Genetic polymorphisms of IL-23R and IL-17A and novel insights into their associations with inflammatory bowel disease. Issue 11 (14th June 2011)

• Record Type: Journal Article
• Authors: Kim, Seung Won; Kim, Eun Soo; Moon, Chang Mo; Park, Jae Jun; Kim, Tae Il; Kim, Won Ho; Cheon, Jae Hee
• Is Part Of: Gut. Volume 60:Issue 11(2011)
• Page Start: 1527
• Page End: 1536
• Publication Date: 2011-06-14
• Subjects: Genetic polymorphism -- IL-17A -- IL-23R -- inflammatory bowel disease; Gastroenterology -- Periodicals; 616.33
• DOI: 10.1136/gut.2011.238477
• Languages: English
• ISSNs: 0017-5749

Abstract

Abstract : Background and Aims: To identify the associations of genetic and epigenetic variations in IL-23R and IL-17A with inflammatory bowel diseases (IBD). Methods: The promoter and exon regions of IL-23R and IL-17A were analysed in 727 subjects (201 Crohn's disease, 268 ulcerative colitis and 258 healthy controls) using DNA sequencing and denaturing high performance liquid chromatography. Transcription factor binding affinity, IL-17A mRNA expression and methylation of the IL-17A promoter were evaluated in peripheral blood mononuclear cells (PBMC) and Jurkat cells. Results: A case–control analysis showed that development of Crohn's disease is associated with the IL-23R variant G149R (OR 0.32, 95% CI 0.15 to 0.68) and IL-17A variant IVS1+18G>C (OR 10.65, 95% CI 1.32 to 85.89). Ulcerative colitis patients showed an association with IL-23R variants G149R (OR 0.41, 95% CI 0.21 to 0.76), IVS4+17C>T (OR 2.89, 95% CI 1.20 to 6.96) and Q3H (OR 0.61, 95% CI 0.38 to 0.99), and IL-17A variants −737C>T (OR 1.50, 95% CI 1.06 to 2.13), −197G>A (OR 0.63, 95% CI 0.40 to 0.97) and IVS1+18 G>C (OR 8.93, 95% CI 1.12 to 70.99). The −877G, −737T and −444A risk alleles of IL-17A displayed higher binding affinities with the transcription factor complex and higher expression levels of IL-17A transcripts. DNA hypomethylation of the IL-17A promoter was observed in PBMC from IBD patients with a significant inverse correlation between methylation extent of IVS1+17 and IL-17A mRNA level. Finally, Jurkat cells recovered IL-17A mRNA expression after exposure to demethylating agent. Conclusions: The results provide insights into the genetic and epigenetic interactions in the IL-23R/IL-17 axis that are associated with elevated expression of IL-17 and IBD pathogenesis.