DNA methylation of IGF2DMR and H19 is associated with fetal and infant growth: the generation R study

• Published in: PloS one Vol. 8; no. 12; p. e81731
• Main Authors: Bouwland-Both, Marieke I, van Mil, Nina H, Stolk, Lisette, Eilers, Paul H C, Verbiest, Michael M P J, Heijmans, Bastiaan T, Tiemeier, Henning, Hofman, Albert, Steegers, Eric A P, Jaddoe, Vincent W V, Steegers-Theunissen, Régine P M
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 12-12-2013; Public Library of Science (PLoS)
• Subjects: Adult; Analysis; Attention deficit hyperactivity disorder; Birth weight; Blood cells; Case-Control Studies; Child development; Childbirth & labor; Children; Deoxyribonucleic acid; Dependent variables; DNA; DNA Methylation; Embryos; Epigenesis, Genetic; Epigenetic inheritance; Epigenetics; Female; Fetal development; Fetus; Fetuses; Gene Expression Regulation, Developmental; Genes; Genetic diversity; Genetic variance; Genomic Imprinting; Gestational age; Growth; Health risk assessment; Humans; Infant, Newborn; Infant, Small for Gestational Age - growth & development; Infant, Small for Gestational Age - metabolism; Infants; Insulin-like growth factor II; Insulin-Like Growth Factor II - genetics; Insulin-Like Growth Factor II - metabolism; Leukocytes; Mediation; Medical records; Medical research; Methylation; Methylenetetrahydrofolate reductase; Methylenetetrahydrofolate Reductase (NADPH2) - genetics; Methylenetetrahydrofolate Reductase (NADPH2) - metabolism; Pregnancy; RNA, Long Noncoding - genetics; RNA, Long Noncoding - metabolism; Small for gestational age; Ultrasound; Umbilical cord; Netherlands
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0081731

Changes in epigenetic programming of embryonic growth genes during pregnancy seem to affect fetal growth. Therefore, in a population-based prospective birth cohort in the Netherlands, we examined associations between fetal and infant growth and DNA methylation of IGF2DMR, H19 and MTHFR. For this study, we selected 69 case children born small-for-gestational age (SGA, birth weight <-2SDS) and 471 control children. Fetal growth was assessed with serial ultrasound measurements. Information on birth outcomes was retrieved from medical records. Infant weight was assessed at three and six months. Methylation was assessed in DNA extracted from umbilical cord white blood cells. Analyses were performed using linear mixed models with DNA methylation as dependent variable. The DNA methylation levels of IGF2DMR and H19 in the control group were, median (90% range), 53.6% (44.5-61.6) and 30.0% (25.6-34.2) and in the SGA group 52.0% (43.9-60.9) and 30.5% (23.9-32.9), respectively. The MTHFR region was found to be hypomethylated with limited variability in the control and SGA group, 2.5% (1.4-4.0) and 2.4% (1.5-3.8), respectively. SGA was associated with lower IGF2DMR DNA methylation (β = -1.07, 95% CI -1.93; -0.21, P-value = 0.015), but not with H19 methylation. A weight gain in the first three months after birth was associated with lower IGF2DMR DNA methylation (β = -0.53, 95% CI -0.91; -0.16, P-value = 0.005). Genetic variants in the IGF2/H19 locus were associated with IGF2DMR DNA methylation (P-value<0.05), but not with H19 methylation. Furthermore, our results suggest a possibility of mediation of DNA methylation in the association between the genetic variants and SGA. To conclude, IGF2DMR and H19 DNA methylation is associated with fetal and infant growth.