Journal Article

Sequence variants in IL10, ARPC2 and multiple other loci contribute to ulcerative colitis susceptibility

Wijmenga, Cisca, Gazouli, Maria, Strachan, David, Sina, Christian, Rutgeerts, Paul, Karlsen, Tom H, Nikolaus, Susanna, Vatn, Morten H, Albrecht, Mario, Onnie, Clive M, Schreiber, Stefan, Rosenstiel, Philip, Mayr, Gabriele, Domingues, Francisco S, Sventoraityte, Jurgita, Weersma, Rinse K, Franke, Andre, Ellinghaus, David, Krawczak, Michael, McArdle, Wendy L, Mathew, Christopher G, Balschun, Tobias, Stokkers, Pieter C F, Nothnagel, Michael, Vermeire, Séverine

2008

Overview

Stefan Schreiber and colleagues report the results of a genome-wide association study for ulcerative colitis. Variants flanking the gene encoding the cytokine IL10 are associated with increased risk of disease, as are several other loci. Inflammatory bowel disease (IBD) typically manifests as either ulcerative colitis (UC) or Crohn's disease (CD). Systematic identification of susceptibility genes for IBD has thus far focused mainly on CD, and little is known about the genetic architecture of UC. Here we report a genome-wide association study with 440,794 SNPs genotyped in 1,167 individuals with UC and 777 healthy controls. Twenty of the most significantly associated SNPs were tested for replication in three independent European case-control panels comprising a total of 1,855 individuals with UC and 3,091 controls. Among the four consistently replicated markers, SNP rs3024505 immediately flanking the IL10 (interleukin 10) gene on chromosome 1q32.1 showed the most significant association in the combined verification samples ( P = 1.35 × 10 −12 ; OR = 1.46 (1.31–1.62)). The other markers were located in ARPC2 and in the HLA-BTNL2 region. Association between rs3024505 and CD (1,848 cases, 1,804 controls) was weak ( P = 0.013; OR = 1.17 (1.01–1.34)). IL10 is an immunosuppressive cytokine that has long been proposed to influence IBD pathophysiology. Our findings strongly suggest that defective IL10 function is central to the pathogenesis of the UC subtype of IBD.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: Actin-Related Protein 2-3 Complex - genetics / Agriculture / Animal Genetics and Genomics / Base Sequence / Biological and medical sciences / Biomedical and Life Sciences / Biomedicine / Bowel disease / Cancer Research / Case-Control Studies / Colitis, Ulcerative - genetics / Crohn's disease / Data analysis / Fundamental and applied biological sciences. Psychology / Gastroenterology. Liver. Pancreas. Abdomen / Gene Function / Genes / Genetic aspects / Genetic Predisposition to Disease / Genetics / Genetics of eukaryotes. Biological and molecular evolution / Genotype & phenotype / Health aspects / Histology / Human Genetics / Humans / Inflammatory bowel disease / Information management / Interleukin-10 / Interleukin-10 - genetics / letter / Medical sciences / Mutation - genetics / Other diseases. Semiology / Quality control / Risk / Risk factors / Single nucleotide polymorphisms / Software packages / Statistical analysis / Stomach. Duodenum. Small intestine. Colon. Rectum. Anus / Ulcerative colitis