Blood Plasma Proteome: A Meta-Analysis of the Results of Protein Quantification in Human Blood by Targeted Mass Spectrometry

Abstract

A meta-analysis of the results of targeted quantitative screening of human blood plasma was performed to generate a reference standard kit that can be used for health analytics. The panel included 53 of the 296 proteins that form a “stable” part of the proteome of a healthy individual; these proteins were found in at least 70% of samples and were characterized by an interindividual coefficient of variation <40%. The concentration range of the selected proteins was 10−10−10−3 M and enrichment analysis revealed their association with rare familial diseases. The concentration of ceruloplasmin was reduced by approximately three orders of magnitude in patients with neurological disorders compared to healthy volunteers, and those of gelsolin isoform 1 and complement factor H were abruptly reduced in patients with lung adenocarcinoma. Absolute quantitative data of the individual proteome of a healthy and diseased individual can be used as the basis for personalized medicine and health monitoring. Storage over time allows us to identify individual biomarkers in the molecular landscape and prevent pathological conditions.

Keywords: human proteome project; knowledge databases; proteome; targeted mass spectrometry analysis.

Figure 2

Meta-analysis of the SRM data for plasma from healthy volunteers. (a) Comparison of the number of published studies employing different proteomic methods in the PubMed database over the past ten years. A descending trend for selected and multiple reaction monitoring over the past years is highlighted in blue. (b) Venn diagram based on a comparison of the datasets obtained using the SRM method by Kopylov et al., Novikova et al., Kuzyk et al., and Gaither et al. [18,33,35,39]. (c) Correlation between protein concentrations (Log 10 (nM)) measured in the plasma of healthy volunteers using the SRM method in four studies [18,33,35,39] and concentrations of the same proteins reported in the Human Protein Atlas database. (d) Range of protein concentrations detected in more than 70% of samples and characterized by the interindividual coefficient of variation <40% obtained via a meta-analysis of studies [18,33,35,39].

Figure 1

Results of the search for publications reporting the selected/multiple reaction monitoring (SRM/MRM) data for humans over the past ten years (2012–2022) using the ScanBious system. The size of the nodes reflects the occurrence of the keywords in the abstracts. The identified key clusters involve search terms related to tumor biomarkers, their sensitivity, specificity, and reproducibility. Of note, SRM analysis was frequently used to study cancer cell lines, such as Jurkat, MCF-7, and HepG2.

Figure 3

Gene Ontology enrichment analysis of the lists of respective proteins obtained using the SRM method. (a) Core proteins (N = 53) belonging to the GO category “Cell Component”, (b) Variable proteins (N = 243) belonging to the GO category “Cell Component”, (c) Core proteins (N = 53) belonging to the GO category “Biological Processes”, (d) Variable proteins (N = 243) belonging to the GO category “Biological Processes”. Core proteins (the most stable ones) are the proteins found in more than 70% of the samples with CV <40%. Variable proteins are those found in less than 70% of the samples or have a CV >40%.

Figure 4

Enrichment analysis of stable proteins found to be associated with diseases according to the DisGeNET database obtained for (a) the list of the most stable proteins and (b) the variable dataset. The combined score is the decimal logarithm of the p-value determined using the Fisher’s test and multiplied by the z-score [41]. “Coverage, %” is the percentage of target protein associated with this disease.