Prenatal tobacco smoke exposure is associated with childhood DNA CpG methylation

• Published in: PloS one 2014-06, Vol.9 (6), p.e99716
• Main Authors: Breton, Carrie V, Siegmund, Kimberly D, Joubert, Bonnie R, Wang, Xinhui, Qui, Weiliang, Carey, Vincent, Nystad, Wenche, Håberg, Siri E, Ober, Carole, Nicolae, Dan, Barnes, Kathleen C, Martinez, Fernando, Liu, Andy, Lemanske, Robert, Strunk, Robert, Weiss, Scott, London, Stephanie, Gilliland, Frank, Raby, Benjamin
• Format: Article
• Language: English
• Subjects: Asthma; Asthma - genetics; Binding sites; Biology and Life Sciences; Child; Child, Preschool; Childhood; Childhood asthma; Children; Consortia; CpG Islands; Deoxyribonucleic acid; DNA; DNA Methylation; DNA microarrays; Environmental health; Epigenesis, Genetic; Epigenetic inheritance; Epigenetics; Exposure; Female; Fetuses; Gene expression; Gene sequencing; Genetic testing; Health aspects; Health care; Health sciences; Hospitals; Humans; Kinases; Loci; Male; Medical schools; Medicine and Health Sciences; Methylation; Nucleotide sequence; Phosphatase; Pregnancy; Pregnant women; Prenatal experience; Prenatal exposure; Prenatal Exposure Delayed Effects; Preventive medicine; Public health; Quality assessment; Quality control; Regression analysis; Smoke; Smoking; Smoking - adverse effects; Smooth muscle; Studies; Tobacco; Tobacco smoke
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0099716

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. To characterize site-specific epigenetic modifications conferred by prenatal smoking exposure within asthmatic children. 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. 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. 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.