Alpha-1 antitrypsin deficiency and Pi*S and Pi*Z SERPINA1 variants are associated with asthma exacerbations.

Autor:	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 JM; Department of Respiratory Medicine, Hospital Universitario de N.S de Candelaria, 38010 Santa Cruz de Tenerife, Spain; Respiratory Medicine, Hospital Universitario de La Palma, 38713 Breña Alta, Santa Cruz de Tenerife, Spain., Pérez JAP; 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, 38320 La Laguna, 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, 38320 La Laguna, 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 MJ; Department of Respiratory Medicine, Hospital Vall d'Hebron, Barcelona, Spain; CIBER de Enfermedades Respiratorias (CIBERES), Instituto de Salud Carlos III, Madrid, Spain., González-Barcala FJ; 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, Badalona, Barcelona, 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 JM; CIBER de Enfermedades Respiratorias (CIBERES), Instituto de Salud Carlos III, Madrid, Spain; Department of Allergy, Hospital Universitario de Navarra, Pamplona, Navarra, 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. Electronic address: mdelpino@ull.edu.es., González-Carracedo MA; 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. Electronic address: mgonzalc@ull.edu.es.
Jazyk:	angličtina
Zdroj:	Pulmonology [Pulmonology] 2023 May 24. Date of Electronic Publication: 2023 May 24.
DOI:	10.1016/j.pulmoe.2023.05.002
Abstrakt:	Introduction and Objectives: 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. Materials and 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. Competing Interests: Conflicts of interest Authors declare they have no competing interests or other interests that might be perceived to influence the interpretation of the manuscript. No supporting institution may gain or lose financially through this publication. E.M.G. report funding from the Board of Economy, Industry, Trade, and Knowledge of the Canary Islands Government, with a European Social Fund co-financing rate managed by the Canary Islands Agency for Research, Innovation, Society and Information (ACIISI). E.H.L. was supported by a fellowship awarded by MCIN/AEI/10.13039/501100011033 and by “ESF Investing in your future” (PRE2018–083,837). V.P. has received grant support from MSD. V.d.P. was supported by CIBER de Enfermedades Respiratorias, ISCIII, Spain. E.H.L., and M.P.Y. report funding from the Spanish Ministry of Science and Innovation (MCIN/AEI/10.13039/501100011033) and by the European Social Fund “ESF Investing in your future” by the European Union. J.P.G reports funding from the Spanish Ministry of Universities. M.P.Y. report grants from the European Regional Development Fund “ERDF A way of making Europe” by the European Union. M.P.Y. reports grant support from GlaxoSmithKline, Spain paid to Fundación Canaria Instituto de Investigación Sanitaria de Canarias (FIISC) for a project outside the submitted work and grants from Instituto de Salud Carlos III, Madrid, Spain. M.P.Y. and J.V. report grants from Instituto de Salud Carlos III, Madrid, Spain. (Copyright © 2023 Sociedade Portuguesa de Pneumologia. Published by Elsevier España, S.L.U. All rights reserved.)
Databáze:	MEDLINE
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