Alpha-1 antitrypsin deficiency associates with asthma exacerbations

Background: Asthma exacerbations are the most important contributors to asthma burden, impacting the patients’ quality of life and increasing their mortality risk. The rs17580 (Pi*S) and rs28929474 (Pi*Z) polymorphisms in the SERPINA1 gene, characterizing alpha-1 antitrypsin (AAT) deficiency, had previously been associated with several respiratory diseases, including asthma. However, their role in asthma exacerbations is unknown. Objective: To assess whether SERPINA1 genetic variants and reduced AAT protein levels are associated with asthma exacerbations. Methods: Genetic data and AAT protein levels measured in serum samples from 452 Canary Islanders from La Palma (Spain) were analyzed as discovery, while genomic data from additional 217 Canary Islanders and 151 mainland Spaniards were analyzed as replication. Logistic regression analyzes were performed for the Pi*S and Pi*Z variants, as well as for reduced AAT levels (<100 mg/dl), adjusted by age, sex, and genotype principal components. Results: In the discovery, a significant association was found for the Pi*S (odds ratio (OR)=1.23, 95% confidence interval (CI):1.09-1.39, p=9.4x10-4) and Pi*Z (OR=1.35, 95%CI:1.12-1.62, p=1.9x10-3) alleles, showing a stronger association when they were combined in the Pi*SZ genotype (OR=1.90, 95%CI:1.46-2.48, p=4.2x10-6). Likewise, AAT deficiency was associated with a higher risk for asthma exacerbations (OR=1.39, p=4x10-5). However, these findings were not replicated in the independent samples (p>0.05). Conclusions:SERPINA1 genetic variants and reduced AAT protein levels could play a potential role in asthma exacerbations that should be further explored. Funding: Grant PID2020-116274RB-I00 funded by MCIN/AEI/10.13039/501100011033.