Genetic polymorphisms of IL-23R and IL-17A and novel insights into their associations with inflammatory bowel disease
- Seung Won Kim1,2,
- Eun Soo Kim1,
- Chang Mo Moon1,
- Jae Jun Park1,
- Tae Il Kim1,
- Won Ho Kim1,2,
- Jae Hee Cheon1,2
- 1Department of Internal Medicine and Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
- 2Brain Korea 21 Project for Medical Science, Yonsei University, Seoul, Korea
- Correspondence to Professor Jae Hee Cheon, Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, 250 Seongsanno, Seodaemun-gu, Seoul 120-752, Korea; Professor Won Ho Kim, Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, 250 Seongsanno, Seodaemun-gu, Seoul 120-752, Korea;
- Received 18 January 2011
- Accepted 16 May 2011
- Published Online First 14 June 2011
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.
See Commentary, p 1447
This paper was presented at the UEGW 2010 in Barcelona, Spain.
Funding This work was supported by a grant from the Korea Research Foundation under the basic research promotion fund of the Ministry of Education and Health Resources Development of Korea (KRF-2008-331-E00105).
Competing interests None.
Patient consent Obtained.
Ethics approval This study was conducted with the approval of the institutional review board of the Severance Hospital in Korea.
Provenance and peer review Not commissioned; externally peer reviewed.