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

Authors
 Seung Won Kim ; Eun Soo Kim ; Jae Hee Cheon ; Won Ho Kim ; Tae Il Kim ; Jae Jun Park ; Chang Mo Moon 
Citation
 Gut, Vol.60(11) : 1527~1536, 2011 
Journal Title
 Gut 
ISSN
 0017-5749 
Issue Date
2011
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.
URI
http://ir.ymlib.yonsei.ac.kr/handle/22282913/94191
DOI
10.1136/gut.2011.238477
Appears in Collections:
1. 연구논문 > 1. College of Medicine > Dept. of Internal Medicine
1. 연구논문 > 1. College of Medicine > Yonsei Biomedical Research Center
Yonsei Authors
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Link
 http://gut.bmj.com/content/60/11/1527
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