title: Epigenome-wide analysis links SMAD3 methylation at birth to asthma in children of asthmatic mothers.
abstract: BACKGROUND
  The timing and mechanisms of asthma inception remain imprecisely defined. Although epigenetic mechanisms likely contribute to asthma pathogenesis, little is known about their role in asthma inception.
  
  
  OBJECTIVE
  We sought to assess whether the trajectory to asthma begins already at birth and whether epigenetic mechanisms, specifically DNA methylation, contribute to asthma inception.
  
  
  METHODS
  We used the Methylated CpG Island Recovery Assay chip to survey DNA methylation in cord blood mononuclear cells from 36 children (18 nonasthmatic and 18 asthmatic subjects by age 9 years) from the Infant Immune Study (IIS), an unselected birth cohort closely monitored for asthma for a decade. SMAD3 methylation in IIS (n = 60) and in 2 replication cohorts (the Manchester Asthma and Allergy Study [n = 30] and the Childhood Origins of Asthma Study [n = 28]) was analyzed by using bisulfite sequencing or Illumina 450K arrays. Cord blood mononuclear cell-derived IL-1β levels were measured by means of ELISA.
  
  
  RESULTS
  Neonatal immune cells harbored 589 differentially methylated regions that distinguished IIS children who did and did not have asthma by age 9 years. In all 3 cohorts methylation in SMAD3, the most connected node within the network of asthma-associated, differentially methylated regions, was selectively increased in asthmatic children of asthmatic mothers and was associated with childhood asthma risk. Moreover, SMAD3 methylation in IIS neonates with maternal asthma was strongly and positively associated with neonatal production of IL-1β, an innate inflammatory mediator.
  
  
  CONCLUSIONS
  The trajectory to childhood asthma begins at birth and involves epigenetic modifications in immunoregulatory and proinflammatory pathways. Maternal asthma influences epigenetic mechanisms that contribute to the inception of this trajectory.
authors.affiliation: Asthma and Airway Disease Research Center, University of Arizona, Tucson, Ariz; Department of Cellular and Molecular Medicine, University of Arizona, Tucson, Ariz.
authors.forename: Avery
authors.initials: A
authors.lastname: DeVries
authors.affiliation: Asthma and Airway Disease Research Center, University of Arizona, Tucson, Ariz.
authors.forename: Gabriela
authors.initials: G
authors.lastname: Wlasiuk
authors.affiliation: Arizona Research Laboratories, University of Arizona, Tucson, Ariz.
authors.forename: Susan J
authors.initials: SJ
authors.lastname: Miller
authors.affiliation: Telethon Kids Institute, University of Western Australia, Perth, Australia.
authors.forename: Anthony
authors.initials: A
authors.lastname: Bosco
authors.affiliation: Asthma and Airway Disease Research Center, University of Arizona, Tucson, Ariz.
authors.forename: Debra A
authors.initials: DA
authors.lastname: Stern
authors.affiliation: Asthma and Airway Disease Research Center, University of Arizona, Tucson, Ariz.
authors.forename: I Carla
authors.initials: IC
authors.lastname: Lohman
authors.affiliation: College of Nursing, University of Arizona, Tucson, Ariz.
authors.forename: Janet
authors.initials: J
authors.lastname: Rothers
authors.affiliation: Telethon Kids Institute, University of Western Australia, Perth, Australia.
authors.forename: Anya C
authors.initials: AC
authors.lastname: Jones
authors.affiliation: Department of Human Genetics, University of Chicago, Chicago, Ill.
authors.forename: Jessie
authors.initials: J
authors.lastname: Nicodemus-Johnson
authors.affiliation: Asthma and Airway Disease Research Center, University of Arizona, Tucson, Ariz.
authors.forename: Monica M
authors.initials: MM
authors.lastname: Vasquez
authors.affiliation: Centre for Respiratory Medicine and Allergy, Institute of Inflammation and Repair, Manchester Academic Health Science Centre, University of Manchester and University Hospital of South Manchester NHS Foundation Trust, Manchester, United Kingdom.
authors.forename: John A
authors.initials: JA
authors.lastname: Curtin
authors.affiliation: Centre for Respiratory Medicine and Allergy, Institute of Inflammation and Repair, Manchester Academic Health Science Centre, University of Manchester and University Hospital of South Manchester NHS Foundation Trust, Manchester, United Kingdom.
authors.forename: Angela
authors.initials: A
authors.lastname: Simpson
authors.affiliation: Centre for Respiratory Medicine and Allergy, Institute of Inflammation and Repair, Manchester Academic Health Science Centre, University of Manchester and University Hospital of South Manchester NHS Foundation Trust, Manchester, United Kingdom.
authors.forename: Adnan
authors.initials: A
authors.lastname: Custovic
authors.affiliation: Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, Wis.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Jackson
authors.affiliation: Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, Wis.
authors.forename: James E
authors.initials: JE
authors.lastname: Gern
authors.affiliation: Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, Wis.
authors.forename: Robert F
authors.initials: RF
authors.lastname: Lemanske
authors.affiliation: Asthma and Airway Disease Research Center, University of Arizona, Tucson, Ariz; CREAL, University Pompeu Fabra, Barcelona, Spain.
authors.forename: Stefano
authors.initials: S
authors.lastname: Guerra
authors.affiliation: Asthma and Airway Disease Research Center, University of Arizona, Tucson, Ariz; Department of Pediatrics, University of Arizona, Tucson, Ariz.
authors.forename: Anne L
authors.initials: AL
authors.lastname: Wright
authors.affiliation: Department of Human Genetics, University of Chicago, Chicago, Ill.
authors.forename: Carole
authors.initials: C
authors.lastname: Ober
authors.affiliation: Asthma and Airway Disease Research Center, University of Arizona, Tucson, Ariz; Department of Pharmacology, University of Arizona, Tucson, Ariz; Arizona Center for the Biology of Complex Diseases, University of Arizona, Tucson, Ariz; Bio5 Institute, University of Arizona, Tucson, Ariz.
authors.forename: Marilyn
authors.initials: M
authors.lastname: Halonen
authors.affiliation: Asthma and Airway Disease Research Center, University of Arizona, Tucson, Ariz; Department of Cellular and Molecular Medicine, University of Arizona, Tucson, Ariz; Arizona Center for the Biology of Complex Diseases, University of Arizona, Tucson, Ariz; Bio5 Institute, University of Arizona, Tucson, Ariz. Electronic address: donata@email.arizona.edu.
authors.forename: Donata
authors.initials: D
authors.lastname: Vercelli
mesh_terms: D001249:Asthma / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D018899:CpG Islands; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005312:Fetal Blood / Q000166:cytology; D006801:Humans; D007231:Infant, Newborn; D053583:Interleukin-1beta / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D009035:Mothers; D011401:Promoter Regions, Genetic; D051900:Smad3 Protein / Q000235:genetics*
chemical_list: D053583:Interleukin-1beta; C497790:SMAD3 protein, human; D051900:Smad3 Protein
keywords: DNA methylation; Epigenetics; SMAD3; childhood asthma