Neonatal DNA methylation distinguishes children who will and will not become asthmatic by age 9 years

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 a combination of methyl binding protein-dependent DNA capture and microarrays 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-1b 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 hub 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-1b, 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. CBMCs from children who did (n=18) or did not (n=18) become asthmatic by age 9 years