Abstract
SummaryThe 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.
Highlights
Biomarkers may have a variety of biomedical applications, including the identification of individuals at risk of clinical outcomes, improving the evaluation of interventions aimed at modifying outcomes, and the elucidation of biological pathways that contribute to health or disease
The identification of good biomarkers could be useful to identify biological processes associated with mortality and to assess the effectiveness of interventions aimed at reducing mortality or extending health span
The discovery of new biomarkers using proteomic approaches has been limited by methods that are demanding of time and resources and have an inherently low throughput
Summary
Biomarkers may have a variety of biomedical applications, including the identification of individuals at risk of clinical outcomes, improving the evaluation of interventions aimed at modifying outcomes, and the elucidation of biological pathways that contribute to health or disease. Studies have been generally restricted to relatively small sample sizes that are inadequate to assess variability on a population scale New approaches, such as aptamer-based or antibody-based affinity proteomics, allow multiplexing and larger sample sizes but are limited to the evaluation of a relatively limited number of candidate proteins (Delfani et al, 2016). We describe the use of these high-throughput proteomic methods in a large cohort of older men, including an initial discovery phase followed by a validation phase in an independent subcohort, for the identification of peptides and proteins associated with mortality. We detect proteins previously well documented to be associated with mortality, and a variety of novel proteins These results provide unique insight into the biological basis of mortality and illustrate the potential utility of this approach for biomarker discovery
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