title: Maternal Smoking during Pregnancy and DNA-Methylation in Children at Age 5.5 Years: Epigenome-Wide-Analysis in the European Childhood Obesity Project (CHOP)-Study.
abstract: Mounting evidence links prenatal exposure to maternal tobacco smoking with disruption of DNA methylation (DNAm) profile in the blood of infants. However, data on the postnatal stability of such DNAm signatures in childhood, as assessed by Epigenome Wide Association Studies (EWAS), are scarce. Objectives of this study were to investigate DNAm signatures associated with in utero tobacco smoke exposure beyond the 12th week of gestation in whole blood of children at age 5.5 years, to replicate previous findings in young European and American children and to assess their biological role by exploring databases and enrichment analysis. DNA methylation was measured in blood of 366 children of the multicentre European Childhood Obesity Project Study using the Illumina Infinium HM450 Beadchip (HM450K). An EWAS was conducted using linear regression of methylation values at each CpG site against in utero smoke exposure, adjusted for study characteristics, biological and technical effects. Methylation levels at five HM450K probes in MYO1G (cg12803068, cg22132788, cg19089201), CNTNAP2 (cg25949550), and FRMD4A (cg11813497) showed differential methylation that reached epigenome-wide significance according to the false-discovery-rate (FDR) criteria (q-value<0.05). Whereas cg25949550 showed decreased methylation (-2% DNAm ß-value), increased methylation was observed for the other probes (9%: cg12803068; 5%: cg22132788; 4%: cg19089201 and 4%: cg11813497) in exposed relative to non-exposed subjects. This study thus replicates previous findings in children ages 3 to 5, 7 and 17 and confirms the postnatal stability of MYO1G, CNTNAP2 and FRMD4A differential methylation. The role of this differential methylation in mediating childhood phenotypes, previously associated with maternal smoking, requires further investigation.
authors.affiliation: Division of Metabolic and Nutritional Medicine, Dr. von Hauner Children's Hospital, Ludwig-Maximilians-University of Munich, University of Munich Medical Centre, Munich, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Rzehak
authors.affiliation: Cancer and Disease Epigenetics Research Group, Murdoch Childrens Research Institute, Royal Children's Hospital, Flemington Road, Parkville, 3052 Victoria Australia.
authors.forename: Richard
authors.initials: R
authors.lastname: Saffery
authors.affiliation: Research Unit of Molecular Epidemiology, Institute of Epidemiology II, Helmholtz Zentrum Muenchen, Munich, Germany.
authors.forename: Eva
authors.initials: E
authors.lastname: Reischl
authors.affiliation: Division of Metabolic and Nutritional Medicine, Dr. von Hauner Children's Hospital, Ludwig-Maximilians-University of Munich, University of Munich Medical Centre, Munich, Germany.
authors.forename: Marcela
authors.initials: M
authors.lastname: Covic
authors.affiliation: Research Unit of Molecular Epidemiology, Institute of Epidemiology II, Helmholtz Zentrum Muenchen, Munich, Germany.
authors.forename: Simone
authors.initials: S
authors.lastname: Wahl
authors.affiliation: Division of Metabolic and Nutritional Medicine, Dr. von Hauner Children's Hospital, Ludwig-Maximilians-University of Munich, University of Munich Medical Centre, Munich, Germany.
authors.forename: Veit
authors.initials: V
authors.lastname: Grote
authors.affiliation: CHC St Vincent, Liège-Rocourt, Belgium.
authors.forename: Annick
authors.initials: A
authors.lastname: Xhonneux
authors.affiliation: CHC St Vincent, Liège-Rocourt, Belgium.
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Langhendries
authors.affiliation: Universitat Rovira I Virgili, Reus, Spain.
authors.forename: Natalia
authors.initials: N
authors.lastname: Ferre
authors.affiliation: Universitat Rovira I Virgili, Reus, Spain.
authors.forename: Ricardo
authors.initials: R
authors.lastname: Closa-Monasterolo
authors.affiliation: University of Milano, Milano, Italy.
authors.forename: Elvira
authors.initials: E
authors.lastname: Verduci
authors.affiliation: University of Milano, Milano, Italy.
authors.forename: Enrica
authors.initials: E
authors.lastname: Riva
authors.affiliation: Children's Memorial Health Institute, Warsaw, Poland.
authors.forename: Piotr
authors.initials: P
authors.lastname: Socha
authors.affiliation: Children's Memorial Health Institute, Warsaw, Poland.
authors.forename: Dariusz
authors.initials: D
authors.lastname: Gruszfeld
authors.affiliation: Division of Metabolic and Nutritional Medicine, Dr. von Hauner Children's Hospital, Ludwig-Maximilians-University of Munich, University of Munich Medical Centre, Munich, Germany.
authors.forename: Berthold
authors.initials: B
authors.lastname: Koletzko
mesh_terms: D002648:Child; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation / Q000235:genetics*; D044127:Epigenesis, Genetic; D005060:Europe; D005260:Female; D053263:Gene Regulatory Networks; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D009765:Obesity / Q000235:genetics*; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000235:genetics*; D012907:Smoking / Q000235:genetics*