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Transcriptome analysis of controlled and therapy-resistant childhood asthma reveals distinct gene expression profiles
Helena Persson1, Andrew T Kwon2, Jordan A Ramilowski2
1Department of Biosciences and Nutrition and Center for Innovative Medicine (CIMED), Karolinska Institutet, Stockholm, Sweden.
Insights
Children with severe asthma (SA) have distinct gene expression profiles in leukocytes compared to controlled asthma. This finding supports the development of new biomarkers and treatments for therapy-resistant asthma.
Area of Science:
- Genomics and Molecular Biology
- Pediatric Pulmonology
- Immunology
Background:
- Severe asthma (SA) in children is characterized by poor disease control despite aggressive treatment.
- Uncontrolled SA leads to significant personal suffering, lung function decline, and high healthcare costs.
- Therapy-resistant asthma is diagnosed when no specific exacerbating factors are identified.
Purpose of the Study:
- To investigate gene expression patterns in children with severe asthma.
- To model regulatory transcription factor networks in peripheral blood leukocytes of children with SA.
- To identify molecular differences between therapy-resistant and controlled asthma in children.
Main Methods:
- Gene expression analysis using Cap Analysis of Gene Expression (CAGE) in three groups: children with SA (n=13), controlled persistent asthma (n=15), and healthy controls (n=9).
- CAGE sequencing was employed to detect transcription start sites of known and novel messenger RNAs (mRNAs) and noncoding RNAs.
- Hierarchical clustering was used to differentiate sample groups based on differentially expressed transcription start sites.
Main Results:
- Distinct gene expression profiles were observed between children with SA and those with controlled asthma, with 1305 differentially expressed transcription start sites identified.
- Expression of RAR-related orphan receptor A (RORA) was significantly upregulated in children with SA.
- Gene network modeling indicated reduced glucocorticoid receptor signaling and heightened mitogen-activated protein kinase and Jun kinase cascade activity in SA patients.
Conclusions:
- Circulating leukocytes exhibit unique gene expression signatures in children with controlled asthma versus those with SA.
- These distinct profiles suggest potential for developing specific molecular biomarkers for severe asthma.
- The findings underscore the necessity for novel therapeutic strategies targeting the molecular pathways implicated in therapy-resistant childhood asthma.
Background:
Children with problematic severe asthma have poor disease control despite high doses of inhaled corticosteroids and additional therapy, leading to personal suffering, early deterioration of lung function, and significant consumption of health care resources. If no exacerbating factors, such as smoking or allergies, are found after extensive investigation, these children are given a diagnosis of therapy-resistant (or therapy-refractory) asthma (SA).
Objective:
We sought to deepen our understanding of childhood SA by analyzing gene expression and modeling the underlying regulatory transcription factor networks in peripheral blood leukocytes.
Methods:
Gene expression was analyzed by using Cap Analysis of Gene Expression in children with SA (n = 13), children with controlled persistent asthma (n = 15), and age-matched healthy control subjects (n = 9). Cap Analysis of Gene Expression sequencing detects the transcription start sites of known and novel mRNAs and noncoding RNAs.
Results:
Sample groups could be separated by hierarchical clustering on 1305 differentially expressed transcription start sites, including 816 known genes and several novel transcripts. Ten of 13 tested novel transcripts were validated by means of RT-PCR and Sanger sequencing. Expression of RAR-related orphan receptor A (RORA), which has been linked to asthma in genome-wide association studies, was significantly upregulated in patients with SA. Gene network modeling revealed decreased glucocorticoid receptor signaling and increased activity of the mitogen-activated protein kinase and Jun kinase cascades in patients with SA.
Conclusion:
Circulating leukocytes from children with controlled asthma and those with SA have distinct gene expression profiles, demonstrating the possible development of specific molecular biomarkers and supporting the need for novel therapeutic approaches.
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