Deep multi-omic profiling reveals molecular signatures that underpin preschool wheeze and asthma

Macowan, Matthew, Pattaroni, Céline, Bonner, Katie, Chatzis, Roxanne, Daunt, Carmel, Gore, Mindy, Custovic, Adnan, Shields, Michael D., Power, Ultan F., Grigg, Jonathan, Roberts, Graham, Ghazal, Peter ORCID: https://orcid.org/0000-0003-0035-2228, Schwarze, Jürgen, Turner, Steve, Bush, Andrew, Saglani, Sejal, Lloyd, Clare M. and Marsland, Benjamin J. 2024. Deep multi-omic profiling reveals molecular signatures that underpin preschool wheeze and asthma. Journal of Allergy and Clinical Immunology 10.1016/j.jaci.2024.08.017

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Abstract

Background Wheezing in childhood is prevalent, with over half of all children experiencing at least one episode by age six. The pathophysiology of wheeze, especially why some children develop asthma while others do not, remains unclear. Objective This study addresses the knowledge gap by investigating the transition from preschool wheeze to asthma using multi-omic profiling. Methods Unsupervised, group-agnostic integrative multi-omic factor analysis was performed using host/bacterial (meta-)transcriptomic and bacterial shotgun metagenomic datasets from bronchial brush samples paired with metabolomic/lipidomic data from bronchoalveolar lavage samples acquired from children 1-17 years old. Results Two multi-omic factors were identified: one characterising preschool-aged recurrent wheeze and another capturing an inferred trajectory from health to wheeze and school-aged asthma. Recurrent wheeze was driven by Type 1-immune signatures, coupled with upregulation of immune-related and neutrophil-associated lipids and metabolites. Comparatively, progression towards asthma from ages 1-18 was dominated by changes related to airway epithelial cell gene expression, Type 2-immune responses, and constituents of the airway microbiome, such as increased Haemophilus influenzae. Conclusion These factors highlighted distinctions between an inflammation-related phenotype in preschool wheeze, and the predominance of airway epithelial-related changes linked with the inferred trajectory toward asthma. These findings provide insights into the differential mechanisms driving the progression from wheeze to asthma and may inform targeted therapeutic strategies.

Item Type:	Article
Status:	In Press
Schools:	Medicine
Additional Information:	License information from Publisher: LICENSE 1: URL: http://creativecommons.org/licenses/by/4.0/, Start Date: 2024-08-27
Publisher:	Elsevier
ISSN:	0091-6749
Date of First Compliant Deposit:	2 September 2024
Date of Acceptance:	23 August 2024
Last Modified:	02 Sep 2024 10:30
URI:	https://orca.cardiff.ac.uk/id/eprint/171714

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