Páska Csilla, Barta Imre, Csoma Zsuzsanna, Gajdócsi Réka, Szél Viktória, Kerpel-Fronius Anna, Solymosi Diána, Örlős Zoltán, Antus Balázs
National Korányi Institute for Pulmonology, Korányi Frigyes út. 1, 1121 Budapest, Hungary.
Int J Mol Sci. 2025 Jun 4;26(11):5400. doi: 10.3390/ijms26115400.
Major mutations of , the gene encoding alpha1-antitrypsin (A1AT), are known to cause severe emphysema. Our study aimed to investigate the role of major mutations modulating A1AT levels in several lung pathologies and control groups. Blood samples were collected from healthy non-smokers (N = 85), healthy smokers (N = 291), healthy ex-smokers (N = 127), smokers with chronic obstructive lung disease (COPD, N = 187), ex-smokers with COPD (N = 64), and patients with asthma (N = 194), interstitial lung disease (ILD) (N = 93), sarcoidosis (N = 30) and cystic fibrosis (N = 26). Clinical and respiratory parameters, A1AT levels, the extent of emphysema and comorbidities on low-dose CT scans were evaluated, and patients answered a smoking history and comorbidity questionnaire. A1AT single-nucleotide polymorphisms were determined for the S, Z, M2/M4, 0 and eQTL locations by SNP probes using real-time PCR. A1AT levels showed significant differences between cigarette smoke-induced and other lung diseases. Compared to controls, A1AT levels were found to be lower in sarcoidosis and increasingly higher in smokers and patients with COPD, ILD and CF, respectively. The presence and pattern of emphysema were found to influence A1AT levels: lower values were observed in COPD patients without emphysema, while higher values were observed in patients with central and panlobular emphysema. Antitrypsin levels increased with COPD GOLD stages and asthma GINA stages. Variable A1AT levels were also found in ILD subgroups. The distribution of variants at the S, Z, M2/M4 and 0 polymorphic sites and the eQTL location showed no significant differences between patient groups with impaired lung function, except for Z heterozygotes, which were prevalent in patients with severe asthma. The eQTL TT genotypes had higher A1AT levels and the occurrence of emphysema and/or bronchitis was increased. A1AT levels correlated with several clinical and respiratory parameters in pulmonary patients, while FEV1/FVC inversely correlated with levels of A1AT. Molar antielastase activity was increased in smokers and patients with lung diseases; however, in COPD, antielastase activity decreased. The most reduced antielastase activity could be found in CF. Certain genotypes were characterized by increased cardiovascular comorbidity scores and antitrypsin levels. Our data suggest that in addition to emphysema, A1AT may play an important role in the development of a wide variety of lung diseases and cardiovascular comorbidities. Further research is needed to clarify the role of A1AT and its regulation in lung pathologies.
已知编码α1-抗胰蛋白酶（A1AT）的基因发生的主要突变会导致严重的肺气肿。我们的研究旨在调查主要突变在几种肺部疾病和对照组中调节A1AT水平的作用。从健康非吸烟者（N = 85）、健康吸烟者（N = 291）、健康戒烟者（N = 127）、患有慢性阻塞性肺疾病（COPD，N = 187）的吸烟者、患有COPD的戒烟者（N = 64）以及患有哮喘（N = 194）、间质性肺疾病（ILD）（N = 93）、结节病（N = 30）和囊性纤维化（N = 26）的患者中采集血样。评估了临床和呼吸参数、A1AT水平、低剂量CT扫描上的肺气肿程度和合并症，并且患者回答了吸烟史和合并症问卷。通过使用实时PCR的SNP探针确定了S、Z、M2/M4、0和eQTL位点的A1AT单核苷酸多态性。A1AT水平在香烟烟雾诱导的疾病和其他肺部疾病之间存在显著差异。与对照组相比，发现结节病患者的A1AT水平较低，而吸烟者以及患有COPD、ILD和CF的患者的A1AT水平分别越来越高。发现肺气肿的存在和模式会影响A1AT水平：在没有肺气肿的COPD患者中观察到较低的值，而在患有中央型和全小叶型肺气肿的患者中观察到较高的值。抗胰蛋白酶水平随着COPD GOLD分期和哮喘GINA分期而增加。在ILD亚组中也发现了可变的A1AT水平。除了Z杂合子在重度哮喘患者中普遍存在外，在肺功能受损的患者组之间，S、Z、M2/M4和0多态性位点以及eQTL位点的变体分布没有显著差异。eQTL TT基因型具有较高的A1AT水平，并且肺气肿和/或支气管炎的发生率增加。A1AT水平与肺部疾病患者的几种临床和呼吸参数相关，而FEV1/FVC与A1AT水平呈负相关。吸烟者和肺部疾病患者的摩尔抗弹性蛋白酶活性增加；然而，在COPD中，抗弹性蛋白酶活性降低。在CF中可以发现抗弹性蛋白酶活性降低最为明显。某些基因型的特征是心血管合并症评分和抗胰蛋白酶水平增加。我们的数据表明，除了肺气肿外，A1AT可能在多种肺部疾病和心血管合并症的发展中起重要作用。需要进一步研究以阐明A1AT及其调节在肺部疾病中的作用。
