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. 2025 Sep;156(3):640-650.
doi: 10.1016/j.jaci.2025.03.020. Epub 2025 Apr 4.

Early-life wheeze trajectories are associated with distinct asthma transcriptomes later in life

Kieran J Phelan  1 , Krishna M Roskin  2 , Jeffrey W Burkle  3 , Wan-Chi Chang  3 , Lisa J Martin  4 , Jocelyn M Biagini  5 , Latha Satish  3 , David B Haslam  6 , Daniel Spagna  3 , Seth Jenkins  3 , Elsie Parmar  3 , Leonard B Bacharier  7 , Tebeb Gebretsadik  8 , Michelle Gill  9 , Diane R Gold  10 , Daniel J Jackson  11 , Christine C Johnson  12 , Susan V Lynch  13 , Kathryn E McCauley  13 , Chris G McKennan  14 , Rachel Miller  15 , Carole Ober  16 , Dennis R Ownby  17 , Patrick H Ryan  18 , Nathan Schoettler  19 , Sweta Singh  20 , Cynthia M Visness  21 , Matthew C Altman  22 , James E Gern  11 , Gurjit K Khurana Hershey  23 ; Environmental Influences on Child Health Outcomes–Children’s Respiratory and Environmental Workgroup
Affiliations

Early-life wheeze trajectories are associated with distinct asthma transcriptomes later in life

Kieran J Phelan et al. J Allergy Clin Immunol. 2025 Sep.

Abstract

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

Objective: We sought to determine how early-life wheeze trajectories impact later life asthma gene expression.

Methods: The Children's Respiratory Environmental Workgroup 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 used to associate gene expression patterns and current asthma with early-life wheeze trajectories.

Results: We investigated 743 children (mean age, 17 ± 5.1 years; 360 [48.5%] male). Four patterns of early-life wheeze were identified: infrequent, transient, late-onset, and 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 with those without asthma.

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

Keywords: Wheeze; asthma; pediatrics; transcriptomics.

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Conflict of interest statement

Disclosure statement Research reported in this publication was supported by the CREW Consortium, Office of the Director, National Institutes of Health (NIH) under award number UH3 OD023282; and grant numbers NIH U24AI179612, K08 HL153955, and NIH U19 AI162310. This work was also supported by award number T32 GM149200-01 for the Medical Scientist Training Program at the University of Cincinnati, T32 5T32HL007752-29 for the Pulmonary Development and Disease Pathogenesis Training Program at Cincinnati Children’s Hospital Medical Center, and 1F30HL172613-01A1. Additional funding was provided by grant numbers NO1-AI-25496, NO1-AI-25482, HHSN272200900052C, HHSN272201000052I, 5UM1AI114271, UM2AI117870, and 5U19AI070235. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. The sponsor, NIH, had no access to the data. All analyses for scientific publication were performed by the study statistician, independently of the sponsor. The lead author wrote all drafts of the manuscript and made revisions on the basis of coauthors and the CREW Publication Committee feedback without input from the sponsor. The study sponsor did not review or approve the manuscript for submission to the journal. Data sharing statement: Raw RNA-sequencing data used in this study have been deposited at the database for Genotypes and Phenotypes (dbGaP) and will be made available on request. Disclosure of potential conflict of interest: L. B. Bacharier is a member of the GINA Science Committee; reports grants from the National Institutes of Health (NIH)/National Institute of Allergy and Infectious Diseases/National Heart, Lung, and Blood Institute, personal fees from GlaxoSmithKline, Genentech/Novartis, Merck, Teva, Boehringer Ingelheim, AstraZeneca, Avillion, WebMD/Medscape, Sanofi/Regeneron, Vectura, Circassia, OM Pharma, and Kinaset, and for DSMB from AstraZeneca, DBV Technologies, and Vertex; and royalties from Elsevier outside the submitted work. D. R. Gold reports grants from the NIH during the conduct of the study. J. E. Gern reports grants from the NIH during the conduct of the study and personal fees from AstraZeneca outside the submitted work. G. K. Khurana Hershey reports grants from the NIH and royalties from Elsevier outside the submitted work.

References

    1. Lötvall J, Akdis CA, Bacharier LB, Bjermer L, Casale TB, Custovic A, et al. Asthma endotypes: a new approach to classification of disease entities within the asthma syndrome. J Allergy Clin Immunol [Internet]. 2011. [cited 2022 Jul 18];127:355–60. Available from: https://pubmed.ncbi.nlm.nih.gov/21281866/ - PubMed
    1. Kaur R, Chupp G. Phenotypes and endotypes of adult asthma: Moving toward precision medicine. J Allergy Clin Immunol [Internet]. 2019. [cited 2022 Apr 25];144:1–12. Available from: https://pubmed.ncbi.nlm.nih.gov/31277742/ - PubMed
    1. Laubhahn K, Phelan KJ, Jackson DJ, Altman MC, Schaub B. What Have Mechanistic Studies Taught Us About Childhood Asthma? J Allergy Clin Immunol Pract. 2023;11:684–92. - PubMed
    1. Jartti T, Gern JE. Role of viral infections in the development and exacerbation of asthma in children. J Allergy Clin Immunol [Internet]. 2017. [cited 2023 Aug 1];140:895–906. Available from: https://pubmed.ncbi.nlm.nih.gov/28987219/ - PMC - PubMed
    1. Bacharier LB, Guilbert TW, Jartti T, Saglani S. Which Wheezing Preschoolers Should be Treated for Asthma? J Allergy Clin Immunol Pract [Internet]. 2021. [cited 2023 Aug 1];9:2611–8. Available from: https://pubmed.ncbi.nlm.nih.gov/33677078/ - PubMed