Can Proteomics Play a Significant Role in the Identification of Biomarkers for Alpha1-Antitrypsin Deficiency?
Abstract
1. Introduction
2. Introducing Alpha1-Antitrypsin Deficiency (AATD) and Potential Treatments
3. Proteomics and Biomarker Discovery
4. Proteomic Analysis of AATD
4.1. Application to Lung and Liver Diseases
4.2. Limitations of Current Proteomic Studies
4.3. Unmet Clinical and Research Needs in AATD
5. Is Proteomics Still in the Early Stages of Research on AATD?
5.1. Integrative Multi-Omics Approaches for Predictive Modeling of AATD
5.2. Clinical Translation of Proteomic Biomarkers: Validation and Implementation
6. Future Perspectives
7. Conclusions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
Abbreviations
AAT | α1-antitrypsin |
AATD | α1-antitrypsin deficiency |
COPD | Chronic obstructive pulmonary disease |
IEF | Isoelectric focusing |
LC-MS/MS | Liquid chromatography tandem mass spectrometry |
DIGE | Two-dimensional difference gel electrophoresis |
IPF | Idiopathic pulmonary fibrosis |
NS | Non-smokers |
HS | Healthy smokers |
ELISA | Enzyme-linked immunosorbent assay |
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Reference | Subjects Investigated * | Source | Proteomic Technique | Main Findings |
---|---|---|---|---|
[21] | P = 5 | Serum | LC-ESI-Triple TOF-MS | MS can easily identify S/Z mutations by detecting mass differences between S/Z and non-S/non-Z peptides. Combining peptide pattern analysis with AAT quantification via immunoassay ensures an accurate assessment of deficiency alleles in most patients. |
[27] | C = 5607 (COPD) P = 317 (GRADS = 133 QUANTUM-1 = 38 Birmingham = 146) | Plasma | SomaScan v4.0 | Common plasma biomarkers have been identified in both AATD and COPD patients, along with proteins associated with emphysema. PiZZ patients also exhibited biomarkers related to DLCO and emphysema. Additionally, PiZZ individuals undergoing augmentation therapy showed near-normal AAT levels. |
[29] | P = 31 (QUANTUM-1) | Serum | Multiplexed immunoassay | Proteome analyses revealed that C-reactive protein, adipocyte fatty acid-binding protein, and tissue plasminogen activator were linked to emphysema progression, highlighting them as potential therapeutic targets for COPD. |
[30] | C = 7 P = 8 | FFPE liver tissues | nanoLC-ESI-Q-Exactive hybrid quadrupole-Orbitrap-MS | Among the 65 proteins upregulated exclusively in adult PiZZ samples, protein disulfide isomerase A4 (PDIA4) emerged as a promising therapeutic target. Its inhibition by cysteamine reduced Z-aggregate formation, while its silencing decreased oxidative stress, a hallmark of AATD-related liver disease. |
[31] | C = 43 (NS = 9 SM without COPD = 9 SM with COPD stage I–II= 8, SM with COPD stage III–IV = 8 IPF = 9) P = 8 | Lung tissue | 2D-DIGE MALDI-TOF/TOF | The proteome analyses showed increased transglutaminase 2 (TGM2) across all sample types, reinforcing its potential as a diagnostic and therapeutic target for AATD-associated COPD. |
[32] | C = 37 (HC = 30 COPD = 7) P = 31 (AATD = 6 COPD-AATD = 25) | Neutrophils Plasma | LC-MS/MS | AAT augmentation therapy influences the neutrophil membrane proteome by altering the levels of membrane-associated proteins in circulating neutrophils of AATD-COPD patients. |
[34] | C = 60 (NS = 25 SM = 20 COPD = 15) AATD = 23 | EBC | ESI-LTQ-Orbitrap-MS SELDI-TOF | Several inflammatory cytokines, type I and II cytokeratins, two isoforms of surfactant protein A (SP-A), calgranulins A and B, and AAT have been identified in the COPD and AATD groups. |
[35] | HC = 11 P = 11 | EBC | NMR | The analyses revealed that pyruvate metabolism is the most prominently involved pathway, with most metabolites originating from pyruvate. |
Category | Unmet Need | Rationale |
---|---|---|
Biomarkers | Pediatric biomarkers | Lack of validated biomarkers to enable early diagnosis in infants and young children. |
Prognostic biomarkers | Identification of markers that can predict disease progression and complications. | |
Biomarkers to guide therapy | Lack of markers that inform therapeutic decision-making and response assessment | |
Standardization/Screening | Robust liver-disease correlates | Need for non-invasive, reliable markers that correlate with liver disease severity and progression. |
Pre-analytical protocols | Absence of standardized procedures for sample collection and handling in proteomic studies on AATD | |
Broad implementation of screening strategies | Insufficient screening, particularly in asymptomatic individuals and family members |
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Grignano, M.A.; D’Amato, M.; Gregorini, M.; Rampino, T.; Iadarola, P.; Viglio, S. Can Proteomics Play a Significant Role in the Identification of Biomarkers for Alpha1-Antitrypsin Deficiency? Int. J. Mol. Sci. 2025, 26, 5085. https://doi.org/10.3390/ijms26115085
Grignano MA, D’Amato M, Gregorini M, Rampino T, Iadarola P, Viglio S. Can Proteomics Play a Significant Role in the Identification of Biomarkers for Alpha1-Antitrypsin Deficiency? International Journal of Molecular Sciences. 2025; 26(11):5085. https://doi.org/10.3390/ijms26115085
Chicago/Turabian StyleGrignano, Maria Antonietta, Maura D’Amato, Marilena Gregorini, Teresa Rampino, Paolo Iadarola, and Simona Viglio. 2025. "Can Proteomics Play a Significant Role in the Identification of Biomarkers for Alpha1-Antitrypsin Deficiency?" International Journal of Molecular Sciences 26, no. 11: 5085. https://doi.org/10.3390/ijms26115085
APA StyleGrignano, M. A., D’Amato, M., Gregorini, M., Rampino, T., Iadarola, P., & Viglio, S. (2025). Can Proteomics Play a Significant Role in the Identification of Biomarkers for Alpha1-Antitrypsin Deficiency? International Journal of Molecular Sciences, 26(11), 5085. https://doi.org/10.3390/ijms26115085