Early neutrophil and persistent eosinophil-associated gene signature in childhood asthma

RATIONALE: Early childhood represents a critical window for asthma susceptibility, marked by developmental and molecular changes, yet their longitudinal pattern remains unclear. OBJECTIVES: To identify differences in longitudinal whole-blood gene expression during early childhood in future asthmatics compared to healthy children. METHODS: We conducted a longitudinal whole-blood transcriptomic analysis at 4 timepoints (1, 4.5, 6, 10.5 years) in a sample of the birth cohort Protection against Allergy Study in Rural Environments (PASTURE) (n = 378), comparing children who developed asthma between ages 6 and 10.5 years with nonasthmatic controls (83/295). Analyses included longitudinal differential gene expression, weighted gene co-expression network analysis, and cis-expression quantitative trait loci analysis. MEASUREMENTS AND MAIN RESULTS: At age 1 year, 42 genes, mostly upregulated in future asthmatics, were associated with neutrophilic inflammation and NLRP3 inflammasome-markers. By 4.5 years, this shifted to a novel eosinophil-related signature (40 genes), remaining increased in asthmatics until 10.5 years. Co-expression analysis confirmed a neutrophilic module at 1 year and eosinophilic modules at 4.5, 6, and 10.5 years, all associated with asthma. Fractional exhaled nitric oxide was associated with the eosinophilic module at age 6 years (P = .003). A total of 86 SNPs were identified modulating the expression of 10 eosinophil-associated genes and GSDMB from this eosinophilic signature. A variant-based genetic risk score was associated with asthma diagnosis (adjusted odds ratio [aOR], 1.47; 95% CI, 1.13-1.93). CONCLUSIONS: We identified a shift from a neutrophil-driven gene signature at age 1 year to a persistent eosinophilic signature at 4.5-10.5 years in asthmatic children, highlighting the 1- to 4.5-year period as the most vulnerable period. Genetic variants strongly influenced the persistent eosinophilic gene signature, comprising potential novel therapeutic targets.