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Circulation. 2015 Mar 3;131(9):774-85. doi: 10.1161/CIRCULATIONAHA.114.013116. Epub 2015 Jan 8.

Metabolite profiling and cardiovascular event risk: a prospective study of 3 population-based cohorts.

Author information

1
From Computational Medicine, Institute of Health Sciences, University of Oulu, Finland (P.W., P.S., T. Tynkkynen, Q.W., M.T., A.J.K., J. Kettunen, M.A.-K.); Department of Chronic Disease Prevention, National Institute for Health and Welfare, Finland (P.W., A.S.H., J. Kettunen, A.J., M.P., V.S.); Institute for Molecular Medicine Finland, University of Helsinki (P.W., A.S.H., M.P., S.P.); NMR Metabolomics Laboratory, School of Pharmacy, University of Eastern Finland, Kuopio (P.S., T. Tynkkynen, Q.W., M.T., M.A.-K.); Faculty of Epidemiology and Public Health, London School of Hygiene and Tropical Medicine, United Kingdom (D.P.-M., J.-P.C.); Institute of Cardiovascular Science, University College London, United Kingdom (T. Tillin, A.D.H., J.-P.C., N.C.); Framingham Heart Study of the National Heart, Lung, and Blood Institute and Boston University School of Medicine, Framingham, MA (A.G., R.S.V.); Genome Analysis Center, Institute of Experimental Genetics, Helmholtz Zentrum München, Neuherberg, Germany (A.A., J.A.); Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Finland (J. Kaikkonen, V.M., O.T.R.); Department of Food and Environmental Sciences, University of Helsinki, Finland (V.M.,); Department of Clinical Physiology, University of Tampere and Tampere University Hospital, Finland (M.K.); Department of Clinical Chemistry, Fimlab Laboratories, and School of Medicine, University of Tampere, Finland (T.L.); Medical Research Council Integrative Epidemiology Unit at the University of Bristol, United Kingdom (D.A.L., T.R.G., M.A.-K.); School of Social and Community Medicine, University of Bristol, United Kingdom (D.A.L., T.R.G., M.A.-K.); Institute of Cardiovascular and Medical Sciences, University of Glasgow, United Kingdom (N.S.); Hannover Medical School, Hannover Unified Biobank, Germany (T.I.); Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany

Abstract

BACKGROUND:

High-throughput profiling of circulating metabolites may improve cardiovascular risk prediction over established risk factors.

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).

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.

KEYWORDS:

amino acids; biological markers; fatty acids; metabolomics; risk factors

PMID:
25573147
PMCID:
PMC4351161
DOI:
10.1161/CIRCULATIONAHA.114.013116
[Indexed for MEDLINE]
Free PMC Article

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