Wheeze and allergic sensitization are the strongest early-life predictors of childhood asthma development; the molecular origins of these early-life phenotypes are poorly understood.
To identify metabolites associated with early-life wheeze, allergic sensitization, and childhood asthma.
We conducted a nested case-control study using ECHO Program cohorts for discovery and independent replication. Wheeze and allergic sensitization were defined by number of wheeze episodes and positive specific IgE at 1 year of age, respectively. Asthma was defined as physician diagnosis of asthma at age 5 or 6 years. We used untargeted metabolomics, controlling for observed and latent confounding factors, to assess associations between the plasma metabolome and early-life wheeze, allergy, and childhood asthma.
Eighteen plasma metabolites were associated with first year wheeze in the discovery cohort (n=338). Z,Z unconjugated bilirubin (UCB) and its related metabolites exhibited a dose-response relationship with wheeze frequency; UCB levels were 13% (β=0.87, 95%CI=0.74-1.02) and 22% (β=0.78, 95%CI=0.68-0.91) lower in children with 1-3 and 4+ wheeze episodes compared to those who never wheezed, respectively. UCB levels were also associated with childhood asthma (β=0.82, 95%CI=0.68-0.98). Similar trends were observed in two independent cohorts. UCB was significantly negatively correlated with eicosanoid- and oxidative stress-related metabolites. There were no significant associations between metabolites and allergic sensitization.
We identified a novel inverse, dose-dependent association between UCB and recurrent wheeze and childhood asthma. Inflammatory lipid mediators and oxidative stress byproducts inversely correlated with UCB, suggesting UCB modulates pathways critical to the development of early-life recurrent wheeze and childhood asthma.

Copyright © 2021. Published by Elsevier Inc.