Loci on 20q13 and 21q22 are associated with pediatric-onset inflammatory bowel disease

Inflammatory bowel disease (IBD) is a common inflammatory disorder with complex etiology that involves both genetic and environmental triggers, including but not limited to defects in bacterial clearance, defective mucosal barrier and persistent dysregulation of the immune response to commensal intestinal bacteria. IBD is characterized by two distinct phenotypes: Crohn's disease (CD) and ulcerative colitis (UC). Previously reported GWA studies have identified genetic variation accounting for a small portion of the overall genetic susceptibility to CD and an even smaller contribution to UC pathogenesis. We hypothesized that stratification of IBD by age of onset might identify additional genes associated with IBD. To that end, we carried out a GWA analysis in a cohort of 1,011 individuals with pediatric-onset IBD and 4,250 matched controls. We identified and replicated significantly associated, previously unreported loci on chromosomes 20q13 (rs2315008[T] and rs4809330[A]; P = 6.30 × 10−8 and 6.95 × 10−8, respectively; odds ratio (OR) = 0.74 for both) and 21q22 (rs2836878[A]; P = 6.01 × 10−8; OR = 0.73), located close to the TNFRSF6B and PSMG1 genes, respectively.

[1]  Chi-Hung Lin,et al.  Modulation of macrophage differentiation and activation by decoy receptor 3 , 2004, Journal of leukocyte biology.

[2]  P. Rutgeerts,et al.  Early lesions of recurrent Crohn's disease caused by infusion of intestinal contents in excluded ileum. , 1998, Gastroenterology.

[3]  L. Cardon,et al.  Inflammatory bowel disease is associated with a TNF polymorphism that affects an interaction between the OCT1 and NF(-kappa)B transcription factors. , 2002 .

[4]  Judy H Cho,et al.  Genome-wide association study identifies new susceptibility loci for Crohn disease and implicates autophagy in disease pathogenesis , 2007, Nature Genetics.

[5]  Thomas Lengauer,et al.  A genome-wide association scan of nonsynonymous SNPs identifies a susceptibility variant for Crohn disease in ATG16L1 , 2007, Nature Genetics.

[6]  D. Jewell,et al.  Contribution of genes of the major histocompatibility complex to susceptibility and disease phenotype in inflammatory bowel disease , 1996, The Lancet.

[7]  K. Mossman.  The Wellcome Trust Case Control Consortium, U.K. , 2008 .

[8]  D. Witcher,et al.  Fas ligand‐induced murine pulmonary inflammation is reduced by a stable decoy receptor 3 analogue , 2003, Immunology.

[9]  Joseph T. Glessner,et al.  Association of the T300A non-synonymous variant of the ATG16L1 gene with susceptibility to paediatric Crohn’s disease , 2007, Gut.

[10]  A. Chiu,et al.  Modulation of Dendritic Cell Differentiation and Maturation by Decoy Receptor 31 , 2002, The Journal of Immunology.

[11]  G. D'Haens,et al.  Endoscopic and histological healing with infliximab anti-tumor necrosis factor antibodies in Crohn's disease: A European multicenter trial. , 1999, Gastroenterology.

[12]  Gonçalo R. Abecasis,et al.  Genetic variants regulating ORMDL3 expression contribute to the risk of childhood asthma , 2007, Nature.

[13]  Judy H. Cho,et al.  A Genome-Wide Association Study Identifies IL23R as an Inflammatory Bowel Disease Gene , 2006, Science.

[14]  Simon Heath,et al.  Novel Crohn Disease Locus Identified by Genome-Wide Association Maps to a Gene Desert on 5p13.1 and Modulates Expression of PTGER4 , 2007, PLoS genetics.

[15]  M. Stephens,et al.  Inference of population structure using multilocus genotype data: linked loci and correlated allele frequencies. , 2003, Genetics.

[16]  C. Johnson.  Progress and Prospects , 1991 .

[17]  J. Satsangi,et al.  Toward an integrated clinical, molecular and serological classification of inflammatory bowel disease: report of a Working Party of the 2005 Montreal World Congress of Gastroenterology. , 2005, Canadian journal of gastroenterology = Journal canadien de gastroenterologie.

[18]  L. Milani,et al.  An insertion-deletion polymorphism in the interferon regulatory Factor 5 (IRF5) gene confers risk of inflammatory bowel diseases. , 2007, Human molecular genetics.

[19]  R. Shamir,et al.  Pediatric onset Crohn's colitis is characterized by genotype‐dependent age‐related susceptibility , 2007, Inflammatory bowel diseases.

[20]  Christopher G Mathew,et al.  Genetics of inflammatory bowel disease: progress and prospects. , 2004, Human molecular genetics.

[21]  Sunghee Kim,et al.  Increased expression of soluble decoy receptor 3 in acutely inflamed intestinal epithelia. , 2005, Clinical immunology.

[22]  S. Hsieh,et al.  Epigenetic control of MHC class II expression in tumor-associated macrophages by decoy receptor 3. , 2008, Blood.

[23]  J. Hugot,et al.  Ileal Involvement Is Age Dependent in Pediatric Crohn's Disease , 2005, Inflammatory bowel diseases.

[24]  Alastair Forbes,et al.  Sequence variants in the autophagy gene IRGM and multiple other replicating loci contribute to Crohn's disease susceptibility , 2007, Nature Genetics.

[25]  Simon C. Potter,et al.  Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls , 2007, Nature.

[26]  A. Keshavarzian,et al.  Apoptosis resistance in ulcerative colitis: High expression of decoy receptors by lamina propria T cells , 2006, European journal of immunology.

[27]  A. Levine,et al.  Resistance of Crohn's disease T cells to multiple apoptotic signals is associated with a Bcl-2/Bax mucosal imbalance. , 1999, Journal of immunology.

[28]  Joseph T. Glessner,et al.  A genome-wide association study identifies KIAA0350 as a type 1 diabetes gene , 2007, Nature.

[29]  Joseph T. Glessner,et al.  Association of variants of the interleukin-23 receptor gene with susceptibility to pediatric Crohn's disease. , 2007, Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association.