title: Altered DNA methylation and differential expression of genes influencing metabolism and inflammation in adipose tissue from subjects with type 2 diabetes.
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.
authors.affiliation: 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.
authors.forename: Emma
authors.initials: E
authors.lastname: Nilsson
authors.affiliation: Wallenberg Laboratory, Sahlgrenska University Hospital, Gothenburg, Sweden.
authors.forename: Per Anders
authors.initials: PA
authors.lastname: Jansson
authors.affiliation: Epigenetics and Diabetes, Department of Clinical Sciences, Lund University Diabetes Centre, Lund University, Clinical Research Centre, Malmö, Sweden.
authors.forename: Alexander
authors.initials: A
authors.lastname: Perfilyev
authors.affiliation: Epigenetics and Diabetes, Department of Clinical Sciences, Lund University Diabetes Centre, Lund University, Clinical Research Centre, Malmö, Sweden.
authors.forename: Petr
authors.initials: P
authors.lastname: Volkov
authors.affiliation: The Centre of Inflammation and Metabolism and the Centre for Physical Activity Research, Department of Infectious Diseases, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Maria
authors.initials: M
authors.lastname: Pedersen
authors.affiliation: Institute of Medicine, Sahlgrenska University Hospital, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Maria K
authors.initials: MK
authors.lastname: Svensson
authors.affiliation: Global Development, Novo Nordisk A/S, Bagsværd, Denmark.
authors.forename: Pernille
authors.initials: P
authors.lastname: Poulsen
authors.affiliation: Department of Endocrinology, Diabetes and Metabolism, Rigshospitalet, Copenhagen, Denmark.
authors.forename: Rasmus
authors.initials: R
authors.lastname: Ribel-Madsen
authors.affiliation: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Nancy L
authors.initials: NL
authors.lastname: Pedersen
authors.affiliation: Diabetes and Endocrinology, Department of Clinical Sciences, Lund University Diabetes Centre, Clinical Research Centre, Lund University, Malmö, Sweden.
authors.forename: Peter
authors.initials: P
authors.lastname: Almgren
authors.affiliation: Diabetes and Endocrinology, Department of Clinical Sciences, Lund University Diabetes Centre, Clinical Research Centre, Lund University, Malmö, Sweden.
authors.forename: João
authors.initials: J
authors.lastname: Fadista
authors.affiliation: Epigenetics and Diabetes, Department of Clinical Sciences, Lund University Diabetes Centre, Lund University, Clinical Research Centre, Malmö, Sweden.
authors.forename: Tina
authors.initials: T
authors.lastname: Rönn
authors.affiliation: The Centre of Inflammation and Metabolism and the Centre for Physical Activity Research, Department of Infectious Diseases, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Bente
authors.initials: B
authors.lastname: Klarlund Pedersen
authors.affiliation: The Centre of Inflammation and Metabolism and the Centre for Physical Activity Research, Department of Infectious Diseases, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Camilla
authors.initials: C
authors.lastname: Scheele
authors.affiliation: Department of Endocrinology, Diabetes and Metabolism, Rigshospitalet, Copenhagen, Denmark.
authors.forename: Allan
authors.initials: A
authors.lastname: Vaag
authors.affiliation: 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.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Ling
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism / Q000473:pathology; D000368:Aged; D016022:Case-Control Studies; D015331:Cohort Studies; D018899:CpG Islands; D056915:DNA Copy Number Variations / Q000235:genetics; D019175:DNA Methylation; D000090943:Delta-5 Fatty Acid Desaturase; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics; D044127:Epigenesis, Genetic; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D015434:Panniculitis / Q000235:genetics; D059467:Transcriptome; D014430:Twins, Monozygotic