Discovery of novel plasma biomarkers for future incident venous thromboembolism by untargeted synchronous precursor selection mass spectrometry proteomics

Abstract

Background Prophylactic anticoagulant treatment may substantially reduce the incidence of venous thromboembolism (VTE) but entails considerable risk of severe bleeding. Identification of individuals at high risk of VTE through the use of predictive biomarkers is desirable in order to achieve a favorable benefit-to-harm ratio. Objective We aimed to identify predictive protein biomarker candidates of VTE. Methods We performed a case-control study of 200 individuals that participated in the Tromsø Study, a population-based cohort, where blood samples were collected before the VTE events occurred. Untargeted tandem mass tag-synchronous precursor selection-mass spectrometry (TMT-SPS-MS3)-based proteomic profiling was used to study the plasma proteomes of each individual. Results Of the 501 proteins detected in a sufficient number of samples to allow multivariate analysis, 46 proteins were associated with VTE case-control status with P-values below the 0.05 significance threshold. The strongest predictive biomarker candidates, assessed by statistical significance, were transthyretin, vitamin K-dependent protein Z and protein/nucleic acid deglycase DJ-1. Conclusions Our untargeted approach of plasma proteome profiling revealed novel predictive biomarker candidates of VTE and confirmed previously reported candidates, thereby providing conceptual support for the validity of the study. A larger nested case-control study will be conducted to validate our findings.

Identification of Common and Rare Genetic Variation Associated With Plasma Protein Levels Using Whole-Exome Sequencing and Mass Spectrometry

“…We examined peptide and protein levels from blood plasma, and genotype data from whole exome sequencing of blood DNA, from 165 individuals from the Tromsø Study (Figure 1A). These individuals consisted of 82 cases and 83 controls that were part of an effort to identify predictive biomarkers for venous thromboembolism 13 and had genotype data available from whole exome sequencing generated as part of an ongoing study of the genetics of VTE 14 . To assess peptide and protein levels, we performed TMT-multiplexed mass spectrometry on blood plasma, identifying 5,608 peptides, corresponding to 664 proteins and 655 genes.…”

Predicting the Risk of Recurrent Venous Thromboembolism: Current Challenges and Future Opportunities

“…Additionally, prospective studies performing large-scale plasma proteomic profiling have identified predictive protein candidates, such as transthyretin, the vitamin K-dependent protein Z, and platelet-derived growth factor-beta (PDGFB), to have strong associations with the development of VTE. These novel biomarkers will require further validation but may be useful in predicting future, incident VTE [135,136].…”

Analysis Ofsome Components of Blood Proteome in “Healthy Population” of Russian Megapolis

“…Currently, proteomics, being one of the most widely known synthetic biological disciplines, is considered as a fundamental basis for the development of personalized laboratory diagnostics [1,7]. In whole, proteome is a set of all protein components of a biological sample [3].…”

“…This allows us to distinguish biomarkers of a number of pathological conditions and diseases, carrying out their molecular diagnosis, including -at an early stage of their formation [5,8,9]. The most commonly analyzed biological sample for proteomic analysis is serum or plasma [6][7][8][9][10].…”

“…In most cases, proteomic analysis involves a mass spectrometric study of biological substrates [7,12,15], but it is also possible to selectively evaluate individual components of the proteome by biochemical analysis Andrew K. Martusevich 1 , Konstantin A. Karuzin 2 of the concentration of metabolites [2,3,8,11]. This is especially important for cohort studies that are performed as part of screening testing of a large population [2, 5,9].…”