Metabolite Profiling and Cardiovascular Event Risk: A Prospective Study of Three Population-Based Cohorts.


Würtz, P; Havulinna, AS; Soininen, P; Tynkkynen, T; Prieto-Merino, D; Tillin, T; Ghorbani, A; Artati, A; Wang, Q; Tiainen, M; Kangas, AJ; Kettunen, J; Kaikkonen, J; Mikkilä, V; Jula, A; Kähönen, M; Lehtimäki, T; Lawlor, DA; Gaunt, TR; Hughes, AD; Sattar, N; Illig, T; Adamski, J; Wang, TJ; Perola, M; Ripatti, S; Vasan, RS; Raitakari, OT; Gerszten, RE; Casas, JP; Chaturvedi, N; Ala-Korpela, M; Salomaa, V; (2015) Metabolite Profiling and Cardiovascular Event Risk: A Prospective Study of Three Population-Based Cohorts. Circulation, 131 (9). pp. 774-85. ISSN 0009-7322 DOI: https://doi.org/10.1161/CIRCULATIONAHA.114.013116

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Abstract

BACKGROUND: High-throughput profiling of circulating metabolites may improve cardiovascular risk prediction over established risk factors.<br/> METHODS AND RESULTS: We applied quantitative nuclear magnetic resonance metabolomics to identify the biomarkers for incident cardiovascular disease during long-term follow-up. Biomarker discovery was conducted in the National Finnish FINRISK study (n=7256; 800 events). Replication and incremental risk prediction was assessed in the Southall and Brent Revisited (SABRE) study (n=2622; 573 events) and British Women's Health and Heart Study (n=3563; 368 events). In targeted analyses of 68 lipids and metabolites, 33 measures were associated with incident cardiovascular events at P<0.0007 after adjusting for age, sex, blood pressure, smoking, diabetes mellitus, and medication. When further adjusting for routine lipids, 4 metabolites were associated with future cardiovascular events in meta-analyses: higher serum phenylalanine (hazard ratio per standard deviation, 1.18; 95% confidence interval, 1.12-1.24; P=4×10(-10)) and monounsaturated fatty acid levels (1.17; 1.11-1.24; P=1×10(-8)) were associated with increased cardiovascular risk, while higher omega-6 fatty acids (0.89; 0.84-0.94; P=6×10(-5)) and docosahexaenoic acid levels (0.90; 0.86-0.95; P=5×10(-5)) were associated with lower risk. A risk score incorporating these 4 biomarkers was derived in FINRISK. Risk prediction estimates were more accurate in the 2 validation cohorts (relative integrated discrimination improvement, 8.8% and 4.3%), albeit discrimination was not enhanced. Risk classification was particularly improved for persons in the 5% to 10% risk range (net reclassification, 27.1% and 15.5%). Biomarker associations were further corroborated with mass spectrometry in FINRISK (n=671) and the Framingham Offspring Study (n=2289).<br/> CONCLUSIONS: Metabolite profiling in large prospective cohorts identified phenylalanine, monounsaturated fatty acids, and polyunsaturated fatty acids as biomarkers for cardiovascular risk. This study substantiates the value of high-throughput metabolomics for biomarker discovery and improved risk assessment.<br/>

Item Type: Article
Faculty and Department: Faculty of Epidemiology and Population Health > Dept of Non-Communicable Disease Epidemiology
PubMed ID: 25573147
Web of Science ID: 350308400004
URI: http://researchonline.lshtm.ac.uk/id/eprint/2338108

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