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Differences in Airway Epithelial Gene Expression in Resilient vs Non-resilient Smokers
Abstract   Peer reviewed

Differences in Airway Epithelial Gene Expression in Resilient vs Non-resilient Smokers

A Oh, M Niederhuber, C Jones, T Brennan, H Liu, K Currin, S Kennedy, S.A Christenson, D Couper, I Barjaktarevic, …
American journal of respiratory and critical care medicine, Vol.211(Supplement_1), pp.A7375-A7375
05/01/2025
DOI: 10.1164/ajrccm.2025.211.Abstracts.A7375

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Abstract

Introduction Resilient smokers, who maintain respiratory health despite smoking, remain poorly characterized. Airway epithelial cell gene expression in resilient smokers can provide insight into mechanisms and pathways that may protect smokers from developing smoking-related lung disease. The objective of this study is to identify genes and potential pathways associated with lung-related resilience. Methods Resilient smokers were defined based on a previously published multi-dimensional definition which includes the absence of: 1) spirometric airflow limitation, 2) symptoms (cough/sputum, dyspnea), 3) radiographic (HRCT) abnormalities, 4) exacerbations, and 5) an accelerated FEV1 decline. “Non-resilient” smokers had preserved spirometry but showed abnormalities in at least one domain of resilience. We analyzed airway epithelial brush samples from 21 resilient and 34 non-resilient smokers from SPIROMICS. Differential gene expression was performed using DESeq2 package in R, which estimates differential expression using generalized linear models. We adjusted for sequencing batch, age (continuous), race, gender, and current smoking status. While controlling for these covariates we evaluated differential gene expression between resilient and non-resilient smokers, the interaction between resilience and smoking status, and in each sub-category of resilient (absence of symptoms, radiographic abnormalities, exacerbations, and accelerated decline in FEV1). Results We identified 98 genes that were differentially expressed (FDR ≤0.1) when comparing resilient to non-resilient smokers, 20 of those genes were up regulated in resilient smokers (Figure 1). Notable genes included cadherin-12 (CDH12), aspartate beta-hydroxylase (ASPH), and protein kinase AMP-activated alpha 2 (PRKAA2). CDH12 is involved in cell adhesion and epithelial integrity. ASPH influences cell adhesion and signaling. PRKAA2 plays role in cellular homeostasis and stress response, which may be altered in non-resilient smokers, affecting cellular metabolism and inflammation. BPI folding containing family A member (BPIFA1) was significantly associated with smoking status in the interaction analysis, suggesting its role in modulating the impact of smoking on resilience. BPIFA1 has anti-microbial properties, regulates immune responses, and contributes mucosal surface protection. Sub-category analysis identified 17 genes associated with resilience to symptoms and 2 genes related to physiologic resilience (FEV1 decline), though no significant genes were associated with radiographic or exacerbation resilience. Conclusion Differential gene expression of airway epithelial cells identified distinct expression patterns between resilient and non-resilient smokers. Specifically, genes associated with epithelial cell adhesion, signaling, and cellular homeostasis were up regulated in resilient smokers. These findings suggest that resilient smokers may have transcriptomic profiles and potential mechanisms that mitigate the effects of cigarette smoke.
 Gene Expression Cell adhesion & migration Generalized linear models Homeostasis Kinases Smoking

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