# Alpha1-Antitrypsin in Lung Diseases: A Cross-Sectional Observational Study

## TL;DR

This study explores how alpha1-antitrypsin levels and genetic variations relate to various lung diseases and comorbidities, finding significant differences across conditions.

## Contribution

The study reveals new insights into how A1AT levels and genetic variants influence diverse lung diseases and cardiovascular comorbidities.

## Key findings

- A1AT levels were lower in sarcoidosis and higher in COPD, ILD, and CF patients.
- eQTL TT genotypes correlated with higher A1AT levels and increased emphysema/bronchitis.
- A1AT levels correlated inversely with FEV1/FVC in pulmonary patients.

## Abstract

Major mutations of SERPINA1, 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 (N0 = 85), healthy smokers (N0 = 291), healthy ex-smokers (N0 = 127), smokers with chronic obstructive lung disease (COPD, N0 = 187), ex-smokers with COPD (N0 = 64), and patients with asthma (N0 = 194), interstitial lung disease (ILD) (N0 = 93), sarcoidosis (N0 = 30) and cystic fibrosis (N0 = 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.