Background
Acute Mountain Sickness (AMS) is one of the diseases that predispose to sudden ascent to high altitudes above 2500 meters. Among the many studies on the occurrence and development of AMS, there are few studies on the severity of AMS. Some unidentified phenotypes or genes that determine the severity of AMS may be vital to elucidating the mechanisms of AMS. This study aimed to explore essential candidate genes and phenotypes for moderate-to-severe AMS to provide evidence for a better understanding of the mechanisms of AMS.
Methods
Nineteen subjects from GSE103927 dataset (Downloaded from the Gene Expression Omnibus database) were classified as having moderate to severe AMS (MS-AMS) and mild or no AMS (NM-AMS) based on the Lake Louise score (LLS). Various bioinformatics analyses, such as weighted gene co-expression network analysis (WGCNA), differentially expressed genes screening, and ROC curves were used to compare the differences between the two groups. Another dataset in the GEO database and Real-time quantitative PCR (RT-qPCR) was used to validate the analysis results.
Result
No statistically significant differences in phenotypic and clinical data existed between the MS-AMS and NM-AMS groups. WGCNA revealed 530 genes associated with LLS. Three hundred sixty-eight differentially expressed genes between the two groups. Eight differential genes are associated with LLS, and their biological functions are related regulating of the apoptotic process and programmed cell death. The ROC curves showed that FAM86B3P, AZU1, and PRKCG had a better predictive performance for MS-AMS. The transcript levels of AZU1 and PRKCG were significantly higher in the MS-AMS group compared to the NM-AMS group, a result validated by another dataset. RT-qPCR showed that the transcript levels of AZU1 and PRKCG were elevated in BEAS-2B cells after hypobaric hypoxia treatment. AZU1 and PRKCG were enriched in the Neutrophil extracellular trap formation pathway, suggesting the importance of this pathway in influencing the severity of AMS.
Conclusion
AZU1 and PRKCG were finally identified as the candidate genes affecting AMS severity. AZU1 and PRKCG may affect the severity of AMS by influencing lung endothelial cell permeability through the Neutrophil extracellular trap formation pathway. Our study provides a new perspective to explore the molecular mechanism of AMS, and inhibiting or targeting these genes may help high altitude acclimation and reduce the occurrence of AMS or moderate to severe AMS.