title: Discovery of New Risk Markers for Ischemic Stroke Using a Novel Targeted Proteomics Chip.
abstract: OBJECTIVE
  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.
authors.affiliation: From the Department of Medical Sciences, Uppsala University Hospital, Uppsala, Sweden. lars.lind@medsci.uu.se.
authors.forename: Lars
authors.initials: L
authors.lastname: Lind
authors.affiliation: From the Department of Medical Sciences, Uppsala University Hospital, Uppsala, Sweden.
authors.forename: Agneta
authors.initials: A
authors.lastname: Siegbahn
authors.affiliation: From the Department of Medical Sciences, Uppsala University Hospital, Uppsala, Sweden.
authors.forename: Bertil
authors.initials: B
authors.lastname: Lindahl
authors.affiliation: From the Department of Medical Sciences, Uppsala University Hospital, Uppsala, Sweden.
authors.forename: Markus
authors.initials: M
authors.lastname: Stenemo
authors.affiliation: From the Department of Medical Sciences, Uppsala University Hospital, Uppsala, Sweden.
authors.forename: Johan
authors.initials: J
authors.lastname: Sundström
authors.affiliation: From the Department of Medical Sciences, Uppsala University Hospital, Uppsala, Sweden.
authors.forename: Johan
authors.initials: J
authors.lastname: Ärnlöv
mesh_terms: D000368:Aged; D002545:Brain Ischemia / Q000175:diagnosis / Q000235:genetics*; D015331:Cohort Studies; D005260:Female; D005500:Follow-Up Studies; D018390:Gene Targeting / Q000379:methods*; D005819:Genetic Markers / Q000235:genetics*; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods*; D011446:Prospective Studies; D040901:Proteomics / Q000379:methods*; D012307:Risk Factors; D020521:Stroke / Q000175:diagnosis / Q000235:genetics*
chemical_list: D005819:Genetic Markers
keywords: adrenomedullin; natriuretic peptide, brain; proteins; risk factors; stroke