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

  • Author(s): 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;
  • Osteoporotic Fractures in Men Study (MrOS) Research Group
  • et al.
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.

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