title: Genome-wide blood DNA methylation alterations at regulatory elements and heterochromatic regions in monozygotic twins discordant for obesity and liver fat.
abstract: 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.
authors: Department of Public Health, University of Helsinki, Helsinki, Finland.
authors: Miina
authors: M
authors: Ollikainen
authors: Department of Public Health, University of Helsinki, Helsinki, Finland.
authors: Khadeeja
authors: K
authors: Ismail
authors: Department of Medical Genetics, Oslo University Hospital and University of Oslo, Oslo, Norway.
authors: Kristina
authors: K
authors: Gervin
authors: Obesity Research Unit, Research Programs Unit, Diabetes and Obesity, University of Helsinki, Helsinki, Finland.
authors: Anjuska
authors: A
authors: Kyllönen
authors: Department of Radiology, HUS Medical Imaging Center, Helsinki University Central Hospital, University of Helsinki, Helsinki, Finland.
authors: Antti
authors: A
authors: Hakkarainen
authors: Department of Radiology, HUS Medical Imaging Center, Helsinki University Central Hospital, University of Helsinki, Helsinki, Finland.
authors: Jesper
authors: J
authors: Lundbom
authors: Obesity Research Unit, Research Programs Unit, Diabetes and Obesity, University of Helsinki, Helsinki, Finland.
authors: Elina A
authors: EA
authors: Järvinen
authors: Division of Epidemiology, The Norwegian Institute of Public Health, Oslo, Norway.
authors: Jennifer R
authors: JR
authors: Harris
authors: Department of Radiology, HUS Medical Imaging Center, Helsinki University Central Hospital, University of Helsinki, Helsinki, Finland.
authors: Nina
authors: N
authors: Lundbom
authors: Department of Psychiatry, Helsinki University Central Hospital, Helsinki, Finland.|Endocrinology, Abdominal Center, Helsinki University Central Hospital, Helsinki, Finland.
authors: Aila
authors: A
authors: Rissanen
authors: Department of Medical Genetics, Oslo University Hospital and University of Oslo, Oslo, Norway.
authors: Robert
authors: R
authors: Lyle
authors: Obesity Research Unit, Research Programs Unit, Diabetes and Obesity, University of Helsinki, Helsinki, Finland.|Endocrinology, Abdominal Center, Helsinki University Central Hospital, Helsinki, Finland.|Institute for Molecular Medicine FIMM, University of Helsinki, Helsinki, Finland.
authors: Kirsi H
authors: KH
authors: Pietiläinen
authors: Department of Public Health, University of Helsinki, Helsinki, Finland.|Institute for Molecular Medicine FIMM, University of Helsinki, Helsinki, Finland.|Department of Mental Health and Substance Abuse Services, National Institute for Health and Welfare, Helsinki, Finland.
authors: Jaakko
authors: J
authors: Kaprio
keywords: DNA methylation; Epigenetics; Liver fat; Monozygotic twins; Obesity