Rinku Sharma, PhD
Rinku Sharma, Anshul Tiwari, Alvin T. Kho, Juan C Celedón, Scott T. Weiss, Kelan G. Tantisira, and Michael J. McGeachie
Michael J. McGeachie
Research Category: Lung Research
Background: Inhaled corticosteroids (ICS) are the most effective and widely used asthma controller medications. However, the response to ICS is variable and difficult to quantify. We previously defined a Cross-sectional Asthma STEroid Response (CASTER) measure based on a combination of asthma control indicators and spirometry measurements. MicroRNAs (miRNAs) can be useful drivers and biomarkers of ICS response.
Methods: We used Lymphoblastoid Cell Lines (LCL) paired designed (dexamethasone (DEX) (1026 mol/L) and a sham (ethanol) control) gene array expression data and serum miRNA (miR-28-5p, miR-339-3p, and miR-432-5p) expression data of 88 children with asthma, who were on ICS. The association between these miRNAs and the transcriptome of Lymphoblastoid Cell Lines in response to a glucocorticoid was assessed through modified Weighted Gene Correlation Network Analysis (WGCNA) and linear mixed-effects model (LMM).
Results: We observed 20 gene modules that demonstrated a coordinated response of LCL cells to dexamethasone treatment. At 10% FDR, two modules were significantly associated with miR-339-3p. The functional enrichment analysis of these two modules revealed enrichment of inflammation-related biological pathways.
Conclusion: miR-339-3p is linked to gene response to glucocorticoid treatment in LCLs. miR-339-3p may be involved in immune dysregulation, which leads to a poor response to ICS treatment.
Although inhaled corticosteroids (ICS) are the most effective and widely used asthma controller medications, they are not equally effective in controlling asthma symptoms in all patients. An estimated 25-30% of patients do not respond to ICS therapy. Clinical asthma management would benefit from a method to identify patients who are poor responders to ICS early on, which could improve upon the current standard of care, which prescribes trial-and-error of ICS: only after ICS treatment appears ineffective are other medications added to or substituted for the ICS. As a result, another effective approach is required. So, in this study, we attempted to identify a blood-based biomarker that could aid in detecting poor responder groups before treatment began. We do this using miRNAs, small RNA molecules that can increase or decrease the amount of particular proteins being produced in cells.