Wurtz, P;
Havulinna, AS;
Soininen, P;
Tynkkynen, T;
Prieto-Merino, D;
Tillin, T;
Ghorbani, A;
... Salomaa, V; + view all
(2015)
Metabolite Profiling and Cardiovascular Event Risk: A Prospective Study of 3 Population-Based Cohorts.
Circulation
, 131
(9)
pp. 774-785.
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. / 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.
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