Decoding the Transcriptional Response to Severe Exacerbations Among African-american Individuals With Asthma

Rationale: Asthma exacerbations are characterized by worsening symptoms and airway obstruction; they can result in severe outcomes, such as emergency visits (ED) and in-patient hospitalization (IP). The molecular immune responses involved in exacerbations remain poorly understood. Therefore, our aim was to identify genes associated with severe exacerbations. Methods: Our study population included African-American individuals from the Study of Asthma Phenotypes and Pharmacogenomic Interactions by Race-Ethnicity (SAPPHIRE). We analyzed the gene expression (RNA-seq) results from 429 healthy controls, 29 individuals with uncontrolled asthma (asthma control test score ≤19 but no history of asthma-related ED/IP), and 15 individuals peri-exacerbation (asthma-related ED/IP ±30 days of assessment). We assessed for differential gene expression, performed a weighted gene correlation network analysis, and modeled via cubic spline regression. Results: We identified 118 and 678 genes upregulated among individuals with uncontrolled asthma and severe exacerbations, respectively. 29 genes were significantly increased in both groups. Network analysis revealed three modules that were positively and significantly associated with severe exacerbations. Of the 678 genes upregulated among individuals with severe exacerbations, 559 (82%) were covered by these three modules. Functional analysis revealed that the semaphorin-plexin signaling pathway, the type-I interferon signaling pathway, and neutrophil degranulation were the top terms in each module. In addition, spline modeling of expression surrounding the timing of events revealed 55 genes with a hill pattern; these genes included NFIL3, a transcription factor controlling IgE production. Conclusions: Our study identified a number of genes associated with severe asthma exacerbations among African Americans, providing new potential biomarkers to predict impending events, as well as targets for treatment and measuring therapeutic response.