Epigenome-wide analysis links SMAD3 methylation at birth to asthma in children of asthmatic mothers

Avery DeVries, Gabriela Wlasiuk, Susan J. Miller, Anthony Bosco, Debra A. Stern, I. Carla Lohman, Janet Rothers, Anya C. Jones, Jessie Nicodemus-Johnson, Monica M. Vasquez, John A. Curtin, Angela Simpson, Adnan Custovic, Daniel J. Jackson, James E. Gern, Robert F. Lemanske, Stefano Guerra, Anne L. Wright, Carole Ober, Marilyn HalonenDonata Vercelli

Research output: Contribution to journalArticlepeer-review

88 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)534-542
Number of pages9
JournalJournal of Allergy and Clinical Immunology
Issue number2
StatePublished - Aug 2017


  • DNA methylation
  • Epigenetics
  • SMAD3
  • childhood asthma

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology


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