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Würtz, P.* ; Havulinna, A.S.* ; Soininen, P.* ; Tynkkynen, T.* ; Prieto-Merino, D.* ; Tillin, T.* ; Ghorbani, A.* ; Artati, A. ; Wang, Q.* ; Tiainen, M.* ; Kangas, A.J.* ; Kettunen, J.* ; Kaikkonen, J.* ; Mikkilä, V.* ; Jula, A.* ; Kähönen, M.* ; Lehtimäki, T.* ; Lawlor, D.A.* ; Gaunt, T.R.* ; Hughes, A.D.* ; Sattar, N.* ; Illig, T. ; Adamski, J. ; Wang, T.J.* ; Perola, M.* ; Ripatti, S.* ; Vasan, R.S.* ; Raitakari, O.T.* ; Gerszten, R.E.* ; Casas, J.P.* ; Chaturvedi, N.* ; Ala-Korpela, M.* ; Salomaa, V.*

Metabolite profiling and cardiovascular event risk: A prospective study of three population-based cohorts.

Circulation 131, 774-785 (2015)

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BACKGROUND: -High-throughput profiling of circulating metabolites may improve cardiovascular risk prediction over established risk factors. METHODS AND RESULTS: -We applied quantitative NMR metabolomics to identify biomarkers for incident cardiovascular disease during long-term follow-up. Biomarker discovery was conducted in the FINRISK study (n=7256; 800 events). Replication and incremental risk prediction was assessed in the 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 and medication. When further adjusting for routine lipids, four metabolites were associated with future cardiovascular events in meta-analyses: higher serum phenylalanine (hazard ratio per standard deviation: 1.18 [95%CI 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 four biomarkers was derived in FINRISK. Risk prediction estimates were more accurate in the two 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 5-10% 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 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.

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