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Int J Epidemiol. 2015 Aug;44(4):1224-37. doi: 10.1093/ije/dyv048. Epub 2015 Apr 10.

DNA methylation mediates the effect of maternal smoking during pregnancy on birthweight of the offspring.

Author information

1
Departments of Epidemiology, l.k.kupers@umcg.nl.
2
Georgia Regents University, Augusta, Georgia, USA.
3
Pulmonology and Genetics, and.
4
Departments of Epidemiology.
5
Departments of Epidemiology, LifeLines Cohort Study, University Medical Center Groningen, Groningen, The Netherlands.
6
MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK.
7
Departments of Epidemiology, Pediatrics, The Generation R Study Group and.
8
Departments of Epidemiology, Pediatrics.
9
Internal Medicine, Erasmus MC, University Medical Center Rotterdam, The Netherlands.

Abstract

BACKGROUND:

We examined whether the effect of maternal smoking during pregnancy on birthweight of the offspring was mediated by smoking-induced changes to DNA methylation in cord blood.

METHODS:

First, we used cord blood of 129 Dutch children exposed to maternal smoking vs 126 unexposed to maternal and paternal smoking (53% male) participating in the GECKO Drenthe birth cohort. DNA methylation was measured using the Illumina HumanMethylation450 Beadchip. We performed an epigenome-wide association study for the association between maternal smoking and methylation followed by a mediation analysis of the top signals [false-discovery rate (FDR) < 0.05]. We adjusted both analyses for maternal age, education, pre-pregnancy BMI, offspring's sex, gestational age and white blood cell composition. Secondly, in 175 exposed and 1248 unexposed newborns from two independent birth cohorts, we replicated and meta-analysed results of eight cytosine-phosphate-guanine (CpG) sites in the GFI1 gene, which showed the most robust mediation. Finally, we performed functional network and enrichment analysis.

RESULTS:

We found 35 differentially methylated CpGs (FDR < 0.05) in newborns exposed vs unexposed to smoking, of which 23 survived Bonferroni correction (P < 1 × 10(-7)). These 23 CpGs mapped to eight genes: AHRR, GFI1, MYO1G, CYP1A1, NEUROG1, CNTNAP2, FRMD4A and LRP5. We observed partial confirmation as three of the eight CpGs in GFI1 replicated. These CpGs partly mediated the effect of maternal smoking on birthweight (Sobel P < 0.05) in meta-analysis of GECKO and the two replication cohorts. Differential methylation of these three GFI1 CpGs explained 12-19% of the 202 g lower birthweight in smoking mothers. Functional enrichment analysis pointed towards activation of cell-mediated immunity.

CONCLUSIONS:

Maternal smoking during pregnancy was associated with cord blood methylation differences. We observed a potentially mediating role of methylation in the association between maternal smoking during pregnancy and birthweight of the offspring. Functional network analysis suggested a role in activating the immune system.

KEYWORDS:

ALSPAC; DOHaD; Epigenetic epidemiology; GECKO; Generation R; epigenome-wide association study; fetal programming

PMID:
25862628
PMCID:
PMC4588868
DOI:
10.1093/ije/dyv048
[Indexed for MEDLINE]
Free PMC Article

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