In this study, we were the first to demonstrate that the common allele homozygotes of rs1384006 C > T of the OXSR1 gene were significantly associated with a higher exacerbation rate and the risk of FE in the nonsmoking asthmatics. OXSR1 has rarely been studied with regard to respiratory diseases, although it plays a role as a salt transportation, and cell volume control through ionic mechanisms[33, 34] and ion transport by bronchial epithelial cells is essential for healthy airways. Imbalance of the transport system is closely related to the pathophysiology of asthma such as dysfunction of epithelial cells and smooth muscles. [35, 36]
Epithelial cells serve to protect airways from inhaled toxic substances and microorganisms. Airway secretory cells secrete mucin as the core glycoproteins of mucus, and cilia on the top of ciliated cells export mucus outside the lung to protect the lung from particles and pathogens.[37] This mucociliary clearance is an important innate defense mechanism that cleans up inhaled allergens and other harmful stimuli.[38] The mucus gel is placed on a fluid layer called an airway-surface liquid (ASL), and the efficacy of mucociliary clearance depends on the ion transport pathways to maintain the depth of ASL.[35, 37]
Previous studies found that asthma is associated with reduced mucociliary clearance, especially during exacerbation. [36, 38] In β-epithelial Na+ channel (Scnnlb) transgenic mice, mucociliary clearance is reduced due to dehydration and thickened mucus.[39] In addition, the Scnnlb transgenic juvenile mice exhibit type 2 airway inflammation such as IL-13, airway eosinophilia, and alternative macrophage activation with reduced mucociliary clearance.[40, 41] In chronic lung diseases including asthma, epithelial Na+ channel blockers, amiloride, or hypertonic saline can restore mucociliary clearance by improving hydration of the airway surfaces. These facts support that there is a close association between the Na+ channel, mucociliary clearance, and asthma.[42, 43] Therefore, the OXSR1 gene, which plays a role in regulating salt, water and cell volume by an ionic mechanism, is likely to play an important role in the mucus concentration, ASL fluid layer, and mucociliary clearance, suggesting that genetic variants of OXSR1 are presumed to be related to frequent exacerbation of asthma through these mechanism.
Recently, oxidative stress and its pathways have been thought to contribute significantly to severe asthma and asthma exacerbations.[44, 45] However, the relationship between OXSR1, a gene related to oxidative stress, and asthma exacerbation has never been studied. OXSR1 is also involved in the regulation of immune responses by interacting with TNF receptor protein kinase C-θ (PKCθ), which is expressed by lymphoid tissues.[25, 34] OXSR1 and WNK1 kinase, an upstream activator of OXSR1, are hardly detectable at basal activity, which may mean that WNK-OXSR1 signaling is regulated tightly in normal physiological conditions.[34]
Interestingly, this genetic effect of rs1384006 C > T was not found in the smoker asthmatics. The reason for this finding could be explained by smoking itself being a strong inducer to exacerbate asthma.[32] Cigarette smoking is associated with accelerated decline of lung function in asthmatics,[46] resulting in worsening of asthma severity,[47] reduction of responsiveness to glucocorticoids,[48] poor asthma control, and a higher hospital admissions.[49]
The most important mechanism that may explain the relative corticosteroid resistance in smokers with asthma and COPD is a reduction in the expression of the enzyme histone deacetylase 2 (HDAC2). A reduction in HDAC activity and HDAC2 expression may account for the amplified inflammation and resistance to the actions of corticosteroids. The p38 mitogen-activated protein kinase (MAPK) pathway is also thought to play a role in corticosteroid insensitivity.[50] Thus, rs1384006 C > T of OXSR1 might not exert any genetic effect in the enhanced MAPK- and reduced HDAC-induced airway inflammation in smokers.
There are some limitations to this study. First, there is still little information about the function of the OXSR1 gene in asthma. According to functional estimation of the SNPs linked with rs1384006 in Asian populations (SNPinfo Web Server, https://snpinfo.niehs.nih.gov/), rs1384006 did not affect transcription factor binding, splicing sites, splicing regulation, or miRNA molecular functions. Additionally, since there is no known CpG island near rs1384006, this SNP is not likely to have an allele-specific effect on methylation of the OXSR1 gene as a CpG-SNP. On the contrary, since little is known about it, it is worthy as an original discovery to be the subject of future genetic studies about asthma exacerbations.
Second, we could not confirm the causal relationship between the minor allele variant of rs1384006 in the OXSR1 gene and asthma exacerbations in this study because it is only a genetic correlation study and a causal relationship needs a functional study. Third, because normal subjects were not included in the study, we cannot compare the SNP frequency with those of non-asthmatic controls. Therefore, further functional experiments are needed to identify its pathophysiology in asthma compared to normal controls.