BACKGROUND: The PI*S variant is one of the most prevalent mutations within alpha-1 antitrypsin deficiency (AATD). The risk of developing AATD-related lung disease in individuals with the PI*SS genotype is poorly defined despite its substantial prevalence. Our study aimed to characterize this genotype and its risk for lung disease and compare it with the PI*ZZ and PI*SZ genotypes using data from the European Alpha-1 antitrypsin Deficiency Research Collaboration international registry. METHOD: Demographic, clinical, functional, and quality of life (QoL) parameters were assessed to compare the PI*SS characteristics with the PI*SZ and PI*ZZ controls. A propensity score with 1:3 nearest-neighbour matching was performed for the most important confounding variables. RESULTS: The study included 1007 individuals, with PI*SS (n = 56; 5.6%), PI*ZZ (n = 578; 57.4%) and PI*SZ (n = 373; 37.0%). The PI*SS population consisted of 58.9% men, with a mean age of 59.2 years and a mean FEV1(% predicted) of 83.4%. Compared to PI*ZZ individuals they had less frequent lung disease (71.4% vs. 82.2%, p = 0.037), COPD (41.4% vs. 60%, p = 0.002), and emphysema (23.2% vs. 51.9%, p < 0.001) and better preserved lung function, fewer exacerbations, lower level of dyspnoea, and better QoL. In contrast, no significant differences were found in the prevalence of lung diseases between PI*SS and PI*SZ, or lung function parameters, exacerbations, dyspnoea, or QoL. CONCLUSIONS: We found that, as expected, the risk of lung disease associated with the PI*SS genotype is significantly lower compared with PI*ZZ, but does not differ from that observed in PI*SZ individuals, despite having higher serum AAT levels. TRIAL REGISTRATION: www. CLINICALTRIALS: gov (ID: NCT04180319).

Centro de Investigación Biomédica en Red de Enfermedades Respiratorias Instituto de Salud Carlos 3 Madrid Spain

Department of Clinical Medicine Faculty of Health Sciences University of Copenhagen Copenhagen Denmark

Department of Internal Medicine and Therapeutics University of Pavia Pavia Italy

Department of Pneumology Thomayer Hospital 1st Faculty of Medicine Charles University Prague Czech Republic

Department of Respiratory Medicine and Allergology Skåne University Hospital Lund University Malmö Sweden

Faculty of Medicine and Health Sciences University of Barcelona Barcelona Spain

Institute of Applied Health Research University of Birmingham Birmingham UK

Pneumology Department Centro Hospitalar Universitário de Santo António Porto Portugal

Pneumology Department Complejo Hospitalario Clínico Universitario de Santiago Santiago de Compostela Spain

Pneumology Department Hospital Beatriz Ângelo Av Carlos Teixeira 3 Loures 2674 514 Portugal

Pneumology Department Hospital Senhora da Oliveira Guimarães Portugal

Pneumology Department Hospital Universitari Vall d'Hebron Vall d'Hebron Research Institute Barcelona Spain

Pneumology Department Hospital Universitario Nuestra Señora de La Candelaria Santa Cruz de Tenerife Spain

Pneumology Department NeumoVigo 1 i Research Group Hospital Álvaro Cunqueiro IIS Galicia Sur Vigo Spain

Pneumology Unit IRCCS San Matteo Hospital Foundation Pavia Italy

Respiratory Medicine University Hospitals Birmingham NHS Foundation Trust Birmingham UK

Section of Respiratory Medicine Department of Medicine Herlev and Gentofte Hospital University of Copenhagen Hellerup Denmark

Unidad Médico Quirúrgica de Enfermedades Respiratorias Instituto de Biomedicina de Sevilla Hospital Universitario Virgen del Rocío Universidad de Sevilla Sevilla Spain

Respir Res. 2025 Jan 24;26(1):37. doi: 10.1186/s12931-024-03066-9. PubMed

Zobrazit více v PubMed

Strnad P, McElvaney NG, Lomas DA. Alpha1-Antitrypsin Deficiency. N Engl J Med. Apr 2020;9(15):1443–55. PubMed

Blanco I, de Serres FJ, Fernandez-Bustillo E, Lara B, Miravitlles M. Estimated numbers and prevalence of PI*S and PI*Z alleles of alpha1-antitrypsin deficiency in European countries. Eur Respir J. 2006;27:77–84. PubMed

Elliott PR, Stein PE, Bilton D, Carrell RW, Lomas DA. Structural explanation for the deficiency of S alpha 1-antitrypsin. Nat Struct Biol. 1996;3:910–1. PubMed

Seixas S, Marques PI. Known mutations at the cause of alpha 1-antitrypsin deficiency an updated overview of SERPINA I variation spectrum. Appl Clin Genet. 2021;14:173–94. PubMed PMC

Ferrarotti I, Thun GA, Zorzetto M, Ottaviani S, Imboden M, Schindler C, et al. Serum levels and genotype distribution of alpha1-antitrypsin in the general population. Thorax. 2012;67:669–74. PubMed

Miravitlles M, Dirksen A, Ferrarotti I, Koblizek V, Lange P, Mahadeva R, et al. European respiratory Society Statement: diagnosis and treatment of pulmonary disease in alpha-1 antitrypsin deficiency. Eur Respir J. 2017;50:1700610. PubMed

Dahl M, Hersh CP, Ly NP, Berkey CS, Silverman EK, Nordestgaard BG. The protease inhibitor PI*S allele and COPD: a meta-analysis. Eur Respir J. 2005;26:67–76. PubMed

McElvaney GN, Sandhaus RA, Miravitlles M, Turino GM, Seersholm N, Wencker M, et al. Clinical considerations in individuals with Alpha-1 antitrypsin PI*SZ genotype. Eur Respir J. 2020;55:pii1902410. PubMed PMC

Nuñez A, Belmonte I, Miranda E, Barrecheguren M, Farago G, Loeb E, et al. Association between circulating alpha-1 antitrypsin polymers and lung and liver disease. Respir Res. 2021;22:244. PubMed PMC

De Serres F, Blanco I. Prevalence of α1-antitrypsin deficiency alleles PI*S and PI*Z worldwide and effective screening for each of the five phenotypic classes PI*MS, PI*MZ, PI*SS, PI*SZ, and PI*ZZ: a comprehensive review. Ther Adv Respir Dis. 2012;6(5):277–95. PubMed

Miravitlles M, Herepath M, Priyendu A, Sharma S, Vilchez T, Vit O, et al. Disease burden associated with alpha-1 antitrypsin deficiency: systematic and structured literature reviews. Eur Respir Rev. 2022;31(163):210262. PubMed PMC

Greulich T, Altraja A, Barrecheguren M, Bals R, Chlumsky J, Chorostowska-Wynimko J, et al. Protocol for the EARCO Registry: a pan-european observational study in patients with α1-antitrypsin deficiency. ERJ Open Res. 2020;6:00181–2019. PubMed PMC

Miravitlles M, Turner AM, Torres-Duran M, Tanash H, Rodríguez-García C, López-Campos JL, et al. Clinical and functional characteristics of individuals with alpha-1 antitrypsin deficiency: EARCO international registry. Respir Res. 2022;23(1):352. PubMed PMC

Miravitlles M, Turner AM, Torres-Duran M, Tanash H, Rodríguez-García C, López-Campos JL, et al. Characteristics of individuals with alpha-1 antitrypsin deficiency from Northern and Southern European countries: EARCO international registry. Eur Respir J. 2023;61(3):2201949. PubMed

Jones PW, Harding G, Berry P, Wilkund I, Chen WH, Kline-Leidy N. Development and first validation of the COPD Assessment Test. Eur Respir J. 2009;34:648–54. PubMed

EuroQoL Group. EuroQol: a new facility for the measurement of health-related quality of life. Health Policy. 1990;16:199–208. PubMed

Greenwood JL, Joy EA, Stanford JB. The physical activity vital sign: a primary care tool to guide counseling for obesity. J Phys Act Health. 2010;7(5):571–6. PubMed

Ramon MA, Esquinas C, Barrecheguren M, Pleguezuelos E, Molina J, Quintano JA, et al. Self-reported daily walking time in COPD: relationship with relevant clinical and functional characteristics. Int J Chron Obstruct Pulmon Dis. 2017;12:1173–81. PubMed PMC

Soler-Cataluña JJ, Martínez-García MA, Sánchez LS, Tordera MP, Sánchez PR. Severe exacerbations and BODE index: two independent risk factors for death in male COPD patients. Respir Med. 2009;103(5):692–9. PubMed

Ogushi F, Hubbard RC, Fells GA, Casolaro MA, Curiel DT, Brantly ML, et al. Evaluation of the S-type of Alpha-1 antitrypsin as an in vivo and in vitro inhibitor of neutrophil elastase. Am Rev Respir Dis. 1988;137:364–70. PubMed

Tan L, Dickens JA, Demeo DL, Miranda E, Perez J, Rashid ST, et al. Circulating polymers in α1-antitrypsin deficiency. Eur Respir J. 2014;43:1501–4. PubMed

Miravitlles M, Anzueto A, Barrecheguren M. Nine controversial questions about augmentation therapy for alpha-1 antitrypsin deficiency: a viewpoint. Eur Respir Rev. 2023;32(170):230170. PubMed PMC

Tonelli AR, Brantly ML. Augmentation therapy in alpha-1 antitrypsin deficiency: advances and controversies. Ther Adv Respir Dis. 2010;4:289–312. PubMed

Attaway A, Majumdar U, Sandhaus RA, Nowacki AS, Stoller JK. An analysis of the degree of concordance among international guidelines regarding alpha-1 antitrypsin deficiency. Int J Chron Obstruct Pulmon Dis. 2019;14:2089–101. PubMed PMC

Torres-Durán M, López-Campos JL, Rodríguez-Hermosa JL, Esquinas C, Martínez-González C, Hernández-Pérez JM, et al. Demographic and clinical characteristics of patients with α1-antitrypsin deficiency genotypes PI*ZZ and PI*SZ in the Spanish registry of EARCO. ERJ Open Res. 2022;8:00213–2022. PubMed PMC

Martín-González E, Hernández-Pérez JM, Pérez JAP, Pérez JAP, Pérez-García J, Herrera-Luis E et al. Alpha-1 antitrypsin deficiency and PI*S and PI*Z SERPINA1 variants are associated with asthma exacerbations. Pulmonology 2023:S2531-0437(23)00091 – 0. PubMed

Hernández-Pérez JM, Martín-González E, González-Carracedo MA. Alpha-1 Antitrypsin Deficiency and SERPINA1 variants could play a role in Asthma exacerbations. Arch Bronconeumol. 2023;59(7):416–7. PubMed

Zobrazit více v PubMed

ClinicalTrials.gov
NCT04180319