Obesity susceptible novel DNA methylation marker on regulatory region of inflammation gene: results from the Korea Epigenome Study (KES)

Introduction Obesity is growing global health concern and highly associated with increased risk of metabolic diseases including type 2 diabetes. We aimed to discover new differential DNA methylation patterns predisposing obesity and prioritize surrogate epigenetic markers in Koreans.Research design and methods We performed multistage epigenome-wide analyses to identify differentially expressed CpGs in obesity using the Illumina HumanMethylationEPIC array (EPIC). Forty-eight CpGs showed significant differences across three phases: 902 whole blood DNAs from two cohorts (phase 1: n=450, phase 2: n=377) and a hospital-based sample (phase 3: n=75). Samples from phase III participants were used to examine whether the 48 CpGs are significant in the fat tissue and influenced gene expression. Furthermore, we investigated the epigenetic effect of CpG loci in childhood obesity (n=94).Results Seven of the 48 CpGs exhibited similar changes in the fat tissue along with gene expression changes. In particular, hypomethylated CpG (cg13424229) on the GATA1 transcription factor cluster of CPA3 promoter was related to its increased gene expression and showed consistent effect in childhood obesity. Interestingly, subsequent analysis using RNA sequencing data from 21 preadipocytes and 26 adipocytes suggested CPA3 as a potential obesity-related gene. Moreover, expression patterns from RNA sequencing and public Gene Expression Omnibus showed the correlation between CPA3 and type 2 diabetes (T2D) and asthma.Conclusions Our finding prioritizes influential genes in obesity and provides new evidence for the role of CPA3 linking obesity, T2D, and asthma.