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Discovery of New Risk Markers for Ischemic Stroke Using a Novel Targeted Proteomics Chip
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Coagulation and inflammation science.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology.
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2015 (English)In: Stroke, ISSN 0039-2499, E-ISSN 1524-4628, Vol. 46, no 12, p. 3340-3347Article in journal (Refereed) Published
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Text
Abstract [en]

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 , 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.

Place, publisher, year, edition, pages
2015. Vol. 46, no 12, p. 3340-3347
Keywords [en]
adrenomedullin, natriuretic peptide, brain, proteins, risk factors, stroke
National Category
Cardiac and Cardiovascular Systems
Identifiers
URN: urn:nbn:se:uu:diva-270960DOI: 10.1161/STROKEAHA.115.010829ISI: 000365534400001PubMedID: 26542692OAI: oai:DiVA.org:uu-270960DiVA, id: diva2:890845
Funder
AstraZenecaEU, European Research Council, 634869Swedish Research Council, 2012-1727Swedish Research Council, 2012-2215Swedish Heart Lung FoundationMarianne and Marcus Wallenberg FoundationAvailable from: 2016-01-05 Created: 2016-01-05 Last updated: 2019-04-09Bibliographically approved
In thesis
1. Molecular Epidemiology of Cardiovascular Disease
Open this publication in new window or tab >>Molecular Epidemiology of Cardiovascular Disease
2019 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Cardiovascular disease is a major cause of morbidity and mortality, with increasing prevalence worldwide.

Identification of risk markers may enable improved prevention by targeting high-risk individuals, earlier disease diagnosis and treatment, as well as stratification of disease subtypes with different treatment options, thereby minimizing side effects while increasing success rates.

The overall aim of this thesis was to investigate associations between proteomic and metabolomic biomarkers, and the development of heart failure and ischemic stroke. Specific objectives were to examine potential causal pathways, and the added value in risk prediction of the identified risk markers.

In Studies I–II, we performed proximity extension assay based proteomic profiling of ≥80 circulating proteins in the Swedish cohorts Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS n=901, median age 70), and the Uppsala Longitudinal Study of Adult Men (ULSAM, n=685, median age 77). In Study I, we identified nine proteins involved in apoptosis, inflammation, matrix remodeling, and fibrinolysis associated with incident heart failure, including growth differentiation factor-15 (GDF-15). In Study II, we identified several proteins associated with incident ischemic stroke, including GDF-15. Both studies revealed potential to improve disease risk prediction by using proteomic data.

In Study III, we performed mass spectrometry-based metabolomic profiling in plasma or serum samples from PIVUS, ULSAM, and TwinGene (total n=3,924). The metabolites urobilin and sphingomyelin (30:1) were associated with incident heart failure.

In Study IV, we followed up on the results of Studies I–II, performing Mendelian randomization analyses (a framework for causal analysis using genetic variants) in 1,053,527 individuals, with 88,448 coronary artery disease cases, 70,305 ischemic stroke cases, and 1,420 heart failure cases. This study supports a causal role of genetically elevated GDF-15 levels in heart failure development, but not in coronary artery disease or ischemic stroke.

In conclusion, we identified multiple biomarkers associated with incident heart failure and ischemic stroke, potentially involved in early disease development. We also saw potential to improve disease risk prediction for incident heart failure and ischemic stroke using proteomics data.

Our findings encourage further large-scale proteomic, metabolomic, and genetic studies to give new insights into heart failure and stroke pathogenesis.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2019. p. 45
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1565
Keywords
Biomarkers, ischemic stroke, heart failure, omics, proteomics, metabolomics, epidemiology, risk marker
National Category
Clinical Medicine
Research subject
Epidemiology
Identifiers
urn:nbn:se:uu:diva-381234 (URN)978-91-513-0634-6 (ISBN)
Public defence
2019-06-04, Humanistiska teatern, Engelska parken, Thundbersvägen 3, Uppsala, 09:00 (English)
Opponent
Supervisors
Available from: 2019-05-14 Created: 2019-04-09 Last updated: 2019-06-18

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Lind, LarsSiegbahn, AgnetaLindahl, BertilStenemo, MarkusSundström, JohanÄrnlöv, Johan
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