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P069 New methylation biomarker panel of inflammatory Mucosa in Korean Crohn’s disease

S. M. Lee1, T. O. Kim*2

1Dongnam Institute of Radiological and Medical Sciences (DIRAMS), Busan, South Korea, 2Inje University Haeundae Paik Hospital, Busan, South Korea

Background

Inflammatory bowel disease (IBD) is known to be caused by a genetic predisposition involving multiple genes; however, there is growing evidence that abnormal interaction with environmental, particularly epigenetic, factors can have a significant contribution during the development of IBD. Although many studies, particularly genome-wide association studies (GWAS), have been performed to identify the genetic changes underlying the pathogenesis of Crohn’s disease (CD), the role of epigenetic changes in the development of complications arising from CD is poorly understood.

Methods

We employed an unbiased approach to define DNA methylation alteration in CD patients using the HumanMethylation450K BeadChip platform. We validated the methylation levels of 19 genes that showed hypermethylation in CD patients compared with normal control. Technical validation was performed using quantitative MSP analysis. And, we performed functional implication of hypermethylated genes in CD analysed by gene-network

Results

Compared with normal controls, the majority of differential DNA methylation in CD patient samples was in the promoter, intergenic, and gene body regions. The DNA methylation profile in CD revealed 134 probes (23 hypermethylated and 111 hypomethylated probes) that were differentially methylated. Among hypermethylated genes in CD patients, we selected candidate genes (ZFP36L1, ANXA2, EP400, FHIT, TPPP, IL5RA, KBTBD11, MDFIC, MUM1, PUSL1, RUNX3, C19orf24, TRPM4, PPP1R15A, CDT1, SFRS1, EPHA4, CCDC42B, and HNRNPUL1) that were hypermethylated (>3-fold increase in methylation) in CD patient samples. We determined the methylation levels of these 19 genes between normal and CD samples from the methylation profile, and indeed found that most of 19 candidate genes were significantly hypermethylated in CD patients compared with normal controls. We validated the methylation levels of 19 genes that showed hypermethylation in CD patients compared with normal control. MSP analysis showed that the Fragile Histidine Triad (FHIT) genes were hypermethylated in a disease-specific manner. Gene network analysis of the hypermethylated candidates suggested putative molecular interactions relevant to IBD pathology.

Conclusion

Our DNA methylation profile identifies newly hypermethylated genes in CD, as well as the gene network associated with disease development, which may contribute to the pathogenesis and activity of IBD.