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Prenatal Tobacco Smoke Exposure Is Associated with Childhood DNA Cpg Methylation Robert Strunk Washington University School of Medicine in St

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Prenatal Tobacco Smoke Exposure Is Associated with Childhood DNA Cpg Methylation Robert Strunk Washington University School of Medicine in St Washington University School of Medicine Digital Commons@Becker Open Access Publications 2014 Prenatal tobacco smoke exposure is associated with childhood DNA CpG methylation Robert Strunk Washington University School of Medicine in St. Louis et al Follow this and additional works at: https://digitalcommons.wustl.edu/open_access_pubs Recommended Citation Strunk, Robert and et al, ,"Prenatal tobacco smoke exposure is associated with childhood DNA CpG methylation." PLoS One.9,6. e99716. (2014). https://digitalcommons.wustl.edu/open_access_pubs/3053 This Open Access Publication is brought to you for free and open access by Digital Commons@Becker. It has been accepted for inclusion in Open Access Publications by an authorized administrator of Digital Commons@Becker. For more information, please contact [email protected]. Prenatal Tobacco Smoke Exposure Is Associated with Childhood DNA CpG Methylation Carrie V. Breton1*, Kimberly D. Siegmund1, Bonnie R. Joubert2, Xinhui Wang1, Weiliang Qui3, Vincent Carey3, Wenche Nystad4, Siri E. Ha˚berg4, Carole Ober5, Dan Nicolae5, Kathleen C. Barnes6, Fernando Martinez7, Andy Liu8, Robert Lemanske9, Robert Strunk10, Scott Weiss3, Stephanie London2, Frank Gilliland1, Benjamin Raby3 on behalf of the Asthma BRIDGE consortium" 1 Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America, 2 Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health, Dept of Health and Human Services, Research Triangle Park, North Carolina, United States of America, 3 Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, United States of America, 4 Norwegian Institute of Public Health, Oslo, Norway, 5 University of Chicago, Chicago, Illinois, United States of America, 6 Johns Hopkins University, Baltimore, Maryland, United States of America, 7 Arizona Respiratory Center, University of Arizona, Arizona, United States of America, 8 National Jewish Health, Denver, Colorado, United States of America, 9 University of Wisconsin, Madison, Wisconsin, United States of America, 10 Washington University School of Medicine, St. Louis, Montana, United States of America Abstract 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. Citation: Breton CV, Siegmund KD, Joubert BR, Wang X, Qui W, et al. (2014) Prenatal Tobacco Smoke Exposure Is Associated with Childhood DNA CpG Methylation. PLoS ONE 9(6): e99716. doi:10.1371/journal.pone.0099716 Editor: Angela H. Ting, Cleveland Clinic Foundation, United States of America Received February 21, 2014; Accepted May 18, 2014; Published June 25, 2014 This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication. Funding: The CAMP Genetics Ancillary Study is supported by U01 HL075419, U01 HL65899, P01 HL083069 R01 HL 086601, from the National Heart, Lung and Blood Institute, National Institutes of Health. The methylation data described here was funded by 5RC2HL101543-02 and NIEHS grants 5P30ES007048 and 1K01ES017801. Also supported in part by the Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health, Dept of Health and Human Services, US. The Norwegian Mother and Child Cohort Study is supported by the Norwegian Ministry of Health and the Ministry of Education and Research, NIH/NIEHS (contract no NO-ES-75558), NIH/NINDS (grant no.1 UO1 NS 047537-01), and the Norwegian Research Council/FUGE (grant no. 151918/S10). KCB was supported in part by the Mary Beryl Patch Turnbull Scholar Program. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * Email: [email protected] " Membership for extended Asthma BRIDGE consortium authorship list in File S1. Introduction and function [2], is associated with changes in children’s neurodevelopment and behavior [3] as well as with impaired lung Smoking while pregnant is associated with a myriad of negative function and increased risk of developing asthma. [4,5,6] health outcomes both for the mother and for the fetus. [1] In utero Moreover, IUS-related deficits in lung function are larger for tobacco smoke exposure (IUS) can damage the placental structure children with asthma. [7]. PLOS ONE | www.plosone.org 1 June 2014 | Volume 9 | Issue 6 | e99716 Maternal Smoking and CpG Methylation One hypothesized mechanism through which IUS may act is by The Norwegian Mother and Child Cohort Study (MoBa) altering the epigenetic landscape within the developing fetus. consisted of 1062 participants in whom the association between Increasingly, scientific reports are linking IUS exposure to maternal cotinine level and DNA methylation in cord blood was alterations in the fetal epigenome, including changes in DNA recently assessed using Illumina’s Infinium HumanMethyla- methylation in numerous genes and tissue types. [8,9] To further tion450 (HM450) BeadChip. [8] Maternal plasma cotinine investigate the association between IUS and epigenetics, we concentrations in the MoBa samples were measured using liquid evaluated the association between IUS exposure and DNA chromatography–tandem mass spectrometry. [12]. methylation in the first phase of subjects participating in the Asthma BioRepository for Integrative Genomic Exploration Ethics Statement (Asthma BRIDGE) study - a subset of asthmatic children originally Written informed consent was provided by all study subjects. from the Childhood Asthma Management Program (CAMP) trial. The institutional review boards (IRB) of the Brigham and [10,11] We designed a study aimed at investigating DNA Women’s Hospital, and each of the participating CAMP study methylation in promoter regions of genes as these are the most centers, approved these protocols. The MoBa study was approved pertinent regulatory regions for gene expression. We interrogated Norwegian Data Inspectorate and the Regional Ethics Committee 27,578 CpG loci using the Illumina HumanMethylation27 for Medical Research and the NIEHS Institutional Review Board. platform - a promoter-centric assay - measured in whole blood samples collected in the CAMP population and replicated our Maternal Smoking Exposure findings in two other populations: 1) the remainder of the Asthma Information regarding IUS exposure was obtained during the BRIDGE project with Illumina HumanMethylation450 (HM450) baseline medical interview for CAMP and Asthma BRIDGE data; and 2) the Norwegian Mother and Child Cohort Study subjects. Children were considered to have IUS exposure if (MoBa). respondents answered affirmatively to the question, ‘‘Did this child’s mother smoke while she was pregnant with this child?’’ Methods Information about current environmental tobacco smoke exposure Study Population was obtained during follow-up interviews with the question, ‘‘Do Asthma BRIDGE is a multicenter initiative to develop a any caretakers of the child currently smoke cigarettes?’’ In MoBa, publicly accessible resource consisting of ,1,500 asthmatics and cotinine concentrations were measured in maternal samples controls with comprehensive phenotype and genomic data. The collected at about 18 weeks of pregnancy using liquid chroma- first phase of the Asthma BRIDGE multicenter initiative consisted tography–tandem mass spectrometry. [12,13] of asthmatic subjects that were originally recruited as part of CAMP, the details of which have been described elsewhere. DNA Methylation [10,11] Briefly, CAMP is a multicenter, randomized,
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