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Genetic polymorphisms of the interleukin 23 receptor and interleukin 17A and their associations with inflammatory bowel diseases

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Dept. of Medical Science/박사
Inflammatory bowel disease (IBD), which includes mainly ulcerative colitis (UC) and Crohn’s disease (CD), is characterized by chronic relapsing intestinal inflammation. Currently, IBD is considered to be caused by a complex interaction of genetic, environmental, and other processes involving immunoregulatory factors of which play a principal role in the pathogenesis of IBD. Recently, a particular subset of T helper cells (Th17 cells) characterized by interleukin 17A (IL-17A or further referred to as IL-17) production was implicated as a critical mediators of autoimmune disease including IBD and the IL-23R gene is known to be a susceptibility gene related to IBD in Caucasian IBD patients, although it has not been detected in Asian populations. Moreover, while there are a few reports on the associations of IL-17A gene polymorphisms, it is still unknown whether IL-17A SNPs are associated with IBD susceptibility except rs2275913 and, if so, how these IL-17A SNPs exactly modulate IBD susceptibility.Thus, It was investigated the associations of genetic and epigenetic variations in IL-23R and IL-17A with the development of IBD in this study. The promoters and exon regions encompassing the intron junctions of IL-23R and IL-17A were analyzed in 728 subjects including 201 CD patients, 268 UC patients, and 259 healthy controls using DNA sequencing and denaturing high performance liquid chromatography. Associations of IL-23R and IL-17A polymorphisms with IBD susceptibility were analyzed and their gene-gene interactions including STAT4 SNPs were tested using logistic regression analysis. Jurkat cells and peripheral blood mononuclear cells (PBMC) were used for in vitro assay as follows. The transcription factor binding activity was determined using electrophoretic mobility shift assay, IL-17A mRNA expression levels by reverse-transcriptase polymerase chain reaction, and methylation status of IL-17A promoter by bisulfite sequencing and pyrosequencing. In CD, a case-control analysis showed that disease development was associated with the IL-23R variant G149R (odds ratios [OR] 0.32, 95% confidence intervals [CI] 0.15–0.68) and IL-17A variant IVS1+18G>C (OR 10.65, 95% CI 1.32–85.89). The analysis for UC showed an association with IL-23R variants G149R (OR 0.41, 95% CI 0.21–0.76), IVS4+17C>T (OR 2.89, 95% CI 1.20–6.96), and Q3H (OR 0.61, 95% CI 0.38-0.99), and IL-17A variants -737C>T (OR 1.50, 95% CI 1.06–2.13), -197G>A (OR 0.63, 95% CI 0.40–0.97), and IVS1+18 G>C (OR 8.93, 95% CI 1.12–70.99). As further evidence of the synergistic effect of the genes in this pathway in the development of IBD, a significant statistical gene-gene interaction among IL-23R, IL-17A and STAT4 were observed. The -877G, -737T, and -444A risk alleles of IL-17A displayed higher binding affinity of transcription factor complex and higher expression levels of IL-17A transcripts. DNA hypomethylation of the IL-17A promoter was observed in PBMCs from IBD patients with a methylation extent of IVS1+17 site and significant inverse correlation between IL-17A mRNA level. Finally, IL-17A mRNA expression was restored after exposure to demethylating agent in Jurkat cells. The results of this study provide insights into the genetic and epigenetic interactions in the IL-23R/IL-17 axis including STAT4 that are associated with elevated expression of IL-17 and IBD pathogenesis.
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