jacques J Dewit Olivier O Gut Ivo I Heath Simon S Laukens Debby D Mni Myriam M Rutgeerts Paul P Van Gossum André A Zelenika Diana D Franchimont Denis D Hugot J P JP de Vos Martine M Vermeire Severine S Louis Edouard E Cardon Lon R LR Anderson Carl A CA Drummond Hazel H Nimmo Elaine E Ahmad Tariq T Prescott Natalie J NJ Onnie Clive M CM Fisher Sheila A SA Marchini Jonathan J Ghori Jilur J Bumpstead Suzannah S Gwillam Rhian R Tremelling Mark M Delukas Panos P Mansfield John J Jewell Derek D Satsangi Jack J Mathew Christopher G CG Parkes Miles M Georges Michel M Daly Mark J MJ Heyman Melvin B MB Ferry George D GD Kirschner Barbara B Lee Jessica J Essers Jonah J Grand Richard R Stephens Michael M Levine Arie A Piccoli David D Van Limbergen John J Cucchiara Salvatore S Monos Dimitri S DS Guthery Stephen L SL Denson Lee L Wilson David C DC Grant Straun F A SF Daly Mark M Silverberg Mark S MS Satsangi Jack J Hakonarson Hakon H

Nature genetics 20091115 12

The inflammatory bowel diseases (IBD) Crohn's disease and ulcerative colitis are common causes of morbidity in children and young adults in the western world. Here we report the results of a genome-wide association study in early-onset IBD involving 3,426 affected individuals and 11,963 genetically matched controls recruited through international collaborations in Europe and North America, thereby extending the results from a previous study of 1,011 individuals with early-onset IBD. We have iden ...[more]

PMID: 19915574

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Project description:Severe forms of inflammatory bowel disease (IBD) that develop in very young children can be caused by variants in a single gene. We performed whole-exome sequence (WES) analysis to identify genetic factors that might cause granulomatous colitis and severe perianal disease, with recurrent bacterial and viral infections, in an infant of consanguineous parents.We performed targeted WES analysis of DNA collected from the patient and her parents. We validated our findings by a similar analysis of DNA from 150 patients with very-early-onset IBD not associated with known genetic factors analyzed in Toronto, Oxford, and Munich. We compared gene expression signatures in inflamed vs noninflamed intestinal and rectal tissues collected from patients with treatment-resistant Crohn's disease who participated in a trial of ustekinumab. We performed functional studies of identified variants in primary cells from patients and cell culture.We identified a homozygous variant in the tripartite motif containing 22 gene (TRIM22) of the patient, as well as in 2 patients with a disease similar phenotype. Functional studies showed that the variant disrupted the ability of TRIM22 to regulate nucleotide binding oligomerization domain containing 2 (NOD2)-dependent activation of interferon-beta signaling and nuclear factor-?B. Computational studies demonstrated a correlation between the TRIM22-NOD2 network and signaling pathways and genetic factors associated very early onset and adult-onset IBD. TRIM22 is also associated with antiviral and mycobacterial effectors and markers of inflammation, such as fecal calprotectin, C-reactive protein, and Crohn's disease activity index scores.In WES and targeted exome sequence analyses of an infant with severe IBD characterized by granulomatous colitis and severe perianal disease, we identified a homozygous variant of TRIM22 that affects the ability of its product to regulate NOD2. Combined computational and functional studies showed that the TRIM22-NOD2 network regulates antiviral and antibacterial signaling pathways that contribute to inflammation. Further study of this network could lead to new disease markers and therapeutic targets for patients with very early and adult-onset IBD.

Dataset Information

Common variants at five new loci associated with early-onset inflammatory bowel disease.

Publications

Common variants at five new loci associated with early-onset inflammatory bowel disease.

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