title: Prenatal tobacco smoke exposure is associated with childhood DNA CpG methylation.
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.
  
  
  OBJECTIVE
  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.
authors: Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America.
authors: Carrie V
authors: CV
authors: Breton
authors: Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America.
authors: Kimberly D
authors: KD
authors: Siegmund
authors: 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.
authors: Bonnie R
authors: BR
authors: Joubert
authors: Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America.
authors: Xinhui
authors: X
authors: Wang
authors: Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
authors: Weiliang
authors: W
authors: Qui
authors: Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
authors: Vincent
authors: V
authors: Carey
authors: Norwegian Institute of Public Health, Oslo, Norway.
authors: Wenche
authors: W
authors: Nystad
authors: Norwegian Institute of Public Health, Oslo, Norway.
authors: Siri E
authors: SE
authors: Håberg
authors: University of Chicago, Chicago, Illinois, United States of America.
authors: Carole
authors: C
authors: Ober
authors: University of Chicago, Chicago, Illinois, United States of America.
authors: Dan
authors: D
authors: Nicolae
authors: Johns Hopkins University, Baltimore, Maryland, United States of America.
authors: Kathleen C
authors: KC
authors: Barnes
authors: Arizona Respiratory Center, University of Arizona, Arizona, United States of America.
authors: Fernando
authors: F
authors: Martinez
authors: National Jewish Health, Denver, Colorado, United States of America.
authors: Andy
authors: A
authors: Liu
authors: University of Wisconsin, Madison, Wisconsin, United States of America.
authors: Robert
authors: R
authors: Lemanske
authors: Washington University School of Medicine, St. Louis, Montana, United States of America.
authors: Robert
authors: R
authors: Strunk
authors: Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
authors: Scott
authors: S
authors: Weiss
authors: 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.
authors: Stephanie
authors: S
authors: London
authors: Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America.
authors: Frank
authors: F
authors: Gilliland
authors: Benjamin
authors: B
authors: Raby
mesh_terms: D001249:Asthma / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D018899:CpG Islands; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005260:Female; D006801:Humans; D008297:Male; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D012907:Smoking / Q000009:adverse effects*