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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. 212, 1214-1226 (2026)
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Open Access Hybrid
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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; Wheeze; Inflammation; Exposure
ISSN (print) / ISBN 1073-449X
e-ISSN 1535-4970
Journal American Journal of Respiratory and Critical Care Medicine
Quellenangaben Volume: 212, Issue: 6, Pages: 1214-1226 Article Number: , Supplement: ,
Publisher American Thoracic Society
Publishing Place Great Clarendon St, Oxford Ox2 6dp, England
Reviewing status Peer reviewed
Institute(s) Institute of Asthma and Allergy Prevention (IAP)
Environmental Health Center (EHC)
Grants Research Committee of the Kuopio University Hospital Catchment Area for the State Research Funding
Khne Foundation-Research
Finnish Institute for Health and Welfare
DFG
German Center for Child and Adolescent Health
Bundesministerium fr Bildung und Forschung
Pivikki and Sakari Sohlberg Foundation
German Center of Lung Research
Juho Vainio Foundation
Federal Ministry of Education and Research
Foundation for Pediatric Research
Yrj Jahnsson Foundation
Farmers' Social Insurance Institution of Finland
Academy of Finland
BMBF
Finnish Cultural Foundation