title: Potential epigenetic dysregulation of genes associated with MODY and type 2 diabetes in humans exposed to a diabetic intrauterine environment: an analysis of genome-wide DNA methylation.
abstract: OBJECTIVE
  The aim of this study is to investigate the potential role of DNA methylation in mediating the increased risk of developing type 2 diabetes in offspring of mothers who had diabetes during pregnancy.
  
  
  METHODS
  Peripheral blood leukocytes were collected from non-diabetic Pima Indians who were either offspring of diabetic mothers (ODM; n=14) or offspring of nondiabetic mothers (ONDM; n=14). The two groups were matched for age, sex, age of mother, and fraction of Pima ethnicity. Differentially methylated regions were determined using a MeDIP-chip assay on an Affymetrix Human Tiling 2.0R Array. Data were analyzed using the model based analysis of tiling arrays (MAT) algorithm, and 4883 regions overlapping with putative promoters, were identified as differentially methylated, having met an empirically derived threshold (nominal p<0.0077). The list of genes with differentially methylated promoters was subjected to KEGG pathway analysis to determine canonical metabolic pathways enriched by these genes.
  
  
  RESULTS
  Pathway analysis of genes with differentially methylated promoters identified the top 3 enriched pathways as maturity onset diabetes of the young (MODY), type 2 diabetes, and Notch signaling. Several genes in these pathways are known to affect pancreatic development and insulin secretion.
  
  
  CONCLUSIONS
  These findings support the hypothesis that epigenetic changes may increase the risk of type 2 diabetes via an effect on β-cell function in the offspring of mothers with diabetes during pregnancy.
authors.affiliation: Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, 1550 East Indian School Road, Phoenix, AZ, 85014.
authors.forename: Melissa C
authors.initials: MC
authors.lastname: del Rosario
authors.affiliation: Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, 1550 East Indian School Road, Phoenix, AZ, 85014.
authors.forename: Vicky
authors.initials: V
authors.lastname: Ossowski
authors.affiliation: Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, 1550 East Indian School Road, Phoenix, AZ, 85014.
authors.forename: William C
authors.initials: WC
authors.lastname: Knowler
authors.affiliation: Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, 1550 East Indian School Road, Phoenix, AZ, 85014.
authors.forename: Clifton
authors.initials: C
authors.lastname: Bogardus
authors.affiliation: Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, 1550 East Indian School Road, Phoenix, AZ, 85014.
authors.forename: Leslie J
authors.initials: LJ
authors.lastname: Baier
authors.affiliation: Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, 1550 East Indian School Road, Phoenix, AZ, 85014. Electronic address: rhanson@phx.niddk.nih.gov.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Hanson
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D019175:DNA Methylation; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D044127:Epigenesis, Genetic / Q000502:physiology*; D005260:Female; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D059647:Gene-Environment Interaction; D015894:Genome, Human; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D011247:Pregnancy; D011254:Pregnancy in Diabetics; D011297:Prenatal Exposure Delayed Effects / Q000235:genetics*; D014599:Uterus / Q000502:physiology; D055815:Young Adult
keywords: Immunoprecipitation; In utero; Maternal diabetes; Microarray