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The metabolites urobilin and sphingomyelin (30:1) are associated with incident heart failure in the general population
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA 02114 USA ; Broad Inst MIT & Harvard, Program Med & Populat Genet, Cambridge, MA 02142 USA ; Broad Inst MIT & Harvard, Stanley Ctr Psychiat Res, Cambridge, MA 02142 USA ; Karolinska Inst, Dept Med Epidemiol & Biostat MEB, Stockholm, Sweden.
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
Karolinska Inst, Dept Neurobiol Care Sci & Soc NVS, Div Family Med & Primary Care, Stockholm, Sweden.
Vise andre og tillknytning
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.

sted, utgiver, år, opplag, sider
2019. Vol. 6, nr 4, s. 764-773
HSV kategori
Identifikatorer
URN: urn:nbn:se:uu:diva-381229DOI: 10.1002/ehf2.12453ISI: 000478602300020PubMedID: 31148414OAI: oai:DiVA.org:uu-381229DiVA, id: diva2:1302751
Forskningsfinansiär
Swedish Research Council, 2017-00641Swedish Research Council, 2012-02215Swedish Heart Lung FoundationEU, Horizon 2020, 634869Tilgjengelig fra: 2019-04-05 Laget: 2019-04-05 Sist oppdatert: 2019-09-24bibliografisk kontrollert
Inngår i avhandling
1. Molecular Epidemiology of Cardiovascular Disease
Åpne denne publikasjonen i ny fane eller vindu >>Molecular Epidemiology of Cardiovascular Disease
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
Biomarkers, ischemic stroke, heart failure, omics, proteomics, metabolomics, epidemiology, risk marker
HSV kategori
Forskningsprogram
Epidemiologi
Identifikatorer
urn:nbn:se:uu:diva-381234 (URN)978-91-513-0634-6 (ISBN)
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

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