title: Epigenetic Alterations in Human Liver From Subjects With Type 2 Diabetes in Parallel With Reduced Folate Levels.
abstract: OBJECTIVE
  Epigenetic variation may contribute to the development of complex metabolic diseases such as type 2 diabetes (T2D). Hepatic insulin resistance is a hallmark of T2D. However, it remains unknown whether epigenetic alterations take place in the liver from diabetic subjects. Therefore, we investigated the genome-wide DNA methylation pattern in the liver from subjects with T2D and nondiabetic controls and related epigenetic alterations to gene expression and circulating folate levels.
  
  
  METHODS
  Liver biopsies were obtained from 35 diabetic and 60 nondiabetic subjects, which are part of the Kuopio Obesity Surgery Study. The genome-wide DNA methylation pattern was analyzed in the liver using the HumanMethylation450 BeadChip. RNA expression was analyzed from a subset of subjects using the HumanHT-12 Expression BeadChip.
  
  
  RESULTS
  After correction for multiple testing, we identified 251 individual CpG sites that exhibit differential DNA methylation in liver obtained from T2D compared with nondiabetic subjects (Q < .05). These include CpG sites annotated to genes that are biologically relevant to the development of T2D such as GRB10, ABCC3, MOGAT1, and PRDM16. The vast majority of the significant CpG sites (94%) displayed decreased DNA methylation in liver from subjects with T2D. The hypomethylation found in liver from diabetic subjects may be explained by reduced folate levels. Indeed, subjects with T2D had significantly reduced erythrocyte folate levels compared with nondiabetic subjects. We further identified 29 genes that displayed both differential DNA methylation and gene expression in human T2D liver including the imprinted gene H19.
  
  
  CONCLUSIONS
  Our study highlights the importance of epigenetic and transcriptional changes in the liver from subjects with T2D. Reduced circulating folate levels may provide an explanation for hypomethylation in the human diabetic liver.
authors.affiliation: Epigenetics and Diabetes Unit (E.N., A.P., C.L.), Department of Clinical Sciences, Lund University Diabetes Centre, 205 02 Malmö, Sweden; Department of Clinical Nutrition (A.M., V.D.d.M., J.P.), Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Department of Surgery (P.K.), University of Eastern Finland and Kuopio University Hospital, and Clinical Nutrition and Obesity Center (J.P.), Kuopio University Hospital, 70211 Kuopio, Finland.
authors.forename: Emma
authors.initials: E
authors.lastname: Nilsson
authors.affiliation: Epigenetics and Diabetes Unit (E.N., A.P., C.L.), Department of Clinical Sciences, Lund University Diabetes Centre, 205 02 Malmö, Sweden; Department of Clinical Nutrition (A.M., V.D.d.M., J.P.), Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Department of Surgery (P.K.), University of Eastern Finland and Kuopio University Hospital, and Clinical Nutrition and Obesity Center (J.P.), Kuopio University Hospital, 70211 Kuopio, Finland.
authors.forename: Ashok
authors.initials: A
authors.lastname: Matte
authors.affiliation: Epigenetics and Diabetes Unit (E.N., A.P., C.L.), Department of Clinical Sciences, Lund University Diabetes Centre, 205 02 Malmö, Sweden; Department of Clinical Nutrition (A.M., V.D.d.M., J.P.), Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Department of Surgery (P.K.), University of Eastern Finland and Kuopio University Hospital, and Clinical Nutrition and Obesity Center (J.P.), Kuopio University Hospital, 70211 Kuopio, Finland.
authors.forename: Alexander
authors.initials: A
authors.lastname: Perfilyev
authors.affiliation: Epigenetics and Diabetes Unit (E.N., A.P., C.L.), Department of Clinical Sciences, Lund University Diabetes Centre, 205 02 Malmö, Sweden; Department of Clinical Nutrition (A.M., V.D.d.M., J.P.), Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Department of Surgery (P.K.), University of Eastern Finland and Kuopio University Hospital, and Clinical Nutrition and Obesity Center (J.P.), Kuopio University Hospital, 70211 Kuopio, Finland.
authors.forename: Vanessa D
authors.initials: VD
authors.lastname: de Mello
authors.affiliation: Epigenetics and Diabetes Unit (E.N., A.P., C.L.), Department of Clinical Sciences, Lund University Diabetes Centre, 205 02 Malmö, Sweden; Department of Clinical Nutrition (A.M., V.D.d.M., J.P.), Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Department of Surgery (P.K.), University of Eastern Finland and Kuopio University Hospital, and Clinical Nutrition and Obesity Center (J.P.), Kuopio University Hospital, 70211 Kuopio, Finland.
authors.forename: Pirjo
authors.initials: P
authors.lastname: Käkelä
authors.affiliation: Epigenetics and Diabetes Unit (E.N., A.P., C.L.), Department of Clinical Sciences, Lund University Diabetes Centre, 205 02 Malmö, Sweden; Department of Clinical Nutrition (A.M., V.D.d.M., J.P.), Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Department of Surgery (P.K.), University of Eastern Finland and Kuopio University Hospital, and Clinical Nutrition and Obesity Center (J.P.), Kuopio University Hospital, 70211 Kuopio, Finland.
authors.forename: Jussi
authors.initials: J
authors.lastname: Pihlajamäki
authors.affiliation: Epigenetics and Diabetes Unit (E.N., A.P., C.L.), Department of Clinical Sciences, Lund University Diabetes Centre, 205 02 Malmö, Sweden; Department of Clinical Nutrition (A.M., V.D.d.M., J.P.), Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Department of Surgery (P.K.), University of Eastern Finland and Kuopio University Hospital, and Clinical Nutrition and Obesity Center (J.P.), Kuopio University Hospital, 70211 Kuopio, Finland.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Ling
mesh_terms: D000328:Adult; D001706:Biopsy; D015992:Body Mass Index; D015331:Cohort Studies; D018899:CpG Islands; D019175:DNA Methylation; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D044127:Epigenesis, Genetic; D005260:Female; D005387:Finland; D005492:Folic Acid / Q000097:blood; D005494:Folic Acid Deficiency / Q000150:complications*; D015390:Gastric Bypass; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D055106:Genome-Wide Association Study; D006801:Humans; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009752:Nutritional Status; D009767:Obesity, Morbid / Q000150:complications / Q000601:surgery
chemical_list: D005492:Folic Acid