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.
Highlights
There is growing evidence from both candidate gene [1] and Epigenome Wide Association Studies (EWAS) that prenatal exposure to maternal tobacco smoking substantially alters DNA methylation (DNAm) in newborn blood [2,3,4,5,6]
An EWAS using the Illumina Infinium HumanMethylation450 BeadChip (HM450K), conducted in 12- to 18-year old offspring of mothers who smoked during pregnancy [6] found persistence of differentially methylated regions (DMRs) in MYO1G and CNTNAP2
Overall 5 CpG sites in genes MYO1G, CNTNAP2 and FRMD4A showed epigenome-wide significance according to the FDR criteria (Table 1)
Summary
There is growing evidence from both candidate gene [1] and Epigenome Wide Association Studies (EWAS) that prenatal exposure to maternal tobacco smoking substantially alters DNA methylation (DNAm) in newborn blood [2,3,4,5,6]. Evidence exists for dosage, tissue-specific and timing of exposure effects Several of these studies have reported similar findings, with changes in methylation consistently observed at AHHR, CNTNAP2, CYP1A1, GFI1 and MYO1G at birth. A similar study using longitudinal blood samples collected at birth, at age 7 and age 17 years [7], demonstrated that some smoking-associated DMRs are time-stable postnatally (AHRR, MYO1G, CYP1A1, CNTNAP2), whereas others are not (ATP9A, GFI1, KLF13). Both the duration and intensity (cigarettes/day) appear important in the observed effect. No equivalent EWAS has yet been carried out in blood of children younger than 7, except a very recent study in 3–5 year old US children [8] using EWAS data to replicate 26 differently methylated CpG sites previously reported in newborns [2]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
