Prenatal tobacco smoke exposure is associated with childhood DNA CpG methylation

Carrie V. Breton, Kimberly D. Siegmund, Bonnie R. Joubert, Xinhui Wang, Weiliang Qui, Vincent Carey, Wenche Nystad, Siri E. Håberg, Carole Ober, Dan Nicolae, Kathleen C. Barnes, Fernando Martinez, Andy Liu, Robert Lemanske, Robert Strunk, Scott Weiss, Stephanie London, Frank Gilliland, Benjamin Raby

Research output: Contribution to journalArticlepeer-review

86 Scopus citations


Background: Smoking while pregnant is associated with a myriad of negative health outcomes in the child. Some of the detrimental effects may be due to epigenetic modifications, although few studies have investigated this hypothesis in detail. Objectives: To characterize site-specific epigenetic modifications conferred by prenatal smoking exposure within asthmatic children. Methods: Using Illumina HumanMethylation27 microarrays, we estimated the degree of methylation at 27,578 distinct DNA sequences located primarily in gene promoters using whole blood DNA samples from the Childhood Asthma Management Program (CAMP) subset of Asthma BRIDGE childhood asthmatics (n = 527) ages 5-12 with prenatal smoking exposure data available. Using beta-regression, we screened loci for differential methylation related to prenatal smoke exposure, adjusting for gender, age and clinical site, and accounting for multiple comparisons by FDR. Results: Of 27,578 loci evaluated, 22,131 (80%) passed quality control assessment and were analyzed. Sixty-five children (12%) had a history of prenatal smoke exposure. At an FDR of 0.05, we identified 19 CpG loci significantly associated with prenatal smoke, of which two replicated in two independent populations. Exposure was associated with a 2% increase in mean CpG methylation in FRMD4A (p = 0.01) and Cllorf52 (p = 0.001) compared to no exposure. Four additional genes, XPNPEP1, PPEF2, SMPD3 and CRYGN, were nominally associated in at least one replication group. Conclusions: These data suggest that prenatal exposure to tobacco smoke is associated with reproducible epigenetic changes that persist well into childhood. However, the biological significance of these altered loci remains unknown.

Original languageEnglish (US)
Article numbere99716
JournalPLoS One
Issue number6
StatePublished - Jun 25 2014

ASJC Scopus subject areas

  • General Agricultural and Biological Sciences
  • General Biochemistry, Genetics and Molecular Biology
  • General Medicine


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