Journal Article Epublish 3 citations
PubMed: 38407261 DOI: 10.1515/cclm-2023-1348
Quantification of circulating alpha-1-antitrypsin polymers associated with different genotypes.
Clin Chem Lab Med 62(10):1980-1990
Authors: Alice M Balderacchi, Mattia Bignotti, Stefania Ottaviani, Andrea Denardo, Valentina Barzon, Emna Ben Khlifa, Guido Vailati, Davide Piloni, Federica Benini, Luciano Corda, Angelo G Corsico, Ilaria Ferrarotti, Annamaria Fra
Affiliations
- Centre for Diagnosis of Inherited Alpha-1 Antitrypsin Deficiency, UOC Pulmonology, 18631Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.
- Experimental Oncology and Immunology, Department of Molecular and Translational Medicine, 9297University of Brescia, Brescia, Italy.
- Department of Internal Medicine and Therapeutics, Pulmonology Unit, 19001University of Pavia, Pavia, Italy.
- Referral Centre for Alpha-1 Antitrypsin Deficiency, 18515 Spedali Civili , Brescia, Italy.
Abstract
OBJECTIVES
Alpha-1-antitrypsin deficiency is a genetic disorder caused by mutations in the gene encoding alpha-1-antitrypsin (AAT), the major serine protease inhibitor in plasma. Reduced AAT levels are associated with elevated risk of developing emphysema mainly due to uncontrolled activity of neutrophil elastase in the lungs. The prevalent Z-AAT mutant and many rare pathogenic AAT variants also predispose to liver disease due to their accumulation as polymeric chains in hepatocytes. Part of these polymers are secreted into the bloodstream and could represent biomarkers of intra-hepatic accumulation. Moreover, being inactive, they further lower lung protection against proteases. Aim of our study is to accurately quantify the percentage of circulating polymers (CP) in a cohort of subjects with different genotypes.
METHODS
CP concentration was measured in plasma or Dried Blood Spot (DBS) by a sensitive sandwich ELISA based on capture by the polymer-specific 2C1 monoclonal antibody.
RESULTS
CP were significantly elevated in patients with the prevalent PI*SZ and PI*ZZ genotypes, with considerable intra-genotype variability. Notably, higher percentage of polymers was observed in association with elevated C-reactive protein. CP levels were also increased in carriers of the M variant, and of M, I, P and M in heterozygosity with Z-AAT.
CONCLUSIONS
These findings highlight the importance of implementing CP quantification in a clinical laboratory. Indeed, the variable amount of CP in patients with the same genotype may correlate with the variable severity of the associated lung and liver diseases. Moreover, CP can reveal the polymerogenic potential of newly discovered ultrarare AAT variants.
MeSH
Plasma, Genotype, Peptide Hydrolases, Polymers, Liver Diseases, Serpins, Emphysema, Alpha 1-Antitrypsin Deficiency, Genes, C-Reactive Protein, Lung