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Molecular Epidemiology of Cardiovascular Disease
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi.
2019 (engelsk)Doktoravhandling, med artikler (Annet vitenskapelig)
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.

sted, utgiver, år, opplag, sider
Uppsala: Acta Universitatis Upsaliensis, 2019. , s. 45
Serie
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1565
Emneord [en]
Biomarkers, ischemic stroke, heart failure, omics, proteomics, metabolomics, epidemiology, risk marker
HSV kategori
Forskningsprogram
Epidemiologi
Identifikatorer
URN: urn:nbn:se:uu:diva-381234ISBN: 978-91-513-0634-6 (tryckt)OAI: oai:DiVA.org:uu-381234DiVA, id: diva2:1303150
Disputas
2019-06-04, Humanistiska teatern, Engelska parken, Thundbersvägen 3, Uppsala, 09:00 (engelsk)
Opponent
Veileder
Tilgjengelig fra: 2019-05-14 Laget: 2019-04-09 Sist oppdatert: 2019-06-18
Delarbeid
1. Circulating proteins as predictors of incident heart failure in the elderly
Åpne denne publikasjonen i ny fane eller vindu >>Circulating proteins as predictors of incident heart failure in the elderly
Vise andre…
2018 (engelsk)Inngår i: European Journal of Heart Failure, ISSN 1388-9842, E-ISSN 1879-0844, Vol. 20, nr 1, s. 55-62Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

Aims

To identify novel risk markers for incident heart failure using proteomic profiling of 80 proteins previously associated with cardiovascular pathology.

Methods and results

Proteomic profiling (proximity extension assay) was performed in two community‐based prospective cohorts of elderly individuals without heart failure at baseline: the Prospective Investigation of the Vasculature in Uppsala Seniors [PIVUS, n = 901, median age 70.2 (interquartile range 70.0–70.3) years, 80 events]; and the Uppsala Longitudinal Study of Adult Men [ULSAM, n = 685, median age 77.8 (interquartile range 76.9–78.1) years, 90 events]. Twenty‐nine proteins were associated with incident heart failure in the discovery cohort PIVUS after adjustment for age and sex, and correction for multiple testing. Eighteen associations replicated in ULSAM. In pooled analysis of both cohorts, higher levels of nine proteins were associated with incident heart failure after adjustment for established risk factors: growth differentiation factor 15 (GDF‐15), T‐cell immunoglobulin and mucin domain 1 (TIM‐1), tumour necrosis factor‐related apoptosis‐inducing ligand receptor 2 (TRAIL‐R2), spondin‐1 (SPON1), matrix metalloproteinase‐12 (MMP‐12), follistatin (FS), urokinase‐type plasminogen activator surface receptor (U‐PAR), osteoprotegerin (OPG), and suppression of tumorigenicity 2 (ST2). Of these, GDF‐15, U‐PAR, MMP‐12, TRAIL‐R2, SPON1 and FS were associated with worsened echocardiographic left ventricular systolic function at baseline, while only TIM‐1 was positively associated with worsened diastolic function (P < 0.02 for all).

Conclusion

Proteomic profiling identified several novel associations between proteins involved in apoptosis, inflammation, matrix remodelling, and fibrinolysis with incident heart failure in elderly individuals. Our results encourage additional studies investigating the underlying mechanisms and the clinical utility of our findings.

Emneord
Biomarkers, Epidemiology, Heart failure, Left ventricular dysfunction, Proteomics, Risk prediction
HSV kategori
Identifikatorer
urn:nbn:se:uu:diva-334416 (URN)10.1002/ejhf.980 (DOI)000423809700007 ()28967680 (PubMedID)
Forskningsfinansiär
EU, Horizon 2020, 634869Swedish Research Council, 2012-2215; 2015-03477; 221-2013-1673Marianne and Marcus Wallenberg Foundation, 2012.0082Swedish Heart Lung Foundation, 20140422; 20150429; 20120169Knut and Alice Wallenberg Foundation, 2013.0126Göran Gustafsson Foundation for promotion of scientific research at Uppala University and Royal Institute of Technology, 1637
Merknad

Tove Fall och Johan Ärnlöv delar på sistaförfattarskapet.

Tilgjengelig fra: 2017-11-23 Laget: 2017-11-23 Sist oppdatert: 2019-04-09bibliografisk kontrollert
2. Discovery of New Risk Markers for Ischemic Stroke Using a Novel Targeted Proteomics Chip
Åpne denne publikasjonen i ny fane eller vindu >>Discovery of New Risk Markers for Ischemic Stroke Using a Novel Targeted Proteomics Chip
Vise andre…
2015 (engelsk)Inngår i: Stroke, ISSN 0039-2499, E-ISSN 1524-4628, Vol. 46, nr 12, s. 3340-3347Artikkel i tidsskrift (Fagfellevurdert) Published
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.

Emneord
adrenomedullin, natriuretic peptide, brain, proteins, risk factors, stroke
HSV kategori
Identifikatorer
urn:nbn:se:uu:diva-270960 (URN)10.1161/STROKEAHA.115.010829 (DOI)000365534400001 ()26542692 (PubMedID)
Forskningsfinansiär
AstraZenecaEU, European Research Council, 634869Swedish Research Council, 2012-1727Swedish Research Council, 2012-2215Swedish Heart Lung FoundationMarianne and Marcus Wallenberg Foundation
Tilgjengelig fra: 2016-01-05 Laget: 2016-01-05 Sist oppdatert: 2019-04-09bibliografisk kontrollert
3. The metabolites urobilin and sphingomyelin (30:1) are associated with incident heart failure in the general population
Åpne denne publikasjonen i ny fane eller vindu >>The metabolites urobilin and sphingomyelin (30:1) are associated with incident heart failure in the general population
Vise andre…
2019 (engelsk)Inngår i: ESC Heart Failure, E-ISSN 2055-5822, Vol. 6, nr 4, s. 764-773Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

Aims: We aimed to investigate whether metabolomic profiling of blood can lead to novel insights into heart failure pathogenesis or improved risk prediction.

Methods: Mass spectrometry-based metabolomic profiling was performed in plasma or serum samples from three community-based cohorts without heart failure at baseline (total n=3,924; 341 incident heart failure events, median follow-up ranging from 4.6 to 13.9 years). Cox proportional hazards models were applied to assess the association of each of the 206 identified metabolites with incident heart failure in the discovery cohorts Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS, n=920) and Uppsala Longitudinal Study of Adult Men (ULSAM, n=1,121). Replication was undertaken in the independent cohort TwinGene (n=1,797). We also assessed whether metabolites could improve the prediction of heart failure beyond established risk factors (age, sex, body mass index, low-density lipoprotein- and high-density lipoprotein-cholesterol, triglycerides, lipid medication, diabetes, systolic and diastolic blood pressure, blood pressure medication, glomerular filtration rate, smoking status, and myocardial infarction prior to or during follow-up).

Results: Higher circulating urobilin and lower sphingomyelin (30:1) were associated with incident heart failure in age- and sex-adjusted models in the discovery and replication sample. The hazard ratio (HR) for urobilin in the replication cohort was estimated to 1.29 per SD unit, 95% confidence interval (CI) 1.03-1.63) and for sphingomyelin (30:1) to 0.72 (95% CI 0.58-0.89). Results remained similar after further adjustment for established heart failure risk factors in meta-analyses of all three cohorts. Urobilin concentrations were inversely associated with left ventricular ejection fraction at baseline in the PIVUS cohort (β= -0.70 (95% CI -1.03-(-0.38)). No improvement in risk prediction was observed when adding the two top metabolites (C-index 0.787 (95% CI 0.752-0.823)) or nine Lasso-selected metabolites (0.790 (95% CI 0.754-0.826)) to a modified Atherosclerosis Risk in Communities (ARIC) heart failure risk score model (0.780 (95% CI 0.745-0.816)).

Conclusions: Our metabolomics study identified associations of circulating levels of the heme breakdown product urobilin, and sphingomyelin (30:1), a cell membrane component involved in signal transduction and apoptosis, with incident heart failure.

HSV kategori
Identifikatorer
urn:nbn:se:uu:diva-381229 (URN)10.1002/ehf2.12453 (DOI)000478602300020 ()31148414 (PubMedID)
Forskningsfinansiär
Swedish Research Council, 2017-00641Swedish Research Council, 2012-02215Swedish Heart Lung FoundationEU, Horizon 2020, 634869
Tilgjengelig fra: 2019-04-05 Laget: 2019-04-05 Sist oppdatert: 2019-09-24bibliografisk kontrollert
4. The role of growth differentiation factor 15 (GDF-15) in cardiovascular disease – a Mendelian Randomization study
Åpne denne publikasjonen i ny fane eller vindu >>The role of growth differentiation factor 15 (GDF-15) in cardiovascular disease – a Mendelian Randomization study
(engelsk)Inngår i: Artikkel i tidsskrift (Annet vitenskapelig) Submitted
HSV kategori
Identifikatorer
urn:nbn:se:uu:diva-381231 (URN)
Tilgjengelig fra: 2019-04-05 Laget: 2019-04-05 Sist oppdatert: 2019-04-09

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