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Quantification of circulating alpha-1-antitrypsin polymers associated with different SERPINA1 genotypes

  • Alice M. Balderacchi ORCID logo , Mattia Bignotti ORCID logo , Stefania Ottaviani ORCID logo , Andrea Denardo ORCID logo , Valentina Barzon ORCID logo , Emna Ben Khlifa ORCID logo , Guido Vailati , Davide Piloni ORCID logo , Federica Benini ORCID logo , Luciano Corda , Angelo G. Corsico ORCID logo , Ilaria Ferrarotti ORCID logo and Annamaria Fra ORCID logo EMAIL logo
Published/Copyright: February 27, 2024
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Clinical Chemistry and Laboratory Medicine (CCLM)
From the journal Clinical Chemistry and Laboratory Medicine (CCLM) Volume 62 Issue 10

Abstract

Objectives

Alpha-1-antitrypsin deficiency is a genetic disorder caused by mutations in the SERPINA1 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 SERPINA1 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 Mmalton variant, and of Mprocida, I, Plowell and Mherleen 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.

Keywords: alpha-1-antitrypsin deficiency; serpins; emphysema; AAT rare variants
Corresponding author: Annamaria Fra, Experimental Oncology and Immunology, Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy, Phone: +390303717468, E-mail:
Alice M. Balderacchi and Mattia Bignotti are joint first authors.

Funding source: Alpha-1 Foundation

Award Identifier / Grant number: 829920

Acknowledgments

We thank Ilaria Bosio for technical assistance, the group of Prof. David Lomas and particularly Dr Nina Heyer-Chauhan (UCL, London, UK) for providing purified 2C1 and 3C11 mAb, and Elena Miranda (La Sapienza University, Rome, Italy) for insightful discussions. We are grateful to Prof. Stefano Calza (University of Brescia, Brescia, Italy) for advice on the statistical analyses.

  1. Research ethics: The study was carried out according to the tenets of the Declaration of Helsinki and the relevant Italian regulations for performing investigation in humans. Patients were enrolled in the study at the Spedali Civili of Brescia (Brescia, Italy) and at the Fondazione IRCCS Policlinico San Matteo (Pavia, Italy) upon approval by the Ethical Committees of the two institutions, respectively No. 4911 of 20th July 2021 and No. 20210075366 of 27th August 2021.

  2. Informed consent: All participants provided written informed to the study.

  3. Author contributions: AF, IF designed the research project; DP, GV, FB, LC, AGC enrolled patients and collected clinical data; AMB, MB, AD, SO, VB, EBK performed experiments; AMB, MB, IF, AF analysed data; AMB, MB, IF, AF wrote the paper. All authors read and approved the manuscript.

  4. Competing interests: The authors state no conflict of interest for this study.

  5. Research funding: This work was supported by a grant from the Alpha-1 Foundation USA (ID: 829920) to AF. The funding organization played no role in the study design; in the collection, analysis and interpretation of the data; in the writing of the report; in the decision to submit the report for publication.

  6. Data availability: Data are reported within the paper in an aggregated form. Individual data can be obtained on request from the corresponding author.

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Supplementary Material

This article contains supplementary material (https://doi.org/10.1515/cclm-2023-1348).

Received: 2023-11-24
Accepted: 2024-02-15
Published Online: 2024-02-27
Published in Print: 2024-09-25

© 2024 Walter de Gruyter GmbH, Berlin/Boston

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https://doi.org/10.1515/cclm-2023-1348
Keywords for this article
alpha-1-antitrypsin deficiency; serpins; emphysema; AAT rare variants

Articles in the same Issue

  1. Frontmatter
  2. Editorial
  3. Six years of progress – highlights from the IFCC Emerging Technologies Division
  4. IFCC Papers
  5. Skin in the game: a review of single-cell and spatial transcriptomics in dermatological research
  6. Bilirubin measurements in neonates: uniform neonatal treatment can only be achieved by improved standardization
  7. Validation and verification framework and data integration of biosensors and in vitro diagnostic devices: a position statement of the IFCC Committee on Mobile Health and Bioengineering in Laboratory Medicine (C-MBHLM) and the IFCC Scientific Division
  8. Linearity assessment: deviation from linearity and residual of linear regression approaches
  9. HTA model for laboratory medicine technologies: overview of approaches adopted in some international agencies
  10. Considerations for applying emerging technologies in paediatric laboratory medicine
  11. A global perspective on the status of clinical metabolomics in laboratory medicine – a survey by the IFCC metabolomics working group
  12. The LEAP checklist for laboratory evaluation and analytical performance characteristics reporting of clinical measurement procedures
  13. General Clinical Chemistry and Laboratory Medicine
  14. Assessing post-analytical phase harmonization in European laboratories: a survey promoted by the EFLM Working Group on Harmonization
  15. Potential medical impact of unrecognized in vitro hypokalemia due to hemolysis: a case series
  16. Quantification of circulating alpha-1-antitrypsin polymers associated with different SERPINA1 genotypes
  17. Targeted ultra performance liquid chromatography tandem mass spectrometry procedures for the diagnosis of inborn errors of metabolism: validation through ERNDIM external quality assessment schemes
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