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Emerging affinity-based proteomic technologies for large-scale plasma profiling in cardiovascular disease

Smith, Gustav LU and Gerszten, Robert E (2017) In Circulation 135(17). p.1651-1664
Abstract

Plasma biomarkers that reflect molecular states of the cardiovascular system are central for clinical decision making. Routinely used plasma biomarkers include troponins, natriuretic peptides, and lipoprotein particles, yet interrogate only a modest subset of pathways relevant to cardiovascular disease. Systematic profiling of a larger portion of circulating plasma proteins (the plasma proteome) will provide opportunities for unbiased discovery of novel markers to improve diagnostic or predictive accuracy. In addition, proteomic profiling may inform pathophysiological understanding and point to novel therapeutic targets. Obstacles for comprehensive proteomic profiling include the immense size and structural heterogeneity of the... (More)

Plasma biomarkers that reflect molecular states of the cardiovascular system are central for clinical decision making. Routinely used plasma biomarkers include troponins, natriuretic peptides, and lipoprotein particles, yet interrogate only a modest subset of pathways relevant to cardiovascular disease. Systematic profiling of a larger portion of circulating plasma proteins (the plasma proteome) will provide opportunities for unbiased discovery of novel markers to improve diagnostic or predictive accuracy. In addition, proteomic profiling may inform pathophysiological understanding and point to novel therapeutic targets. Obstacles for comprehensive proteomic profiling include the immense size and structural heterogeneity of the proteome, and the broad range of abundance levels, as well. Proteomewide, untargeted profiling can be performed in tissues and cells with tandem mass spectrometry. However, applications to plasma are limited by the need for complex preanalytical sample preparation stages limiting sample throughput. Multiplexing of targeted methods based on capture and detection of specific proteins are therefore receiving increasing attention in plasma proteomics. Immunoaffinity assays are the workhorse for measuring individual proteins but have been limited for proteomic applications by long development times, cross-reactivity preventing multiplexing, specificity issues, and incomplete sensitivity to detect proteins in the lower range of the abundance spectrum (below picograms per milliliter). Emerging technologies to address these issues include nucleotide-labeled immunoassays and aptamer reagents that can be automated for efficient multiplexing of thousands of proteins at high sample throughput, coupling of affinity capture methods to mass spectrometry for improved specificity, and ultrasensitive detection systems to measure low-abundance proteins. In addition, proteomics can now be integrated with modern genomics tools to comprehensively relate proteomic profiles to genetic variants, which may both influence binding of affinity reagents and serve to validate the target specificity of affinity assays. The application of deep quantitative proteomic profiling to large cohorts has thus become increasingly feasible with emerging affinity methods. The aims of this article are to provide the broad readership of Circulation with a timely overview of emerging methods for affinity proteomics and recent progress in cardiovascular medicine based on such methods.

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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Biomarkers, Cardiovascular diseases, Epidemiology, Plasma, Proteomics
in
Circulation
volume
135
issue
17
pages
14 pages
publisher
Lippincott Williams and Wilkins
external identifiers
  • scopus:85018251207
  • wos:000400006400016
ISSN
0009-7322
DOI
10.1161/CIRCULATIONAHA.116.025446
language
English
LU publication?
yes
id
968767fe-c744-484c-8491-1eccd86aa788
date added to LUP
2017-05-18 09:43:44
date last changed
2017-09-18 11:36:13
@article{968767fe-c744-484c-8491-1eccd86aa788,
  abstract     = {<p>Plasma biomarkers that reflect molecular states of the cardiovascular system are central for clinical decision making. Routinely used plasma biomarkers include troponins, natriuretic peptides, and lipoprotein particles, yet interrogate only a modest subset of pathways relevant to cardiovascular disease. Systematic profiling of a larger portion of circulating plasma proteins (the plasma proteome) will provide opportunities for unbiased discovery of novel markers to improve diagnostic or predictive accuracy. In addition, proteomic profiling may inform pathophysiological understanding and point to novel therapeutic targets. Obstacles for comprehensive proteomic profiling include the immense size and structural heterogeneity of the proteome, and the broad range of abundance levels, as well. Proteomewide, untargeted profiling can be performed in tissues and cells with tandem mass spectrometry. However, applications to plasma are limited by the need for complex preanalytical sample preparation stages limiting sample throughput. Multiplexing of targeted methods based on capture and detection of specific proteins are therefore receiving increasing attention in plasma proteomics. Immunoaffinity assays are the workhorse for measuring individual proteins but have been limited for proteomic applications by long development times, cross-reactivity preventing multiplexing, specificity issues, and incomplete sensitivity to detect proteins in the lower range of the abundance spectrum (below picograms per milliliter). Emerging technologies to address these issues include nucleotide-labeled immunoassays and aptamer reagents that can be automated for efficient multiplexing of thousands of proteins at high sample throughput, coupling of affinity capture methods to mass spectrometry for improved specificity, and ultrasensitive detection systems to measure low-abundance proteins. In addition, proteomics can now be integrated with modern genomics tools to comprehensively relate proteomic profiles to genetic variants, which may both influence binding of affinity reagents and serve to validate the target specificity of affinity assays. The application of deep quantitative proteomic profiling to large cohorts has thus become increasingly feasible with emerging affinity methods. The aims of this article are to provide the broad readership of Circulation with a timely overview of emerging methods for affinity proteomics and recent progress in cardiovascular medicine based on such methods.</p>},
  author       = {Smith, Gustav and Gerszten, Robert E},
  issn         = {0009-7322},
  keyword      = {Biomarkers,Cardiovascular diseases,Epidemiology,Plasma,Proteomics},
  language     = {eng},
  month        = {04},
  number       = {17},
  pages        = {1651--1664},
  publisher    = {Lippincott Williams and Wilkins},
  series       = {Circulation},
  title        = {Emerging affinity-based proteomic technologies for large-scale plasma profiling in cardiovascular disease},
  url          = {http://dx.doi.org/10.1161/CIRCULATIONAHA.116.025446},
  volume       = {135},
  year         = {2017},
}