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The Role of Programmed Cell Death-Related Genes in Asthma, Chronic Obstructive Pulmonary Disease, and Lung Function:
1Department of General Practice, Affiliated Hospital of Nantong University, Nantong, Jiangsu, People's Republic of China.
Purpose:
Programmed cell death (PCD) has been linked to asthma, chronic obstructive pulmonary disease (COPD) and lung function, but the underlying genetic determinants remain unclear.
Patients And Methods:
A comprehensive multi-omics analysis was conducted by integrating genome-wide association studies (GWAS) with methylation quantitative trait loci (mQTL), expression quantitative trait loci (eQTL), and protein quantitative trait loci (pQTL) data. To determine the causality between exposures and respiratory traits, Summary Data-Based Mendelian Randomization (SMR) and colocalization analyses were applied. External validation was performed using replication cohorts, along with transcriptome-wide association studies (TWAS), gene-based analysis, and tissue-specific analysis. Additionally, enrichment analysis was carried out to identify biological pathways linked to respiratory traits. To explore potential therapeutic targets, drug prediction and molecular docking analyses were employed to assess the pharmacological feasibility of candidate compounds.
Results:
Through the integration of multi-omics analysis, we identified six PCD-related genes associated with respiratory traits. ERBB3, SFRP1, and FGFR1 demonstrated tier 1 evidence, linking them to COPD in never-smokers, forced expiratory volume in 1 second (FEV1), and FEV1/forced vital capacity (FVC), respectively. Additionally, HSPA1B and MAPK3 were classified as tier 2 genes, associated with non-allergic asthma risk and overall COPD risk, respectively. IDUA, categorized as a tier 3 gene, was related to overall asthma. These genes play critical roles in apoptotic signaling, mesenchymal development, and molecular binding processes, emphasizing their biological significance. Additionally, molecular docking demonstrated stable binding for candidate drugs and proteins encoded by identified genes.
Conclusion:
Our study offers critical insights into the genetic basis of asthma, COPD, and lung function by identifying six genes as potential biomarkers and therapeutic targets, contributing to the development of more effective interventions for these respiratory traits.
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