Abstract
Knowledge of epigenetically regulated biomarkers linked to obesity development is still scarce. Improving molecular understanding of the involved factors and pathways would improve obesity phenotype characterization and reveal potentially relevant targets for obesity intervention. The Illumina Infinium HumanMethylation450 BeadChip was used in a leucocyte epigenome-wide association study (EWAS) to quantify differential DNA methylation in 60 lean compared with 60 obese young women. Replication was done in monozygotic twins discordant for obesity. At adolescence and adulthood, the two weight groups differed significantly in obesity-related traits and metabolic risk factors. Differential hypomethylation was overrepresented in obese compared to lean women. In the adjusted model, the EWAS revealed 10 differentially methylated CpG sites linked to 8 gene loci – COX6A1P2/FGD2, SBNO2, TEX41, RPS6KA2, IGHE/IGHG1/IGHD, DMAP1, SOCS3, and SETBP1– and an enhancer locus at chromosome 2 (2p25.1). The sites linked to TEX41, IGHE/IGHG1/IGHD, DMAP1, and SETBP1 were novel findings, while COX6A1P/FGD2, SBNO2, RPS6KA2, and SOCS3 had been identified previously with concordant direction of effects. RPS6KA2, DMAP1, and SETBP1 were replicated in the BMI-discordant monozygotic twin cohort using the FDR of 5%.
Highlights
Obesity has become a huge global health burden[1,2] with the concurrent risks of co-morbidities such as cardiovascular disease, type 2 diabetes[3], and various types of cancer[4]
This notion is oversimplified[13], as recent research has indicated that DNA methylation at gene promoters and enhancers are associated with gene silencing, whereas higher methylation in the gene body is associated with active gene expression[14]
The two groups were significantly different for most relevant obesity and metabolic risk factors: triglycerides, glucose, HDL cholesterol, blood pressure, serum micro C-reactive protein, thyroid stimulating hormone, and Type 2 diabetes risk score[39] at adulthood
Summary
Obesity has become a huge global health burden[1,2] with the concurrent risks of co-morbidities such as cardiovascular disease, type 2 diabetes[3], and various types of cancer[4]. The epigenetic modification that leads to altered DNA methylation in cytosine-guanine dinucleotide (CpG) rich regions may result in altered gene expression[8,9] with effects on timing and regulation of specific genes during various parts of the life course. For obesity-related traits, two groups of epigenetic markers are hypothesized to provide effects: a more permanent group that may pre-dispose to obesity and a less permanent group that is a consequence of obesity[15]. An intriguing question is whether DNA methylation alterations are a consequence rather than a cause of obesity, and several recent studies have indicated that the methylation alterations at the majority of BMI-associated CpGs precede obesity development[19,20]. Through a Mendelian randomization (MR) approach, it has been found that maternal glycaemia and epigenetic regulation of leptin in offspring probably contributes to long-term programming of the child’s adiposity in later life[22]
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