title: DNA methylation of IGF2DMR and H19 is associated with fetal and infant growth: the generation R study.
abstract: 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.
authors.affiliation: The Generation R Study Group, Erasmus Medical Centre, Rotterdam, The Netherlands ; Department of Obstetrics and Gynecology, Erasmus Medical Centre, Rotterdam, The Netherlands.
authors.forename: Marieke I
authors.initials: MI
authors.lastname: Bouwland-Both
authors.affiliation: The Generation R Study Group, Erasmus Medical Centre, Rotterdam, The Netherlands ; Department of Obstetrics and Gynecology, Erasmus Medical Centre, Rotterdam, The Netherlands ; Department of Child and Adolescent Psychiatry/Psychology, Erasmus Medical Centre, Rotterdam, The Netherlands.
authors.forename: Nina H
authors.initials: NH
authors.lastname: van Mil
authors.affiliation: Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands ; Netherlands Consortium of Healthy Aging, Rotterdam/Leiden, The Netherlands.
authors.forename: Lisette
authors.initials: L
authors.lastname: Stolk
authors.affiliation: Department of Biostatistics, Erasmus Medical Centre, Rotterdam, The Netherlands.
authors.forename: Paul H C
authors.initials: PH
authors.lastname: Eilers
authors.affiliation: Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands.
authors.forename: Michael M P J
authors.initials: MM
authors.lastname: Verbiest
authors.affiliation: Netherlands Consortium of Healthy Aging, Rotterdam/Leiden, The Netherlands ; Department of Molecular Epidemiology, Leiden University Medical Centre, Leiden, The Netherlands.
authors.forename: Bastiaan T
authors.initials: BT
authors.lastname: Heijmans
authors.affiliation: Department of Child and Adolescent Psychiatry/Psychology, Erasmus Medical Centre, Rotterdam, The Netherlands ; Department of Epidemiology, Erasmus Medical Centre, Rotterdam, The Netherlands.
authors.forename: Henning
authors.initials: H
authors.lastname: Tiemeier
authors.affiliation: Department of Epidemiology, Erasmus Medical Centre, Rotterdam, The Netherlands.
authors.forename: Albert
authors.initials: A
authors.lastname: Hofman
authors.affiliation: Department of Obstetrics and Gynecology, Erasmus Medical Centre, Rotterdam, The Netherlands.
authors.forename: Eric A P
authors.initials: EA
authors.lastname: Steegers
authors.affiliation: The Generation R Study Group, Erasmus Medical Centre, Rotterdam, The Netherlands ; Department of Epidemiology, Erasmus Medical Centre, Rotterdam, The Netherlands ; Department of Pediatrics, Erasmus Medical Centre, Rotterdam, The Netherlands.
authors.forename: Vincent W V
authors.initials: VW
authors.lastname: Jaddoe
authors.affiliation: Department of Obstetrics and Gynecology, Erasmus Medical Centre, Rotterdam, The Netherlands ; Department of Clinical Genetics, Erasmus Medical Centre, Rotterdam, The Netherlands.
authors.forename: Régine P M
authors.initials: RP
authors.lastname: Steegers-Theunissen
mesh_terms: D000328:Adult; D016022:Case-Control Studies; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005260:Female; D005333:Fetus; D018507:Gene Expression Regulation, Developmental; D018392:Genomic Imprinting; D006801:Humans; D007231:Infant, Newborn; D007236:Infant, Small for Gestational Age / Q000254:growth & development / Q000378:metabolism*; D007335:Insulin-Like Growth Factor II / Q000235:genetics* / Q000378:metabolism; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics* / Q000378:metabolism; D062085:RNA, Long Noncoding / Q000235:genetics* / Q000378:metabolism
chemical_list: C094335:H19 long non-coding RNA; C035170:IGF2 protein, human; D062085:RNA, Long Noncoding; D007335:Insulin-Like Growth Factor II; C573423:MTHFR protein, human; D042965:Methylenetetrahydrofolate Reductase (NADPH2)