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Zhang, Mingming

University of British Columbia

Background: The allergen inhalation challenge model is an experimental model used to fast-track asthma medications into the clinic. The clinical endpoint of this model is the attenuation of the late-phase asthmatic response (LAR), a strong decline in lung function that occurs 3-7 hours post-allergen inhalation challenge. The LAR shares similar symptomatic and pathologic characteristics with the chronic asthma, which is characterized with recurrent exacerbations and gradually worsening of lung function. Thus, we hypothesize that gene-expression biomarkers are predictive of the LAR and can provide novel insights into underlying exacerbations in chronic persistent asthma and asthma severity. Methods: 35 mild allergic asthmatic participants were recruited for allergic inhalation challenge. Blood samples were taken before the challenge for gene expression profiling for a targeted set of gene-transcripts related to immune processes. Classification models using sparse partial least squares discriminant analysis (sPLSDA) were used to identify a mRNA biomarker panel that could discriminate between participants that developed the LAR as compared to those that did not. Classification performance was estimated using 5-fold cross-validation repeated 20 times (20x5-fold CV). These LAR-mRNA biomarkers as well as those identified from previous studies were evaluated in public gene-expression datasets related to asthma exacerbations and severity. This evaluation was based on determining the performance (20x5-fold CV) of PLSDA models in which the variables were fixed to only contain the LAR-mRNA biomarkers. Results: A mRNA biomarker panel comprised of 40 gene-transcripts could predict the LAR with an AUC of 73%. These biomarkers alone and in combination with existing LAR-mRNA biomarkers were predictive of asthma exacerbations albeit much better in males than females (AUC> 0.70). Further these LAR-mRNA biomarkers could also predict asthma severity, although the performance was much higher when restricting to bronchoalveolar lavage samples as compared to blood samples. Conclusion: LAR mRNA biomarkers may represent a baseline inflammatory state in the blood that can predispose an asthmatic individual to develop the LAR. Further these LAR may be important in contributed to asthma exacerbations and progression to severe asthma. Future research is needed to validate these biomarkers as a diagnostic for worsening asthma and potential therapeutics.

Text

2025-04-23

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/90724

Genome Science and Technology

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/