Impact of Gene Expression Associated with Glucocorticoid-Induced Transcript 1 (GLCCI1) on Severe Asthma and Future Exacerbation

Abstract

Genetic variations in glucocorticoid-induced transcript 1 (GLCCI1) have been associated with the response to corticosteroid treatment. However, the associations of GLCCI1 polymorphisms or gene expression with the prognosis of asthma and pathophysiological factors related to steroid insensitivity remain unclear. We sought to investigate the associations of GLCCI1, nuclear factor (erythroid-derived 2)-like 2 (Nrf2), and histone deacetylase 2 (HDAC2) mRNA expression levels and the GLCCI1 rs37973 polymorphism with asthma severity and future exacerbation in patients with asthma. Subjects included 25 patients with severe asthma and 127 patients with nonsevere asthma. mRNA expression levels in peripheral blood mononuclear cells were measured and evaluated as predictors of severe asthma using receiver operating characteristic (ROC) analysis. The hazard ratios of the mRNA expression levels for time to first exacerbation in the 1-year follow-up period were calculated. GLCCI1, Nrf2, and HDAC2 mRNA expression levels were significantly lower in patients with severe asthma than in patients with nonsevere asthma and could predict severe asthma with an area under the ROC curve of 0.68, 0.71, and 0.65, respectively. In contrast, no relationship was found between the GLCCI1 rs37973 polymorphism and severe asthma. The hazard ratios for asthma exacerbation in patients with low GLCCI1, Nrf2, and HDAC2 mRNA expression levels were 3.24 (95% confidence interval, 1.42-7.40), 3.13 (1.37-7.16), and 2.98 (1.22-7.25), respectively. Patients with severe asthma could be distinguished by lower GLCCI1, Nrf2, and HDAC2 mRNA levels in peripheral blood cells, and all of these gene signatures could predict future asthma exacerbations.

The Complicated Role of Nuclear Factor Erythroid-Derived 2-Like 2 in Allergy and Asthma

“…This group further showed that Nrf2 is specifically cytoprotective in airway epithelial cells in this model (Sussan et al, 2015). Consistent with this, Hirai et al, showed low Nrf2 expression correlated with increased severity in human asthma patients (Hirai et al, 2019). A study by Brown et al showed that consumption of the Nrf2 activator sulforaphane ameliorated bronchoconstriction in 60% of individuals with moderate asthma.…”

Circulating microRNA‐15b‐5p as a biomarker for asthma‐COPD overlap

“…Increased activity of PI3K was reported in patients with COPD and the model mouse of asthma 24,25 . PI3K activations are also known to associate with steroid‐insensitivity in patients with COPD and severe asthma through a reduction in nuclear levels of histone deacetylase 2, which plays an important role in the steroid response 25‐27 . Among other pathways, the transforming growth factor‐β (TGF‐β) signaling pathway is involved in airway inflammation and tissue remodeling 28,29 .…”

“…24,25 PI3K activations are also known to associate with steroid-insensitivity in patients with COPD and severe asthma through a reduction in nuclear levels of histone deacetylase 2, which plays an important role in the steroid response. [25][26][27] Among other pathways, the transforming growth factor-β (TGF-β) signaling pathway is involved in airway inflammation and tissue remodeling. 28,29 Moreover, among the target genes of miR-15p-5p, AKT3, E2F3, MAP2K1, MAPK8, PIK3R1, RAF1, and VEGFA are associated with pathways implicated in both asthma and COPD.…”

Thioredoxin-1: A Promising Target for the Treatment of Allergic Diseases

“…In the pathogenesis of allergic asthma, reduced expression of antioxidant genes is also observed, such as Nrf2. Clinical studies have shown that with the reduction of Nrf2 expression in the body, asthma becomes more serious ( 21 , 22 ), and the application of Nrf2 agonists significantly relaxes the bronchi and improves the symptoms ( 23 ), suggesting that the occurrence of allergic asthma is not only related to Th2 inflammatory reaction but also has a close relationship with oxidative stress.…”