Alpha-1 antitrypsin deficiency and Pi*S and Pi*Z SERPINA1 variants are associated with asthma exacerbations
Por:
Martín-González E., Hernández-Pérez J.M., Pérez J.A.P., Pérez-García J., Herrera-Luis E., González-Pérez R., González-González O., Mederos-Luis E., Sánchez-Machín I., Poza-Guedes P., Sardón O., Corcuera P., Cruz M.J., González-Barcala F.J., Martínez-Rivera C., Mullol J., Muñoz X., Olaguibel J.M., Plaza V., Quirce S., Valero A., Sastre J., Korta-Murua J., del Pozo V., Lorenzo-Díaz F., Villar J., Pino-Yanes M., González-Carracedo M.A.
Publicada:
31 dic 2025
Ahead of Print:
1 ene 2023
Resumen:
Introduction and objectivesAsthma 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.Materials and methodsIn 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.ResultsIn 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).ConclusionsAAT deficiency could be a potential therapeutic target for asthma exacerbations in specific populations.
Filiaciones:
Martín-González E.:
Genomics and Health Group, Department of Biochemistry, Microbiology, Cell Biology and Genetics, Universidad de La Laguna (ULL), 38200 La Laguna, Tenerife, Spain
Hernández-Pérez J.M.:
Department of Respiratory Medicine, Hospital Universitario de N.S de Candelaria, Santa Cruz de Tenerife, 38010, Spain
Respiratory Medicine, Hospital Universitario de La Palma, 38713 Breña Alta, Santa Cruz de Tenerife, Spain
Hospital Universitario de La Palma, 38713 Breña Alta, Santa Cruz de Tenerife, Spain
Pérez J.A.P.:
Genomics and Health Group, Department of Biochemistry, Microbiology, Cell Biology and Genetics, Universidad de La Laguna (ULL), 38200 La Laguna, Tenerife, Spain
Instituto Universitario de Enfermedades Tropicales y Salud Pública de Canarias, Universidad de La Laguna (ULL), La Laguna, Tenerife, Spain
Pérez-García J.:
Genomics and Health Group, Department of Biochemistry, Microbiology, Cell Biology and Genetics, Universidad de La Laguna (ULL), 38200 La Laguna, Tenerife, Spain
Herrera-Luis E.:
Genomics and Health Group, Department of Biochemistry, Microbiology, Cell Biology and Genetics, Universidad de La Laguna (ULL), 38200 La Laguna, Tenerife, Spain
González-Pérez R.:
Allergy Department, Hospital Universitario de Canarias, 38320 La Laguna, Tenerife, Spain
Severe Asthma Unit, Allergy Department, Hospital Universitario de Canarias, La Laguna, 38320, Spain
González-González O.:
Hospital Universitario de La Palma, 38713 Breña Alta, Santa Cruz de Tenerife, Spain
Mederos-Luis E.:
Allergy Department, Hospital Universitario de Canarias, 38320 La Laguna, Tenerife, Spain
Sánchez-Machín I.:
Allergy Department, Hospital Universitario de Canarias, 38320 La Laguna, Tenerife, Spain
Poza-Guedes P.:
Allergy Department, Hospital Universitario de Canarias, 38320 La Laguna, Tenerife, Spain
Severe Asthma Unit, Allergy Department, Hospital Universitario de Canarias, La Laguna, 38320, Spain
Sardón O.:
Division of Pediatric Respiratory Medicine, Hospital Universitario Donostia, San Sebastián, Spain
Department of Pediatrics, University of the Basque Country (UPV/EHU), San Sebastián, Spain
Corcuera P.:
Division of Pediatric Respiratory Medicine, Hospital Universitario Donostia, San Sebastián, Spain
Cruz M.J.:
Department of Respiratory Medicine, Hospital Vall d'Hebron, Barcelona, Spain
CIBER de Enfermedades Respiratorias (CIBERES), Instituto de Salud Carlos III, Madrid, Spain
González-Barcala F.J.:
Department of Respiratory Medicine, Complejo Hospitalario Universitario de Santiago, Santiago de Compostela, La Coruña, Spain
Martínez-Rivera C.:
CIBER de Enfermedades Respiratorias (CIBERES), Instituto de Salud Carlos III, Madrid, Spain
Department of Respiratory Medicine, Hospital Germans Trias i Pujol, Barcelona, Badalona, Spain
Mullol J.:
CIBER de Enfermedades Respiratorias (CIBERES), Instituto de Salud Carlos III, Madrid, Spain
Rhinology Unit & Smell Clinic, ENT Department, Clinical and Experimental Respiratory Immunoallergy (IDIBAPS), Universitat de Barcelona, Barcelona, Spain
Muñoz X.:
Department of Respiratory Medicine, Hospital Vall d'Hebron, Barcelona, Spain
CIBER de Enfermedades Respiratorias (CIBERES), Instituto de Salud Carlos III, Madrid, Spain
Olaguibel J.M.:
CIBER de Enfermedades Respiratorias (CIBERES), Instituto de Salud Carlos III, Madrid, Spain
Department of Allergy, Hospital Universitario de Navarra, Navarra, Pamplona, Spain
Plaza V.:
CIBER de Enfermedades Respiratorias (CIBERES), Instituto de Salud Carlos III, Madrid, Spain
Department of Respiratory Medicine, Hospital de la Santa Creu i Sant Pau, Instituto de Investigación Biomédica Sant Pau (IIB Sant Pau), Barcelona, Spain
Quirce S.:
CIBER de Enfermedades Respiratorias (CIBERES), Instituto de Salud Carlos III, Madrid, Spain
Department of Allergy, Hospital Universitario La Paz, IdiPAZ, Madrid, Spain
Valero A.:
CIBER de Enfermedades Respiratorias (CIBERES), Instituto de Salud Carlos III, Madrid, Spain
Allergy Unit & Severe Asthma Unit, Pneumonology and Allergy Department, Hospital Clínic, IDIBAPS, Universitat de Barcelona, Barcelona, Spain
Sastre J.:
CIBER de Enfermedades Respiratorias (CIBERES), Instituto de Salud Carlos III, Madrid, Spain
Department of Allergy, Hospital Universitario Fundación Jiménez Díaz, Madrid, Spain
Korta-Murua J.:
Division of Pediatric Respiratory Medicine, Hospital Universitario Donostia, San Sebastián, Spain
del Pozo V.:
CIBER de Enfermedades Respiratorias (CIBERES), Instituto de Salud Carlos III, Madrid, Spain
Department of Immunology, Instituto de Investigación Sanitaria Hospital Universitario Fundación Jiménez Díaz, Madrid, Spain
Lorenzo-Díaz F.:
Genomics and Health Group, Department of Biochemistry, Microbiology, Cell Biology and Genetics, Universidad de La Laguna (ULL), 38200 La Laguna, Tenerife, Spain
Instituto Universitario de Enfermedades Tropicales y Salud Pública de Canarias, Universidad de La Laguna (ULL), La Laguna, Tenerife, Spain
Villar J.:
CIBER de Enfermedades Respiratorias (CIBERES), Instituto de Salud Carlos III, Madrid, Spain
Multidisciplinary Organ Dysfunction Evaluation Research Network (MODERN), Research Unit, Hospital Universitario Dr. Negrín, Las Palmas de Gran Canaria, Spain
Pino-Yanes M.:
Genomics and Health Group, Department of Biochemistry, Microbiology, Cell Biology and Genetics, Universidad de La Laguna (ULL), 38200 La Laguna, Tenerife, Spain
CIBER de Enfermedades Respiratorias (CIBERES), Instituto de Salud Carlos III, Madrid, Spain
Instituto de Tecnologías Biomédicas (ITB), Universidad de La Laguna (ULL), San Cristóbal de La Laguna, Tenerife, Spain
González-Carracedo M.A.:
Genomics and Health Group, Department of Biochemistry, Microbiology, Cell Biology and Genetics, Universidad de La Laguna (ULL), 38200 La Laguna, Tenerife, Spain
Instituto Universitario de Enfermedades Tropicales y Salud Pública de Canarias, Universidad de La Laguna (ULL), La Laguna, Tenerife, Spain
Green Submitted, gold, All Open Access; Gold
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