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 To assess whether the trajectory to asthma begins already at birth and epigenetic mechanisms, specifically DNA methylation, contribute to asthma inception. Methods We 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. Results Neonatal 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. Conclusions The 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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Purpose of the review Asthma and allergic diseases are among the most prevalent chronic non-communicable diseases of childhood. While epidemiologic studies suggest that asthma begins in the pre-school years, the lack of firm diagnostic criteria to distinguish children who will wheeze only transiently during early life lower respiratory illnesses from children who will wheeze persistently and develop asthma prevents pinpointing the time at which disease truly begins. Epigenetic mechanisms link gene regulation to environmental cues and developmental trajectories. This article reviews the search for epigenetic predictors of asthma and/or allergy that can be identified already at birth and/or in early life. Recent findings DNA methylation signatures associated with asthma and/or allergy at birth, and time-dependent DNA methylation signatures associated with allergic disease phenotypes in early life have been identified. Summary The identification of early epigenetic predictors of allergic diseases points to a potential role of epigenetic mechanisms in regulating the inception of, and the susceptibility to these diseases. Predictive signatures to more accurately estimate a child’s risk for asthma and allergy may improve childhood asthma diagnosis. Moreover, understanding the biological implications of these signatures may help elucidate novel disease pathways and endotypes.