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 α-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.
| Original language | English (US) |
|---|---|
| Journal | Aging Cell |
| DOIs | |
| State | Accepted/In press - Jan 1 2018 |
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Keywords
- Aging
- Biomarker
- Inflammation
- Men
- Mortality
- Proteomics
ASJC Scopus subject areas
- Aging
- Cell Biology
Cite this
High-throughput serum proteomics for the identification of protein biomarkers of mortality in older men. / Orwoll, Eric; 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; Lapidus, Jodi.
In: Aging Cell, 01.01.2018.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - High-throughput serum proteomics for the identification of protein biomarkers of mortality in older men
AU - Orwoll, Eric
AU - Wiedrick, Jack
AU - Jacobs, Jon
AU - Baker, Erin S.
AU - Piehowski, Paul
AU - Petyuk, Vladislav
AU - Gao, Yuqian
AU - Shi, Tujin
AU - Smith, Richard D.
AU - Bauer, Douglas C.
AU - Cummings, Steven R.
AU - Nielson, Carrie
AU - Lapidus, Jodi
PY - 2018/1/1
Y1 - 2018/1/1
N2 - 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 α-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.
AB - 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 α-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.
KW - Aging
KW - Biomarker
KW - Inflammation
KW - Men
KW - Mortality
KW - Proteomics
UR - http://www.scopus.com/inward/record.url?scp=85041307766&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85041307766&partnerID=8YFLogxK
U2 - 10.1111/acel.12717
DO - 10.1111/acel.12717
M3 - Article
C2 - 29399943
AN - SCOPUS:85041307766
JO - Aging Cell
JF - Aging Cell
SN - 1474-9718
ER -