Epigenome-wide Analysis Links SMAD3 Methylation at Birth to Asthma in Children of Asthmatic Mothers

Publication date: Available online 21 December 2016
Source:Journal of Allergy and Clinical Immunology
Author(s): 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 Halonen, Donata Vercelli
BackgroundThe 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.ObjectiveTo assess whether the trajectory to asthma begins already at birth and epigenetic mechanisms, specifically DNA methylation, contribute to asthma inception.MethodsWe used Methylated CpG Island Recovery Assay (MIRA)-chip to survey DNA methylation in cord blood mononuclear cells (CBMC) from 36 children (18 non-asthmatic, 18 asthmatic by age 9) 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 two replication cohorts (The Manchester Asthma and Allergy Study, n=30, and the Childhood Origins of ASThma Study, n=28) was analyzed by bisulfite sequencing or Illumina 450K arrays. CBMC-derived IL-1β was measured by ELISA.ResultsNeonatal immune cells harbored 589 differentially methylated regions (DMRs) that distinguished IIS children who did and did not develop asthma by age 9. In all three cohorts, methylation in SMAD3, the most connected node within the network of asthma-associated DMRs, 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.ConclusionsThe trajectory to childhood asthma begins at birth and involves epigenetic modifications in immunoregulatory and pro-inflammatory pathways. Maternal asthma influences epigenetic mechanisms that contribute to the inception of this trajectory.

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CAPSULE SUMMARY: The trajectory to childhood asthma begins at birth and involves epigenetic (DNA methylation) modifications in innate pro-inflammatory and immunoregulatory pathways. Maternal asthma appears to strongly influence this trajectory.


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