Introduction and Objectives The majority of asthmatics can be well-controlled using inhaled corticosteroids (ICS) and long-acting β2-agonists (LABAs). However, approximately 5% have a severe, refractory form of the disease and are often difficult to treat. Corticosteroid (CS) Insensitivity is the defining feature of these asthmatics known as “severe” asthmatics. The molecular mechanisms underlying CS insensitivity are not fully known. Here, we hypothesise that reduction in the expression of the Glucocorticoid receptor (GR) and Importin 7 are related to CS insensitivity. This aims project were to compare the gene expression of GR and Importin 7 between severe asthmatics and mild/moderate asthmatics or healthy controls of the U-BIOPRED cohort. We then investigated whether changes in their expression, correlated with changes in clinical features and expression of other genes.

Methods The U-BIOPRED database contains data on mRNA expression, lung function, medication usage, blood, urine and sputum samples for their subjects (n=611). Using an unbiased approach to analyse the data we will initially used Gene Set Variation Analysis (GSVA) to look for differences in expression of GR and Importin 7 between the severe asthma, mild/moderate asthma and healthy volunteer cohorts. We then characterised the asthmatics into subjects with high (top 25%, compared to healthy controls) or low (bottom 25%) expression of GR or Importin 7 and then compared clinical characteristics and gene expression profiles between the high and low expressing GR or Importin-7 groups.

Results Severe and non-severe asthmatics had reduced GR expression in endobronchial biopsy and brushings samples compared to healthy controls. There were no significant differences in lung function, blood analytes or exacerbation rates between high or low GR expression groups. Severe non-smoking asthmatics had reduced Importin 7 expression in sputum compared to mild/moderate asthmatics and healthy controls. Low Importin 7 group had lower means in FEV1%, FEV1/FVC, higher means in blood and sputum neutrophils%, IL-6 and hCRP.

Conclusions Reduced Importin-7 expression in sputum samples of asthmatics correlated with reduced lung function scores, increased neutrophilic inflammation and more oral CS use.