期刊
CLINICAL EPIGENETICS
卷 7, 期 -, 页码 -出版社
BMC
DOI: 10.1186/s13148-015-0073-5
关键词
DNA methylation; Epigenetics; Monozygotic twins; Obesity; Liver fat
资金
- Academy of Finland [251316, 100499, 205585, 118555, 141054, 266286, 272376]
- Sigrid Juselius Foundation
- Helsinki University Hospital Research Funds
- Novo Nordisk
- Finnish Diabetes Research Foundation
- Finnish Foundation for Cardiovascular Research
- Biomedicum Helsinki
- Jalmari and Rauha Ahokas Foundation
- Academy of Finland Center of Excellence in Complex Disease Genetics [213506, 129680]
- European Network for Genetic and Genomic Epidemiology (ENGAGE) [201413]
- Molecular Targets Open for Regulation by the gut flora New Avenues for improved Diet to Optimize European health (TORNADO) [FP7-KBBE-222720]
- EPITRAIN -Innovative techniques
- BioSHaRE-EU [HEALTH-F4-2010-261433]
- European Union
- Novo Nordisk Fonden [NNF10OC1013354] Funding Source: researchfish
Background: The current epidemic of obesity and associated diseases calls for swift actions to better understand the mechanisms by which genetics and environmental factors affect metabolic health in humans. Monozygotic (MZ) twin pairs showing discordance for obesity suggest that epigenetic influences represent one such mechanism. We studied genome-wide leukocyte DNA methylation variation in 30 clinically healthy young adult MZ twin pairs discordant for body mass index (BMI; average within-pair BMI difference: 5.4 +/- 2.0 kg/m(2)). Results: There were no differentially methylated cytosine-guanine (CpG) sites between the co-twins discordant for BMI. However, stratification of the twin pairs based on the level of liver fat accumulation revealed two epigenetically highly different groups. Significant DNA methylation differences (n = 1,236 CpG sites (CpGs)) between the co-twins were only observed if the heavier co-twins had excessive liver fat (n = 13 twin pairs). This unhealthy pattern of obesity was coupled with insulin resistance and low-grade inflammation. The differentially methylated CpGs included 23 genes known to be associated with obesity, liver fat, type 2 diabetes mellitus (T2DM) and metabolic syndrome, and potential novel metabolic genes. Differentially methylated CpG sites were overrepresented at promoters, insulators, and heterochromatic and repressed regions. Based on predictions by overlapping histone marks, repressed and weakly transcribed sites were significantly more often hypomethylated, whereas sites with strong enhancers and active promoters were hypermethylated. Further, significant clustering of differentially methylated genes in vitamin, amino acid, fatty acid, sulfur, and renin-angiotensin metabolism pathways was observed. Conclusions: The methylome in leukocytes is altered in obesity associated with metabolic disturbances, and our findings indicate several novel candidate genes and pathways in obesity and obesity-related complications.
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