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

Abstract

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.

Fig. 1

Association signals in the IL23R gene region on chromosome 1p31. (A) Genomic locations of genes on chromosome 1p31 between 67,260,000 and 67,580,000 base pairs (Build 35). (B) The negative log₁₀ association P-values (Cochran-Mantel-Haenszel chi-square test) from the combined Jewish and non-Jewish case-control cohorts are plotted for genotyped markers in the region. (C) Pairwise r² plot for International HapMap CEU data. The intensity of the shading is proportional to r². The IL23R gene is contained within two blocks of linkage disequilibrium, and the association signals are strongest in the centromeric block, which contains exons 5 to 11 and extends into the intergenic region between IL23R and IL12RB2. Note that markers in the block encompassing the IL12RB2 gene do not demonstrate significant association.