Genetic and Computational Insights into SERPINA1 rs17580 as a Susceptibility Biomarker for COPD Progression

Chronic obstructive pulmonary disease (COPD) is a progressive respiratory disorder influenced by both environmental and genetic factors. Variations in the SERPINA1 gene, particularly rs17580 (Glu288Val), may alter α₁-antitrypsin function and increase susceptibility to COPD. This study aimed to investigate the association of the SERPINA1 rs17580 variant with COPD progression using genetic and computational analyses.

A total of 300 participants, including 250 clinically diagnosed COPD patients and 50 healthy controls, were recruited for this study. Genomic DNA was extracted from peripheral blood samples, and the SERPINA1 rs17580 (Glu288Val) polymorphism was genotyped using Tetra ARMS-PCR and confirmed by Sanger sequencing. In-silico analyses included protein stability prediction, miRNA binding site assessment, and protein-protein interaction analysis using STRING. Additionally, CRISPR/Cas9 gRNAs targeting SERPINA1 were computationally designed and evaluated for potency and off-target effects to facilitate potential functional validation.

In a cohort of 300 participants (250 COPD, 50 controls), COPD patients exhibited reduced lung function (FEV₁/FVC), lower serum A1AT (1.18 vs 1.41 g/L), higher smoking exposure, comorbidities, exacerbations, and reduced physical activity. The SERPINA1 rs17580 (Glu288Val) variant, low-frequency and deleterious (SIFT 0.01, PolyPhen-2 0.998), was confirmed by sequencing. Structural analysis showed increased flexibility, destabilization (ΔΔG -1.24 to -1.78 kcal/mol), and altered dynamics, while functional assessment indicated Glu288 is highly conserved and pathogenic (87% probability). Population analysis revealed MM 60%, SS 10.7%, and ZZ 2%, with allele frequencies differing globally. The mutation affected protein-protein interactions and pathways related to protease-antiprotease balance, inflammation, emphysema, and liver disease. It also altered miRNA binding and mRNA stability (ΔG +6.8 kcal/mol), potentially modulating SERPINA1 expression. A top-ranked CRISPR gRNA showed 100% specificity and minimal offtargets, supporting the feasibility of functional studies.

The findings highlight the SERPINA1 rs17580 (Glu288Val) variant as a key genetic determinant influencing COPD susceptibility through structural destabilization and dysregulation of α₁-antitrypsin function. This genetic insight advances the understanding of COPD pathogenesis and underscores the potential for personalized interventions, including early genetic screening and targeted therapeutic strategies, to reduce disease progression and improve patient outcomes.

These findings highlight rs17580 as a potential genetic biomarker for COPD susceptibility and provide insights for targeted therapeutic strategies.