Abstract
Alpha-1-antitrypsin (A1AT or SERPINA1) has been proposed as a putative biomarker distinguishing healthy from diseased donors throughout several proteomics studies. However, the SERPINA1 gene displays high variability of frequent occurring genotypes among the general population. These different genotypes may affect A1AT expression and serum protein concentrations, and this is often not known, ignored, and/or not reported in serum proteomics studies. Here, we address allele-specific protein serum levels of A1AT in donors carrying the normal M variants of A1AT by measuring the proteoform profiles of purified A1AT from 81 serum samples, originating from 52 donors. When focusing on heterozygous donors, our data clearly reveal a statistically relevant difference in allele-specific protein serum levels of A1AT. In donors with genotype PI*M1VM1A, the experimentally observed ratio was approximately 1:1 (M1V/M1A, 1.00:0.96 ± 0.07, n = 17). For individuals with genotype PI*M1VM2, this ratio was 1:1.28 (M1V/M2, 1.00:1.31, ±0.19, n = 7). For genotypes PI*M1VM3 and PI*M1AM3, a significant higher amount of M3 was observed compared to the M1-subtypes (M1V/M3, 1.00:1.84 ± 0.35, n = 8; M1A/M3, 1.00:1.61 ± 0.33, n = 5). We argue that these observations are important and should be considered when analyzing serum A1AT levels before proposing A1AT as a putative serum biomarker.
Original language | English |
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Pages (from-to) | 1331-1338 |
Number of pages | 8 |
Journal | Journal of Proteome Research |
Volume | 22 |
Issue number | 4 |
Early online date | 22 Mar 2023 |
DOIs | |
Publication status | Published - 7 Apr 2023 |
Bibliographical note
Publisher Copyright:© 2023 The Authors. Published by American Chemical Society.
Funding
We acknowledge support from the Netherlands Organization for Scientific Research (NWO) funding the Netherlands Proteomics Centre through the X-omics Road Map program (project 184.034.019). D.C. and A.J.R.H. acknowledge further support by the NWO Satin Grant 731.017.202.
Funders | Funder number |
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Netherlands Proteomics Centre | 184.034.019, 731.017.202 |
Nederlandse Organisatie voor Wetenschappelijk Onderzoek |
Keywords
- allele-specific protein serum levels
- alpha-1-antitrypsin
- alpha-1-antitrypsin deficiency
- biomarkers
- gene variants
- genotypes
- native mass spectrometry
- proteogenomics