Genome-wide blood DNA methylation alterations at regulatory elements and heterochromatic regions in monozygotic twins discordant for obesity and liver fat

Miina Ollikainen; Khadeeja Ismail; Kristina Gervin; Anjuska Kyllönen; Antti Hakkarainen; Jesper Lundbom; Elina A Järvinen; Jennifer R Harris; Nina Lundbom; Aila Rissanen; Robert Lyle; Kirsi H Pietiläinen; Jaakko Kaprio

doi:10.1186/s13148-015-0073-5

Genome-wide blood DNA methylation alterations at regulatory elements and heterochromatic regions in monozygotic twins discordant for obesity and liver fat

Clin Epigenetics. 2015 Apr 2;7(1):39. doi: 10.1186/s13148-015-0073-5. eCollection 2015.

Authors

Miina Ollikainen¹, Khadeeja Ismail¹, Kristina Gervin², Anjuska Kyllönen³, Antti Hakkarainen⁴, Jesper Lundbom⁴, Elina A Järvinen³, Jennifer R Harris⁵, Nina Lundbom⁴, Aila Rissanen^{6

7}, Robert Lyle², Kirsi H Pietiläinen^#^{3

7

8}, Jaakko Kaprio^#^{1

8

9}

Affiliations

¹ Department of Public Health, University of Helsinki, Helsinki, Finland.
² Department of Medical Genetics, Oslo University Hospital and University of Oslo, Oslo, Norway.
³ Obesity Research Unit, Research Programs Unit, Diabetes and Obesity, University of Helsinki, Helsinki, Finland.
⁴ Department of Radiology, HUS Medical Imaging Center, Helsinki University Central Hospital, University of Helsinki, Helsinki, Finland.
⁵ Division of Epidemiology, The Norwegian Institute of Public Health, Oslo, Norway.
⁶ Department of Psychiatry, Helsinki University Central Hospital, Helsinki, Finland.
⁷ Endocrinology, Abdominal Center, Helsinki University Central Hospital, Helsinki, Finland.
⁸ Institute for Molecular Medicine FIMM, University of Helsinki, Helsinki, Finland.
⁹ Department of Mental Health and Substance Abuse Services, National Institute for Health and Welfare, Helsinki, Finland.

^# Contributed equally.

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.

Keywords: DNA methylation; Epigenetics; Liver fat; Monozygotic twins; Obesity.