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

  1. Charlotte Ling1
  1. 1Epigenetics and Diabetes, Department of Clinical Sciences, Lund University Diabetes Centre, Lund University, CRC, Malmö, Sweden
  2. 2Department of Endocrinology, Diabetes and Metabolism, Rigshospitalet, Copenhagen, Denmark
  3. 3Wallenberg Laboratory, Sahlgrenska University Hospital, Gothenburg, Sweden
  4. 4The Centre of Inflammation and Metabolism and the Centre for Physical Activity Research, Department of Infectious Diseases, Rigshospitalet, University of Copenhagen, Denmark
  5. 5Institute of Medicine, Sahlgrenska University Hospital, University of Gothenburg, Sweden
  6. 6Global Development, Novo Nordisk A/S, Bagsværd, Denmark
  7. 7Department of Medical Epidemiology and Biostatistics, Karolinska institutet, Stockholm, Sweden
  8. 8Diabetes and Endocrinology, Department of Clinical Sciences, Lund University Diabetes Centre, CRC, Lund University, Malmö, Sweden
  1. Corresponding Author: Emma Nilsson, E-mail: emma_a.nilsson{at}med.lu.se and Charlotte Ling, charlotte.ling{at}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 discordant 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 controls. 1,410 of these sites did also show differential DNA methylation in the twins discordant for T2D. For the differentially methylated sites, the heritability estimate was 0.28. We also identified 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.

  • Received September 20, 2013.
  • Accepted April 14, 2014.

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