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Diabetes. 2014 Sep;63(9):2962-76. doi: 10.2337/db13-1459. Epub 2014 May 8.

Altered DNA methylation and differential expression of genes influencing metabolism and inflammation in adipose tissue from subjects with type 2 diabetes.

Author information

1
Epigenetics and Diabetes, Department of Clinical Sciences, Lund University Diabetes Centre, Lund University, Clinical Research Centre, Malmö, Sweden Department of Endocrinology, Diabetes and Metabolism, Rigshospitalet, Copenhagen, Denmark emma_a.nilsson@med.lu.se charlotte.ling@med.lu.se.
2
Wallenberg Laboratory, Sahlgrenska University Hospital, Gothenburg, Sweden.
3
Epigenetics and Diabetes, Department of Clinical Sciences, Lund University Diabetes Centre, Lund University, Clinical Research Centre, Malmö, Sweden.
4
The Centre of Inflammation and Metabolism and the Centre for Physical Activity Research, Department of Infectious Diseases, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
5
Institute of Medicine, Sahlgrenska University Hospital, University of Gothenburg, Gothenburg, Sweden.
6
Global Development, Novo Nordisk A/S, Bagsværd, Denmark.
7
Department of Endocrinology, Diabetes and Metabolism, Rigshospitalet, Copenhagen, Denmark.
8
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
9
Diabetes and Endocrinology, Department of Clinical Sciences, Lund University Diabetes Centre, Clinical Research Centre, Lund University, Malmö, Sweden.
10
Epigenetics and Diabetes, Department of Clinical Sciences, Lund University Diabetes Centre, Lund University, Clinical Research Centre, Malmö, Sweden emma_a.nilsson@med.lu.se charlotte.ling@med.lu.se.

Abstract

Genetics, epigenetics, and environment may together affect the susceptibility for type 2 diabetes (T2D). Our aim was to dissect molecular mechanisms underlying T2D using genome-wide expression and DNA methylation data in adipose tissue from monozygotic twin pairs discordant for T2D and independent case-control cohorts. In adipose tissue from diabetic twins, we found decreased expression of genes involved in oxidative phosphorylation; carbohydrate, amino acid, and lipid metabolism; and increased expression of genes involved in inflammation and glycan degradation. The most differentially expressed genes included ELOVL6, GYS2, FADS1, SPP1 (OPN), CCL18, and IL1RN. We replicated these results in adipose tissue from an independent case-control cohort. Several candidate genes for obesity and T2D (e.g., IRS1 and VEGFA) were differentially expressed in discordant twins. We found a heritable contribution to the genome-wide DNA methylation variability in twins. Differences in methylation between monozygotic twin pairs discordant for T2D were subsequently modest. However, 15,627 sites, representing 7,046 genes including PPARG, KCNQ1, TCF7L2, and IRS1, showed differential DNA methylation in adipose tissue from unrelated subjects with T2D compared with control subjects. A total of 1,410 of these sites also showed differential DNA methylation in the twins discordant for T2D. For the differentially methylated sites, the heritability estimate was 0.28. We also identified copy number variants (CNVs) in monozygotic twin pairs discordant for T2D. Taken together, subjects with T2D exhibit multiple transcriptional and epigenetic changes in adipose tissue relevant to the development of the disease.

PMID:
24812430
DOI:
10.2337/db13-1459
[Indexed for MEDLINE]
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