Discovery of New Risk Markers for Ischemic Stroke Using a Novel Targeted Proteomics Chip

Stroke. 2015 Dec;46(12):3340-7. doi: 10.1161/STROKEAHA.115.010829. Epub 2015 Nov 5.


Background and purpose: Emerging technologies have made it possible to simultaneously evaluate a large number of circulating proteins as potential new stroke risk markers.

Methods: We explored associations between 85 cardiovascular proteins, assessed by a proteomics chip, and incident ischemic stroke in 2 independent cohorts of elderly (Prospective Investigation of the Vasculature in Uppsala Seniors [PIVUS]: n=977; 50% women, mean age=70.1 years, 71 fatal/nonfatal ischemic stroke events during 10.0 years; and Uppsala Longitudinal Study in Adult Men [ULSAM]: n=720, mean age=77.5 years, 75 ischemic stroke events during 9.5 years). The proteomics chip uses 2 antibodies for each protein and a polymerase chain reaction step to achieve a high-specific binding and the possibility to measure multiple proteins in parallel, but gives no absolute concentrations.

Results: In PIVUS, 16 proteins were related to incident ischemic stroke using a false discovery rate of 5%. Of these, N-terminal pro-B-type natriuretic peptide (P=0.0032), adrenomedullin (P=0.018), and eosinophil cationic protein (P=0.0071) were replicated in ULSAM after adjustment for established stroke risk factors. In predefined secondary meta-analyses of individual data, interleukin-27 subunit α, growth/differentiation factor 15, urokinase plasminogen activator surface receptor, tumor necrosis factor receptor superfamily member 6, macrophage colony-stimulating factor 1, and matrix metalloproteinase-7 were also potential risk markers for ischemic stroke after adjustment for multiple comparisons (P<0.0006). The addition of N-terminal pro-B-type natriuretic peptide, adrenomedullin, and eosinophil cationic protein to a model with established risk factors increased the C-statistic from 0.629 to 0.689 (P=0.001).

Conclusions: Our data suggest that large-scale proteomics analysis is a promising way of discovering novel biomarkers that could substantially improve the prediction of ischemic stroke.

Keywords: adrenomedullin; natriuretic peptide, brain; proteins; risk factors; stroke.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Brain Ischemia / diagnosis
  • Brain Ischemia / genetics*
  • Cohort Studies
  • Female
  • Follow-Up Studies
  • Gene Targeting / methods*
  • Genetic Markers / genetics*
  • Humans
  • Longitudinal Studies
  • Male
  • Oligonucleotide Array Sequence Analysis / methods*
  • Prospective Studies
  • Proteomics / methods*
  • Risk Factors
  • Stroke / diagnosis
  • Stroke / genetics*


  • Genetic Markers