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Hum Mol Genet. 2015 Jul 1;24(13):3792-813. doi: 10.1093/hmg/ddv124. Epub 2015 Apr 10.

Impact of age, BMI and HbA1c levels on the genome-wide DNA methylation and mRNA expression patterns in human adipose tissue and identification of epigenetic biomarkers in blood.

Author information

1
Department of Clinical Sciences, Epigenetics and Diabetes and.
2
Department of Endocrinology, Rigshospitalet, Tagensvej 20, DK-2200 Copenhagen, Denmark, Faculty of Health Sciences, University of Copenhagen, Blegdamsvej 3, DK-2200 Copenhagen, Denmark.
3
Department of Physiology/Endocrinology, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Medicinaregatan 11, Box 434, 405 30 Gothenburg, Sweden.
4
Department of Endocrinology, Rigshospitalet, Tagensvej 20, DK-2200 Copenhagen, Denmark.
5
Department of Endocrinology, Rigshospitalet, Tagensvej 20, DK-2200 Copenhagen, Denmark, Steno Diabetes Center, Niels Steensensvej 2, DK-2820 Gentofte, Denmark.
6
Wallenberg Laboratory, Sahlgrenska University Hospital, Gothenburg, Sweden.
7
Department of Clinical Sciences, Vascular Diseases, Lund University, 205 02 Malmö, Sweden.
8
The Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Metabolic Genetics, University of Copenhagen, Universitetsparken 1, 2100 Copenhagen, Denmark and.
9
Department of Clinical Sciences, Diabetes and Endocrinology, Lund University Diabetes Centre, CRC, 205 02 Malmö, Sweden.
10
Department of Physiology/Endocrinology, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Medicinaregatan 11, Box 434, 405 30 Gothenburg, Sweden, Department of Physiology and Pharmacology, Karolinska Institutet, 171 77 Stockholm, Sweden.
11
Department of Clinical Sciences, Epigenetics and Diabetes and Department of Endocrinology, Rigshospitalet, Tagensvej 20, DK-2200 Copenhagen, Denmark.
12
Department of Clinical Sciences, Epigenetics and Diabetes and charlotte.ling@med.lu.se.

Abstract

Increased age, BMI and HbA1c levels are risk factors for several non-communicable diseases. However, the impact of these factors on the genome-wide DNA methylation pattern in human adipose tissue remains unknown. We analyzed the DNA methylation of ∼480 000 sites in human adipose tissue from 96 males and 94 females and related methylation to age, BMI and HbA1c. We also compared epigenetic signatures in adipose tissue and blood. Age was significantly associated with both altered DNA methylation and expression of 1050 genes (e.g. FHL2, NOX4 and PLG). Interestingly, many reported epigenetic biomarkers of aging in blood, including ELOVL2, FHL2, KLF14 and GLRA1, also showed significant correlations between adipose tissue DNA methylation and age in our study. The most significant association between age and adipose tissue DNA methylation was found upstream of ELOVL2. We identified 2825 genes (e.g. FTO, ITIH5, CCL18, MTCH2, IRS1 and SPP1) where both DNA methylation and expression correlated with BMI. Methylation at previously reported HIF3A sites correlated significantly with BMI in females only. HbA1c (range 28-46 mmol/mol) correlated significantly with the methylation of 711 sites, annotated to, for example, RAB37, TICAM1 and HLA-DPB1. Pathway analyses demonstrated that methylation levels associated with age and BMI are overrepresented among genes involved in cancer, type 2 diabetes and cardiovascular disease. Our results highlight the impact of age, BMI and HbA1c on epigenetic variation of candidate genes for obesity, type 2 diabetes and cancer in human adipose tissue. Importantly, we demonstrate that epigenetic biomarkers in blood can mirror age-related epigenetic signatures in target tissues for metabolic diseases such as adipose tissue.

PMID:
25861810
DOI:
10.1093/hmg/ddv124
[Indexed for MEDLINE]

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