Abstract
Background Airway obstruction and wheezing in preschool children with recurrent viral infections are a major clinical problem, and are recognised as a risk factor for the development of chronic asthma. We aimed to analyse whether gene expression profiling provides evidence for pathways that delineate distinct groups of children with wheeze, and in combination with clinical information could contribute to diagnosis and prognosis of disease development.
Methods We analysed leukocyte transcriptomes from preschool children (6 months–3 years) at acute wheeze (n=107), and at a revisit 2–3 months later, comparing them to age-matched healthy controls (n=66). RNA-sequencing applying GlobinLock was used. The cases were followed clinically until age 7 years. Differential expression tests, weighted correlation network analysis and logistic regression were applied and correlations to 76 clinical traits evaluated.
Findings Significant enrichment of genes involved in the innate immune responses was observed in children with wheeze. We identified a unique acute wheeze-specific gene-module, which was associated with vitamin D levels (p<0.005) in infancy, and asthma medication and FEV1%/FVC (forced expiratory volume in 1 s/forced vital capacity) ratio several years later, at age 7 years (p<0.005). A model that predicts leukotriene receptor antagonist medication at 7 years of age with high accuracy was developed (area under the curve 0.815, 95% CI 0.668–0.962).
Interpretation Gene expression profiles in blood from preschool wheezers predict asthma symptoms at school age, and therefore serve as biomarkers. The acute wheeze-specific gene module suggests that molecular phenotyping in combination with clinical information already at an early episode of wheeze may help to distinguish children who will outgrow their wheeze from those who will develop chronic asthma.
Abstract
Gene expression profiles at acute preschool wheeze correlate with vitamin D, and asthma medication and lung function several years later. These profiles provide candidate prognostic biomarkers and support the role of immune response in preschool wheeze. http://bit.ly/318Ilde
Footnotes
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Author contributions: S. Katayama designed, developed and performed statistical and bioinformatic analyses. K. Stenberg Hammar and G. Hedlin, clinical characterisation. K. Krjutškov developed lab procedures and generated the data by RNA-seq. E. Einarsdottir contributed to the bioinformatic analysis. J. Kere conceived the study together with C. Söderhäll and supervised transcriptome analyses. C. Söderhäll conceived the study and coordinated the analyses and the project. S. Katayama, K. Stenberg Hammar, K. Krjutškov, E. Einarsdottir, G. Hedlin, J. Kere and C. Söderhäll contributed to the interpretation of the data. S. Katayama and C. Söderhäll wrote the manuscript, and all authors read, edited and approved the manuscript.
Conflict of interest: S. Katayama has nothing to disclose.
Conflict of interest: K. Stenberg Hammar has nothing to disclose.
Conflict of interest: K. Krjutškov has a patent “GlobinLock – blocking oligonucleotides” pending.
Conflict of interest: E. Einarsdottir has nothing to disclose.
Conflict of interest: G. Hedlin has nothing to disclose.
Conflict of interest: J. Kere has acted as scientific advisor for Blueprint Genetics, Inc., Helsinki, Finland, outside the submitted work; and has a patent GlobinLock method pending.
Conflict of interest: C. Söderhäll has nothing to disclose.
Support statement: This work was supported by The Swedish Heart-Lung Foundation, Stiftelsen Sven Jerrings fond, the Centre for Allergy Research at Karolinska Institutet, the Swedish Association for Allergology (SFFA), Freemason Child House Foundation in Stockholm, Konsul Th C Berghs stiftelse, the Swedish Asthma and Allergy Association's Research Foundation, EU FP7-PEOPLE-2012-28 IAPP, SARM (grant number EU324509). Work in the J. Kere laboratory is supported by the Swedish Research Council, Knut and Alice Wallenberg Foundation, and Sigrid Jusélius Foundation. J. Kere is a recipient of the Royal Society Wolfson Research Merit Award. Funding sources had no role in the study design, in the collection, analysis, and interpretation of data, in the writing of the report, or in the decision to submit the paper for publication. Funding information for this article has been deposited with the Crossref Funder Registry.
- Received January 24, 2019.
- Accepted October 7, 2019.
- Copyright ©ERS 2020
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