Aberrant Promoter Methylation of the Suppressor of Cytokine Signaling 3 (SOCS3) Gene in Colorectal Mucosa Is Associated with Susceptibility to Ulcerative Colitis

Background: Growing evidence supports that changes in the expression of the suppressor of cytokine sig- naling 3 (SOCS3) protein contribute to the pathogenesis of types of inflammatory bowel diseases (IBDs), including ulcerative colitis (UC). Despite the importance of the currently known genetic risk map, an increasing number of observations reveal that epigenetic modifications, including DNA methylation, are considered as or even more important for IBD pathogenesis than genetic predisposition. We investigated the hypothesis that alterations in DNA methylation status at the promoter region within the SOCS3 gene in colorectal tissue specimens may be involved in the susceptibility to UC. Methods: WWe studied extracted DNA from colorectal biopsies of 15 ulcerative colitis cases and 15 age— and sex-matched healthy controls and performed genotype analyses of the promoter methylation status of the SOCS3 gene, using the real-time quantitative multiplex methylation-specific PCR (QM-MSP) assay to show evidence of differential methylation between cases of ulcerative colitis and healthy controls. Results: Based on methylation assay data profiling, we found that the mean CpG island methylation lev- els at the SOCS3 gene promoter region in colorectal mucosa of patients with UC was significantly higher than mucosa from healthy controls (ulcerative colitis vs. healthy controls; 0.00007±0.0018 vs. 0.07±0.142, P<0.000). Conclusion: Our data provide an important insight into the influence of epigenetic aberrances in the SOCS3 gene such that the inactivation of the SOCS3 gene by promoter hypermethylation might be a risk factor for inflamed mucosa of UC. It might also fundamentally contribute to the initiation of the inflammatory process and development of UC.