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

IF 10.4 2区医学 Q1 RESPIRATORY SYSTEM Pulmonology Pub Date : 2025-12-31 Epub Date: 2024-10-25 DOI:10.1016/j.pulmoe.2023.05.002

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

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引用次数: 0

Abstract

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.

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α -1抗胰蛋白酶缺乏和Pi*S和Pi*Z SERPINA1变异与哮喘加重有关。

简介和目的:哮喘是一种慢性气道炎症性疾病。哮喘患者可能会经历潜在的危及生命的发作性发作，称为急性发作，这可能会显著增加哮喘负担。SERPINA1基因的Pi*S和Pi*Z变异通常涉及α -1抗胰蛋白酶(AAT)缺乏，以前与哮喘有关。AAT缺乏与哮喘之间的联系可能表现为弹性酶/抗弹性酶失衡。然而，它们在哮喘加重中的作用尚不清楚。我们的目的是评估SERPINA1基因变异和AAT蛋白水平降低是否与哮喘恶化有关。材料与方法:在发现分析中，对来自西班牙拉帕尔马(La Palma, Canary Islands, Spain)的369例受试者进行SERPINA1 Pi*S和Pi*Z变异及血清AAT水平的分析。作为复制，我们分析了来自两项研究的基因组数据，这些数据集中在525名西班牙人，以及来自UK Biobank、FinnGen和GWAS Catalog (Open Targets Genetics)的公开数据。采用logistic回归模型分析SERPINA1 Pi*S和Pi*Z变异与AAT缺乏与哮喘加重之间的关系，包括年龄、性别和基因型主成分为协变量。结果:研究发现，Pi*S(比值比[OR]=2.38, 95%可信区间[CI]= 1.40 ~ 4.04, p值=0.001)和Pi*Z (OR=3.49, 95%CI=1.55 ~ 7.85, p值=0.003)与哮喘发作风险升高相关(OR=5.18, 95%CI=1.58 ~ 16.92, p值=0.007)，AAT蛋白水平升高与哮喘发作风险升高相关(OR= 0.72, 95%CI=0.57 ~ 0.91, p值=0.005)。Pi*Z与急性发作的关联在两代加那利岛民血统的西班牙人样本中得到了重复(OR=3.79, p值=0.028)，在芬兰人群中发现了与哮喘住院的显著关联(OR=1.12, p值=0.007)。结论:AAT缺乏可能是特定人群哮喘加重的潜在治疗靶点。

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来源期刊

Pulmonology Medicine-Pulmonary and Respiratory Medicine

CiteScore

14.30

自引率

5.10%

发文量

159

审稿时长

19 days

期刊介绍： Pulmonology (previously Revista Portuguesa de Pneumologia) is the official journal of the Portuguese Society of Pulmonology (Sociedade Portuguesa de Pneumologia/SPP). The journal publishes 6 issues per year and focuses on respiratory system diseases in adults and clinical research. It accepts various types of articles including peer-reviewed original articles, review articles, editorials, and opinion articles. The journal is published in English and is freely accessible through its website, as well as Medline and other databases. It is indexed in Science Citation Index Expanded, Journal of Citation Reports, Index Medicus/MEDLINE, Scopus, and EMBASE/Excerpta Medica.