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Foppiano, F.* ; Böck, A.* ; Beerweiler, C.* ; Urner, K.* ; Ege, M.* ; Schmaußer-Hechfellner, E. ; Skevaki, C.* ; Frey, U.* ; Riedler, J.* ; Frei, R.* ; Lauener, R.* ; Roduit, C.* ; Karvonen, A.M.* ; Roponen, M.* ; Pekkanen, J.* ; Divaret-Chauveau, A.* ; Barnig, C.* ; von Mutius, E. ; Schaub, B.*

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

Am. J. Respir. Crit. Care Med., DOI: 10.1093/ajrccm/aamag142 (2026)
DOI
Open Access Green as soon as Postprint is submitted to ZB.
RationaleEarly childhood represents a critical window for asthma susceptibility, marked by developmental and molecular changes, yet their longitudinal pattern remains unclear.ObjectivesTo identify differences in longitudinal whole-blood gene expression during early childhood in future asthmatics compared to healthy children.MethodsWe conducted a longitudinal whole-blood transcriptomic analysis at four timepoints (1, 4.5, 6, 10.5 years) in a sample of the birth cohort PASTURE (n = 378), comparing children who developed asthma between 6 and 10.5 years with non-asthmatic controls (83/295). Analyses included longitudinal differential gene expression, weighted gene co-expression network analysis, and cis-eQTL analysis.Measurements and main resultsAt age 1, 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 (P = .003). 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 (aOR[95% CI]= 1.47[1.13-1.93]).ConclusionWe identified a shift from a neutrophil-driven gene signature at age 1 to a persistent eosinophilic signature at 4.5 to 10.5 years in asthmatic children, highlighting the 1 to 4.5-year period as most vulnerable period. Genetic variants strongly influenced the persistent eosinophilic gene signature, comprising potential novel therapeutic targets.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Asthma ; Exhaled Nitric Oxide ; Longitudinal Study ; Snp ; Gene Signature ; Cohort ; Eosinophilic ; Gene ; Single-nucleotide Polymorphism
ISSN (print) / ISBN 1073-449X
e-ISSN 1535-4970
Journal American Journal of Respiratory and Critical Care Medicine
Publisher American Thoracic Society
Reviewing status Peer reviewed
Institute(s) Institute of Asthma and Allergy Prevention (IAP)
Environmental Health Center (EHC)