Biomaterial Database

Alpha-1 antitrypsin deficiency and PiS and PiZ SERPINA1 variants are associated with asthma exacerbations. 2023

Elena Martín-González, and José M Hernández-Pérez, and José A Pérez Pérez, and Javier Pérez-García, and Esther Herrera-Luis, and Ruperto González-Pérez, and Orelvis González-González, and Elena Mederos-Luis, and Inmaculada Sánchez-Machín, and Paloma Poza-Guedes, and Olaia Sardón, and Paula Corcuera, and María J Cruz, and Francisco J González-Barcala, and Carlos Martínez-Rivera, and Joaquim Mullol, and Xavier Muñoz, and José M Olaguibel, and Vicente Plaza, and Santiago Quirce, and Antonio Valero, and Joaquín Sastre, and Javier Korta-Murua, and Victoria Del Pozo, and Fabián Lorenzo-Díaz, and Jesús Villar, and María Pino-Yanes, and Mario A González-Carracedo

Genomics and Health Group, Department of Biochemistry, Microbiology, Cell Biology and Genetics, Universidad de La Laguna (ULL), 38200 La Laguna, Tenerife, Spain.

OBJECTIVE Asthma is a chronic inflammatory disease of the airways. Asthma patients may experience potentially life-threatening episodic flare-ups, known as exacerbations, which may significantly contribute to the asthma burden. The Pi*S and Pi*Z variants of the SERPINA1 gene, which usually involve alpha-1 antitrypsin (AAT) deficiency, had previously been associated with asthma. The link between AAT deficiency and asthma might be represented by the elastase/antielastase imbalance. However, their role in asthma exacerbations remains unknown. Our objective was to assess whether SERPINA1 genetic variants and reduced AAT protein levels are associated with asthma exacerbations. METHODS In the discovery analysis, SERPINA1 Pi*S and Pi*Z variants and serum AAT levels were analyzed in 369 subjects from La Palma (Canary Islands, Spain). As replication, genomic data from two studies focused on 525 Spaniards and publicly available data from UK Biobank, FinnGen, and GWAS Catalog (Open Targets Genetics) were analyzed. The associations between SERPINA1 Pi*S and Pi*Z variants and AAT deficiency with asthma exacerbations were analyzed with logistic regression models, including age, sex, and genotype principal components as covariates. RESULTS In the discovery, a significant association with asthma exacerbations was found for both Pi*S (odds ratio [OR]=2.38, 95% confidence interval [CI]= 1.40-4.04, p-value=0.001) and Pi*Z (OR=3.49, 95%CI=1.55-7.85, p-value=0.003)Likewise, AAT deficiency was associated with a higher risk for asthma exacerbations (OR=5.18, 95%CI=1.58-16.92, p-value=0.007) as well as AAT protein levels (OR= 0.72, 95%CI=0.57-0.91, p-value=0.005). The Pi*Z association with exacerbations was replicated in samples from Spaniards with two generations of Canary Islander origin (OR=3.79, p-value=0.028), and a significant association with asthma hospitalizations was found in the Finnish population (OR=1.12, p-value=0.007). CONCLUSIONS AAT deficiency could be a potential therapeutic target for asthma exacerbations in specific populations.