Gestational diabetes mellitus epigenetically affects genes predominantly involved in metabolic diseases

Offspring exposed to gestational diabetes mellitus (GDM) have an increased risk for chronic diseases, and one promising mechanism for fetal metabolic programming is epigenetics. Therefore, we postulated that GDM exposure impacts the offspring’s methylome and used an epigenomic approach to explore this hypothesis. Placenta and cord blood samples were obtained from 44 newborns, including 30 exposed to GDM. Women were recruited at first trimester of pregnancy and followed until delivery. GDM was assessed after a 75-g oral glucose tolerance test at 24–28 weeks of pregnancy. DNA methylation was measured at > 485,000 CpG sites (Infinium HumanMethylation450 BeadChips). Ingenuity Pathway Analysis was conducted to identify metabolic pathways epigenetically affected by GDM. Our results showed that 3,271 and 3,758 genes in placenta and cord blood, respectively, were potentially differentially methylated between samples exposed or not to GDM (p-values down to 1 × 10−06; none reached the genome-wide significance levels), with more than 25% (n = 1,029) being common to both tissues. Mean DNA methylation differences between groups were 5.7 ± 3.2% and 3.4 ± 1.9% for placenta and cord blood, respectively. These genes were likely involved in the metabolic diseases pathway (up to 115 genes (11%), p-values for pathways = 1.9 × 10−13 < p < 4.0 × 10−03; including diabetes mellitus p = 4.3 × 10−11). Among the differentially methylated genes, 326 in placenta and 117 in cord blood were also associated with newborn weight. Our results therefore suggest that GDM has epigenetic effects on genes preferentially involved in the metabolic diseases pathway, with consequences on fetal growth and development, and provide supportive evidence that DNA methylation is involved in fetal metabolic programming.

[1]  Mohamed F Ghalwash,et al.  DNA methylation differences at growth related genes correlate with birth weight: a molecular signature linked to developmental origins of adult disease? , 2012, BMC Medical Genomics.

[2]  P. O S I T I O N S T A T E M E N T,et al.  Diagnosis and Classification of Diabetes Mellitus , 2011, Diabetes Care.

[3]  I B Khavin,et al.  [WHO classification of diabetes mellitus]. , 1984, Problemy endokrinologii.

[4]  Xirong Guo,et al.  Pre-Pregnancy Body Mass Index in Relation to Infant Birth Weight and Offspring Overweight/Obesity: A Systematic Review and Meta-Analysis , 2013, PloS one.

[5]  Denise V. D’Angelo,et al.  Gestational weight gain by body mass index among US women delivering live births, 2004-2005: fueling future obesity. , 2009, American journal of obstetrics and gynecology.

[6]  A. Bird,et al.  Epigenetic regulation of gene expression: how the genome integrates intrinsic and environmental signals , 2003, Nature Genetics.

[7]  S. Akira,et al.  Control of Adipose Tissue Inflammation Through TRB1 , 2010, Diabetes.

[8]  P. Catalano,et al.  Maternal Weight Gain in Women Who Develop Gestational Diabetes Mellitus , 2012, Obstetrics and gynecology.

[9]  S. Ring,et al.  DNA Methylation Patterns in Cord Blood DNA and Body Size in Childhood , 2012, PloS one.

[10]  C. Hales,et al.  Type 2 (non-insulin-dependent) diabetes mellitus: the thrifty phenotype hypothesis , 1992, Diabetologia.

[11]  T. Haaf,et al.  Metabolic Programming of MEST DNA Methylation by Intrauterine Exposure to Gestational Diabetes Mellitus , 2013, Diabetes.

[12]  The association between pregnancy weight gain and birthweight: a within-family comparison , 2010, The Lancet.

[13]  D. Lawlor,et al.  Association of Maternal Diabetes Mellitus in Pregnancy With Offspring Adiposity Into Early Adulthood: Sibling Study in a Prospective Cohort of 280 866 Men From 248 293 Families , 2011, Circulation.

[14]  A. Plagemann.  Maternal diabetes and perinatal programming. , 2011, Early human development.

[15]  S. Chu,et al.  Prepregnancy Obesity Prevalence in the United States, 2004–2005 , 2009, Maternal and Child Health Journal.

[16]  Nilesh J Samani,et al.  Dense Genotyping of Candidate Gene Loci Identifies Variants Associated With High-Density Lipoprotein Cholesterol , 2011, Circulation. Cardiovascular genetics.

[17]  S. Murphy,et al.  Insulin-like growth factor 2/H19 methylation at birth and risk of overweight and obesity in children. , 2012, The Journal of pediatrics.

[18]  P. Zimmet,et al.  Diagnosis and classification of diabetes mellitus , 2002 .

[19]  P. Gluckman,et al.  The fetal, neonatal, and infant environments-the long-term consequences for disease risk. , 2005, Early human development.

[20]  Javier Martín,et al.  Genetic association of vasoactive intestinal peptide receptor with rheumatoid arthritis: altered expression and signal in immune cells. , 2008, Arthritis and rheumatism.

[21]  Keith M. Godfrey,et al.  Epigenetic Gene Promoter Methylation at Birth Is Associated With Child’s Later Adiposity , 2011, Diabetes.

[22]  A. Prentice,et al.  Season of Conception in Rural Gambia Affects DNA Methylation at Putative Human Metastable Epialleles , 2010, PLoS genetics.

[23]  R. Jensen,et al.  VIP and PACAP: recent insights into their functions/roles in physiology and disease from molecular and genetic studies , 2011, Current opinion in endocrinology, diabetes, and obesity.

[24]  M. Hanson,et al.  Epigenetic regulation of transcription: a mechanism for inducing variations in phenotype (fetal programming) by differences in nutrition during early life? , 2007, British Journal of Nutrition.

[25]  E. Finkelstein,et al.  Obesity and severe obesity forecasts through 2030. , 2012, American journal of preventive medicine.

[26]  Luigi Bouchard,et al.  Leptin Gene Epigenetic Adaptation to Impaired Glucose Metabolism During Pregnancy , 2010, Diabetes Care.

[27]  John B Carlin,et al.  DNA methylation analysis of multiple tissues from newborn twins reveals both genetic and intrauterine components to variation in the human neonatal epigenome. , 2010, Human molecular genetics.

[28]  D. Dabelea,et al.  Cardiovascular risk factors in children exposed to maternal diabetes in utero , 2011, Diabetologia.

[29]  B. Nordestgaard,et al.  TRIB1 and GCKR Polymorphisms, Lipid Levels, and Risk of Ischemic Heart Disease in the General Population , 2011, Arteriosclerosis, thrombosis, and vascular biology.

[30]  Maicon Falavigna,et al.  Gestational diabetes and pregnancy outcomes - a systematic review of the World Health Organization (WHO) and the International Association of Diabetes in Pregnancy Study Groups (IADPSG) diagnostic criteria , 2012, BMC Pregnancy and Childbirth.

[31]  Marie-France Hivert,et al.  Placental Adiponectin Gene DNA Methylation Levels Are Associated With Mothers’ Blood Glucose Concentration , 2012, Diabetes.

[32]  K. Vehik,et al.  Association of exposure to diabetes in utero with adiposity and fat distribution in a multiethnic population of youth: the Exploring Perinatal Outcomes among Children (EPOCH) Study , 2010, Diabetologia.

[33]  B. Metzger,et al.  Long-term effects of the intrauterine environment. The Northwestern University Diabetes in Pregnancy Center. , 1998, Diabetes care.

[34]  C. Lawton.  Highlights of the 2003 Clinical Practice Guidelines for the prevention and management of diabetes in Canada. , 2004, CANNT journal = Journal ACITN.

[35]  K. Gunderson,et al.  High density DNA methylation array with single CpG site resolution. , 2011, Genomics.

[36]  Dolores Corella,et al.  Six new loci associated with blood low-density lipoprotein cholesterol, high-density lipoprotein cholesterol or triglycerides in humans , 2008, Nature Genetics.

[37]  Hein Putter,et al.  Variation, patterns, and temporal stability of DNA methylation: considerations for epigenetic epidemiology , 2010, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[38]  P. Zimmet,et al.  Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: diagnosis and classification of diabetes mellitus. Provisional report of a WHO Consultation , 1998, Diabetic medicine : a journal of the British Diabetic Association.

[39]  S. Murphy,et al.  Differentially Methylated Regions of Imprinted Genes in Prenatal, Perinatal and Postnatal Human Tissues , 2012, PloS one.

[40]  J. Bunt,et al.  Intrauterine exposure to diabetes is a determinant of hemoglobin A(1)c and systolic blood pressure in pima Indian children. , 2005, The Journal of clinical endocrinology and metabolism.

[41]  K. Vehik,et al.  Association of Intrauterine Exposure to Maternal Diabetes and Obesity With Type 2 Diabetes in Youth , 2008, Diabetes Care.

[42]  T. Lohman,et al.  Anthropometric Standardization Reference Manual , 1988 .

[43]  A. Caspi,et al.  A longitudinal study of epigenetic variation in twins , 2010, Epigenetics.

[44]  Lin Huang,et al.  Anti-hyperglycemic, antioxidant and anti-inflammatory effects of VIP and a VPAC1 agonist on streptozotocin-induced diabetic mice , 2011, Peptides.