Genetic polymorphisms of IL-23R and IL-17A and novel insights into their associations with inflammatory bowel disease

Seung Won Kim, Eun Soo Kim, Chang Mo Moon, Jae Jun Park, Tae Il Kim, Won Ho Kim, Jae Hee Cheon

Research output: Contribution to journalArticle

86 Citations (Scopus)

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 caseecontrol 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.

Original languageEnglish
Pages (from-to)1527-1536
Number of pages10
JournalGut
Volume60
Issue number11
DOIs
Publication statusPublished - 2011 Nov

All Science Journal Classification (ASJC) codes

  • Gastroenterology

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