A High-Confidence Human Plasma Proteome Reference Set with Estimated Concentrations in PeptideAtlas

Institute for Systems Biology, Seattle, WA 98109, USA.
Molecular &amp Cellular Proteomics (Impact Factor: 6.56). 06/2011; 10(9):M110.006353. DOI: 10.1074/mcp.M110.006353
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Human blood plasma can be obtained relatively noninvasively and contains proteins from most, if not all, tissues of the body. Therefore, an extensive, quantitative catalog of plasma proteins is an important starting point for the discovery of disease biomarkers. In 2005, we showed that different proteomics measurements using different sample preparation and analysis techniques identify significantly different sets of proteins, and that a comprehensive plasma proteome can be compiled only by combining data from many different experiments. Applying advanced computational methods developed for the analysis and integration of very large and diverse data sets generated by tandem MS measurements of tryptic peptides, we have now compiled a high-confidence human plasma proteome reference set with well over twice the identified proteins of previous high-confidence sets. It includes a hierarchy of protein identifications at different levels of redundancy following a clearly defined scheme, which we propose as a standard that can be applied to any proteomics data set to facilitate cross-proteome analyses. Further, to aid in development of blood-based diagnostics using techniques such as selected reaction monitoring, we provide a rough estimate of protein concentrations using spectral counting. We identified 20,433 distinct peptides, from which we inferred a highly nonredundant set of 1929 protein sequences at a false discovery rate of 1%. We have made this resource available via PeptideAtlas, a large, multiorganism, publicly accessible compendium of peptides identified in tandem MS experiments conducted by laboratories around the world.

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Available from: Parag Mallick, Oct 08, 2015
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    • "Using this library and the OpenSWATH software framework (Rost et al, 2014), we confidently identified 4,271 unique peptides at an FDR of 1%, corresponding to 534 distinct proteins in all the unfractionated and non-enriched plasma samples (Fig 2A and Supplementary Table S2). Their levels in plasma were estimated to cover six orders of magnitude according to human plasma Peptide- Atlas database (Farrah et al, 2011), reaching, for some proteins, to levels as low as several nanograms per milliliter (Supplementary Fig S2A). On average, 3,520 peptides and 425 proteins were identified from each twin sample. "
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    ABSTRACT: The degree and the origins of quantitative variability of most human plasma proteins are largely unknown. Because the twin study design provides a natural opportunity to estimate the relative contribution of heritability and environment to different traits in human population, we applied here the highly accurate and reproducible SWATH mass spectrometry technique to quantify 1,904 peptides defining 342 unique plasma proteins in 232 plasma samples collected longitudinally from pairs of monozygotic and dizygotic twins at intervals of 2-7 years, and proportioned the observed total quantitative variability to its root causes, genes, and environmental and longitudinal factors. The data indicate that different proteins show vastly different patterns of abundance variability among humans and that genetic control and longitudinal variation affect protein levels and biological processes to different degrees. The data further strongly suggest that the plasma concentrations of clinical biomarkers need to be calibrated against genetic and temporal factors. Moreover, we identified 13 cis-SNPs significantly influencing the level of specific plasma proteins. These results therefore have immediate implications for the effective design of blood-based biomarker studies. © 2015 The Authors. Published under the terms of the CC BY 4.0 license.
    Molecular Systems Biology 02/2015; 11(2). DOI:10.15252/msb.20145728 · 10.87 Impact Factor
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    • "Vitamin D-binding protein is a multifunctional protein of the albumin family and its primary role is to transport vitamin D. Its other functions include actin scavenging during tissue damage, fatty acid transport, macrophage and osteoclast activation as well as enhancement of complement component 5a (C5a)-mediated neutrophil and macrophage chemotaxis by binding to C5a [37]. Whereas many studies point toward an association of low vitamin D levels and AD (reviewed in [38]), the potential role of vitamin D-binding protein in AD Fig. 3. Gene ontologies enriched amongst 50 differentially abundant proteins against the background of the human plasma proteome (using the Human Plasma Proteome Project reference set [24]). A) The top 20 enriched biological processes. "
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    ABSTRACT: To unlock the full potential of disease modifying treatments, it is essential to develop early biomarkers for Alzheimer's disease (AD). For practical reasons, blood-based markers that could provide a signal at the stage of mild cognitive impairment (MCI) or even earlier would be ideal. Using the proteomic approach of isobaric tagging for relative and absolute quantitation (iTRAQ), we compared the plasma protein profiles of MCI, AD, and cognitively normal control subjects from two independent cohorts: the Sydney Memory and Ageing Study (261 MCI subjects, 24 AD subjects, 411 controls) and the Hunter Community Study (180 MCI subjects, 153 controls). The objective was to identify any proteins that are differentially abundant in MCI and AD plasma in both cohorts, since they might be of interest as potential biomarkers, or could help direct future mechanistic studies. Proteins representative of biological processes relevant to AD pathology, such as the complement system, the coagulation cascade, lipid metabolism, and metal and vitamin D and E transport, were found to differ in abundance in MCI. In particular, levels of complement regulators C1 inhibitor and factor H, fibronectin, ceruloplasmin, and vitamin D-binding protein were significantly decreased in MCI participants from both cohorts. Several apolipoproteins, including apolipoprotein AIV, B-100, and H were also significantly decreased in MCI. Most of these proteins have previously been reported as potential biomarkers for AD; however, we show for the first time that a significant decrease in plasma levels of two potential biomarkers (fibronectin and C1 inhibitor) is evident at the MCI stage.
    Journal of Alzheimer's disease: JAD 01/2015; 43(4):1355-73. DOI:10.3233/JAD-141266 · 4.15 Impact Factor
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    • "Transitions were calculated using Skyline version (MacLean et al., 2010) and corresponded to singly charged y-ions from doubly or triply charged precursors in the range of 350 to 1250 Da. Transitions were selected based on software internal predictions , discovery proteomics data, and spectral data available through the Human NIST spectral libraries (Farrah et al., 2011). Method refinement was performed on quality control samples. "
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    ABSTRACT: Extensive research efforts have generated genomic, transcriptomic, proteomic, and functional data hoping to elucidate psychiatric pathophysiology. Selected reaction monitoring, a recently developed targeted proteomic mass spectrometric approach, has made it possible to evaluate previous findings and hypotheses with high sensitivity, reproducibility, and quantitative accuracy. Here, we have developed a labelled multiplexed selected reaction monitoring assay, comprising 56 proteins previously implicated in the aetiology of major psychiatric disorders, including cell type markers or targets and effectors of known psychopharmacological interventions. We analyzed postmortem anterior prefrontal cortex (Brodmann area 10) tissue of patients diagnosed with schizophrenia (n=22), bipolar disorder (n=23), and major depressive disorder with (n=11) and without (n=11) psychotic features compared with healthy controls (n=22). Results agreed with several previous studies, with the finding of alterations of Wnt-signalling and glutamate receptor abundance predominately in bipolar disorder and abnormalities in energy metabolism across the neuropsychiatric disease spectrum. Calcium signalling was predominantly affected in schizophrenia and affective psychosis. Interestingly, we were able to show a decrease of all 4 tested oligodendrocyte specific proteins (MOG, MBP, MYPR, CNPase) in bipolar disorder and to a lesser extent in schizophrenia and affective psychosis. Finally, we provide new evidence linking ankyrin 3 specifically to affective psychosis and the 22q11.2 deletion syndrome-associated protein septin 5 to schizophrenia. Our study highlights the potential of selected reaction monitoring to evaluate the protein abundance levels of candidate markers of neuropsychiatric spectrum disorders, providing a high throughput multiplex platform for validation of putative disease markers and drug targets. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail:
    The International Journal of Neuropsychopharmacology 10/2014; 18(1). DOI:10.1093/ijnp/pyu015 · 4.01 Impact Factor
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