Early-Life Wheeze Trajectories Are Associated with Distinct Asthma Transcriptomes Later in Life.

Rationale: Early childhood wheeze is characterized by heterogeneous trajectories having differential associations with later life asthma development.

Methods: The Children's Respiratory Environmental Workgroup (CREW) is a collective of 12 birth cohorts, 7 of which conducted an additional visit with a nasal lavage collected and subjected to bulk RNA-sequencing. Early-life wheeze trajectories were defined using latent class analysis of longitudinal early-life wheezing data. Weighted gene correlation network analysis was utilized to associate gene expression patterns and current asthma with early-life wheeze trajectories.

Results: We investigated 743 children (mean [SD] age 17 [5.1] years, 360 [48.5%] male). Four patterns of early life wheeze were identified: infrequent, transient, late-onset, persistent. Early life transient wheeze was associated with gene expression patterns related to increased antiviral response and late-onset wheeze was associated with decreased insulin signaling and glucose metabolism. Early-life persistent wheeze was associated with gene expression modules of type 2 inflammation and epithelial development, but these modules did not distinguish those with current asthma. Children who had persistent wheeze in early life and current asthma displayed a unique increase in expression of genes enriched for neuronal processes and ciliated epithelial function compared to those without asthma.

Conclusions: Early-life longitudinal wheeze trajectories are associated with specific asthma transcriptomes later in life. These data suggest early-life asthma prevention strategies may be most beneficial when tailored to the specific wheeze pattern.