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Title: High-throughput serum proteomics for the identification of protein biomarkers of mortality in older men

Abstract

The biological perturbations associated with incident mortality are not well elucidated, and there are limited biomarkers for the prediction of mortality. We used a novel high throughput proteomics approach to identify serum peptides and proteins associated with 5 year mortality in community dwelling men age >65 years who participated in a longitudinal observational study of musculoskeletal aging (Osteoporotic Fractures in Men: MrOS). In a discovery phase, serum specimens collected at baseline in 2473 men were analyzed using liquid chromatography-ion mobility-mass spectrometry, and incident mortality in the subsequent 5 years was ascertained by tri-annual questionnaire. Rigorous statistical methods were utilized to identify 56 peptides (31 proteins) that were associated with 5-year mortality. In an independent replication phase, selected reaction monitoring was used to examine 21 of those peptides in baseline serum from 750 additional men; 81% of those peptides remained significantly associated with mortality. Mortality-associated proteins included a variety involved in inflammation or complement activation; several have been previously linked to mortality (e.g. C reactive protein, alpha 1-antichymotrypsin) and others are not previously known to be associated with mortality. Other novel proteins of interest included pregnancy-associated plasma protein, VE cadherin, leucine-rich a-2 glycoprotein 1, vinculin, vitronectin, mast/stem cell growth factor receptormore » and Saa4. A panel of peptides improved the predictive value of a commonly used clinical predictor of mortality. Overall, these results suggest that complex inflammatory pathways, and proteins in other pathways, are linked to 5-year mortality risk. This work may serve to identify novel biomarkers for near term mortality.« less

Authors:
ORCiD logo [1];  [1];  [2];  [2];  [2];  [2];  [2];  [2];  [2];  [3];  [4]; ORCiD logo [1];  [1]
  1. Oregon Health & Science University, Portland OR USA
  2. Biological Science Division, Pacific Northwest National Laboratory, Richland WA USA
  3. Department of Medicine, University of California, San Francisco CA USA
  4. California Pacific Medical Center Research Institute, San Francisco CA USA
Publication Date:
Research Org.:
Pacific Northwest National Lab. (PNNL), Richland, WA (United States)
Sponsoring Org.:
USDOE
Contributing Org.:
for the Osteoporotic Fractures in Men Study (MrOS) Research Group
OSTI Identifier:
1503582
Report Number(s):
PNNL-SA-131443
Journal ID: ISSN 1474-9718
DOE Contract Number:  
AC05-76RL01830
Resource Type:
Journal Article
Journal Name:
Aging Cell
Additional Journal Information:
Journal Volume: 17; Journal Issue: 2; Journal ID: ISSN 1474-9718
Country of Publication:
United States
Language:
English

Citation Formats

Orwoll, Eric S., Wiedrick, Jack, Jacobs, Jon, Baker, Erin S., Piehowski, Paul, Petyuk, Vladislav, Gao, Yuqian, Shi, Tujin, Smith, Richard D., Bauer, Douglas C., Cummings, Steven R., Nielson, Carrie M., and Lapidus, Jodi. High-throughput serum proteomics for the identification of protein biomarkers of mortality in older men. United States: N. p., 2018. Web. doi:10.1111/acel.12717.
Orwoll, Eric S., Wiedrick, Jack, Jacobs, Jon, Baker, Erin S., Piehowski, Paul, Petyuk, Vladislav, Gao, Yuqian, Shi, Tujin, Smith, Richard D., Bauer, Douglas C., Cummings, Steven R., Nielson, Carrie M., & Lapidus, Jodi. High-throughput serum proteomics for the identification of protein biomarkers of mortality in older men. United States. doi:10.1111/acel.12717.
Orwoll, Eric S., Wiedrick, Jack, Jacobs, Jon, Baker, Erin S., Piehowski, Paul, Petyuk, Vladislav, Gao, Yuqian, Shi, Tujin, Smith, Richard D., Bauer, Douglas C., Cummings, Steven R., Nielson, Carrie M., and Lapidus, Jodi. Mon . "High-throughput serum proteomics for the identification of protein biomarkers of mortality in older men". United States. doi:10.1111/acel.12717.
@article{osti_1503582,
title = {High-throughput serum proteomics for the identification of protein biomarkers of mortality in older men},
author = {Orwoll, Eric S. and Wiedrick, Jack and Jacobs, Jon and Baker, Erin S. and Piehowski, Paul and Petyuk, Vladislav and Gao, Yuqian and Shi, Tujin and Smith, Richard D. and Bauer, Douglas C. and Cummings, Steven R. and Nielson, Carrie M. and Lapidus, Jodi},
abstractNote = {The biological perturbations associated with incident mortality are not well elucidated, and there are limited biomarkers for the prediction of mortality. We used a novel high throughput proteomics approach to identify serum peptides and proteins associated with 5 year mortality in community dwelling men age >65 years who participated in a longitudinal observational study of musculoskeletal aging (Osteoporotic Fractures in Men: MrOS). In a discovery phase, serum specimens collected at baseline in 2473 men were analyzed using liquid chromatography-ion mobility-mass spectrometry, and incident mortality in the subsequent 5 years was ascertained by tri-annual questionnaire. Rigorous statistical methods were utilized to identify 56 peptides (31 proteins) that were associated with 5-year mortality. In an independent replication phase, selected reaction monitoring was used to examine 21 of those peptides in baseline serum from 750 additional men; 81% of those peptides remained significantly associated with mortality. Mortality-associated proteins included a variety involved in inflammation or complement activation; several have been previously linked to mortality (e.g. C reactive protein, alpha 1-antichymotrypsin) and others are not previously known to be associated with mortality. Other novel proteins of interest included pregnancy-associated plasma protein, VE cadherin, leucine-rich a-2 glycoprotein 1, vinculin, vitronectin, mast/stem cell growth factor receptor and Saa4. A panel of peptides improved the predictive value of a commonly used clinical predictor of mortality. Overall, these results suggest that complex inflammatory pathways, and proteins in other pathways, are linked to 5-year mortality risk. This work may serve to identify novel biomarkers for near term mortality.},
doi = {10.1111/acel.12717},
journal = {Aging Cell},
issn = {1474-9718},
number = 2,
volume = 17,
place = {United States},
year = {2018},
month = {2}
}