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. 2023 Sep:35:101493.
doi: 10.1016/j.bbrep.2023.101493. Epub 2023 Jun 2.

Identification of potential biomarkers to predict organ morbidity in COVID-19: A repository based proteomics perspective

Sabyasachi Bandyopadhyay  1 , Madhan Vishal Rajan  2 , Punit Kaur  2 , Gururao Hariprasad  2
Affiliations

Identification of potential biomarkers to predict organ morbidity in COVID-19: A repository based proteomics perspective

Sabyasachi Bandyopadhyay et al. Biochem Biophys Rep. 2023 Sep.

Abstract

SARS-CoV-2 causes substantial extrapulmonary manifestations in addition to pulmonary disease. Some of the major organs affected are cardiovascular, hematological and thrombotic, renal, neurological, and digestive systems. These types of muti-organ dysfunctions make it difficult and challenging for clinicians to manage and treat COVID-19 patients. The article focuses to identify potential protein biomarkers that can flag various organ systems affected in COVID-19. Publicly reposited high throughput proteomic data from human serum (HS), HEK293T/17 (HEK) and Vero E6 (VE) kidney cell culture were downloaded from ProteomeXchange consortium. The raw data was analyzed in Proteome Discoverer 2.4 to delineate the complete list of proteins in the three studies. These proteins were analyzed in Ingenuity Pathway Analysis (IPA) to associate them to various organ diseases. The shortlisted proteins were analyzed in MetaboAnalyst 5.0 to shortlist potential biomarker proteins. These were then assessed for disease-gene association in DisGeNET and validated by Protein-protein interactome (PPI) and functional enrichment studies (GO_BP, KEGG and Reactome pathways) in STRING. Protein profiling resulted in shortlisting 20 proteins in 7 organ systems. Of these 15 proteins showed at least 1.25-fold changes with a sensitivity and specificity of 70%. Association analysis further shortlisted 10 proteins with a potential association with 4 organ diseases. Validation studies established possible interacting networks and pathways affected, confirmingh the ability of 6 of these proteins to flag 4 different organ systems affected in COVID-19 disease. This study helps to establish a platform to seek protein signatures in different clinical phenotypes of COVID-19. The potential biomarker candidates that can flag organ systems involved are: (a) Vitamin K-dependent protein S and Antithrombin-III for hematological disorders; (b) Voltage-dependent anion-selective channel protein 1 for neurological disorders; (c) Filamin-A for cardiovascular disorder and, (d) Peptidyl-prolyl cis-trans isomerase A and Peptidyl-prolyl cis-trans isomerase FKBP1A for digestive disorders.

Keywords: COVID-19 sequela; Organ diseases; Protein biomarker; Proteomics; Repository data.

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Conflict of interest statement

Authors report no conflict of interest in this work.

Figures

Image 1
Graphical abstract
Fig. 1
Fig. 1
Protein profiling associated with organ diseases in COVID-19. (A) Heatmap of Disease and Biofunction (D&B) in Ingenuity Pathway Analysis (IPA); (B) Heatmap of Tox Function (TF) in IPA; and (C) Venn diagram showing proteins composition in the three studies.
Fig. 2
Fig. 2
Assessment of diagnostic accuracy of biomarker candidates for various organ pathologies in COVID-19. (A) Receiver Operating Characteristics and Box-Whisker plot for up-regulated proteins, and (B) Receiver Operating Characteristics and Box-Whisker plot for down-regulated proteins. Blue indicates Area Under Curve; Red dot indicates optimal cut-off for the best sensitivity and specificity values. Green and red boxes indicate the range of 1st and 3rd quartiles for healthy controls and COVID-19 patients, respectively. Black dots represent individual readings, and yellow diamond represents the median for the concentrations in the two phenotypes. Fold Change and p-values (* < 0.05; ** < 0.01; *** < 0.001) are mentioned alongside the Box-Whisker plot. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)
Fig. 3
Fig. 3
Disease Gene Association analysis. (A) Association of biomarker proteins with various organ pathologies. Grey nodes indicate biomarker proteins and coloured nodes indicate diseases. (B) Bar diagrams showing 10 biomarker proteins implicated in various diseases. Orange, cyan, pink, blue and yellow represent hematological, neurological, cardiovascular, digestive and renal disorders, respectively. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)
Fig. 4
Fig. 4
Protein-protein interactome (PPI) and functional enrichment analyses. (A–F) PPI and functional enrichment analyses of individual biomarker protein. Coloured bars indicate strength of enrichment processes (represented by left y-axis) and black diamonds indicate False Discovery Rate of enrichment processes (represented by right y-axis). Red node represents upregulated protein, green node represents downregulated protein, and grey node represents interacting protein. Orange, cyan, pink, and blue represent hematological, neurological, cardiovascular, and digestive, respectively. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)
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