Metabolite Profiling and Cardiovascular Event Risk: A Prospective Study of 3 Population-Based Cohorts

• Published in: Circulation (New York, N.Y.) Vol. 131; no. 9; pp. 774 - 785
• Main Authors: Würtz, Peter, Havulinna, Aki S, Soininen, Pasi, Tynkkynen, Tuulia, Prieto-Merino, David, Tillin, Therese, Ghorbani, Anahita, Artati, Anna, Wang, Qin, Tiainen, Mika, Kangas, Antti J, Kettunen, Johannes, Kaikkonen, Jari, Mikkilä, Vera, Jula, Antti, Kähönen, Mika, Lehtimäki, Terho, Lawlor, Debbie A, Gaunt, Tom R, Hughes, Alun D, Sattar, Naveed, Illig, Thomas, Adamski, Jerzy, Wang, Thomas J, Perola, Markus, Ripatti, Samuli, Vasan, Ramachandran S, Raitakari, Olli T, Gerszten, Robert E, Casas, Juan-Pablo, Chaturvedi, Nish, Ala-Korpela, Mika, Salomaa, Veikko
• Format: Journal Article
• Language: English
• Published: United States by the American College of Cardiology Foundation and the American Heart Association, Inc 03.03.2015
• Subjects: Adolescent; Adult; Age Distribution; Aged; Biomarkers - blood; Blood Pressure; Cardiovascular Agents - therapeutic use; Cardiovascular Diseases - blood; Cardiovascular Diseases - epidemiology; Child; Comorbidity; Diabetes Mellitus - blood; Diabetes Mellitus - epidemiology; Docosahexaenoic Acids - blood; Endophenotypes - blood; Fatty Acids, Monounsaturated - blood; Fatty Acids, Omega-6 - blood; Female; Finland - epidemiology; Health Surveys; High-Throughput Screening Assays - methods; Humans; Male; Mass Spectrometry; Metabolomics - methods; Middle Aged; Nuclear Magnetic Resonance, Biomolecular; Phenylalanine - blood; Prospective Studies; Risk Assessment; Risk Factors; Sex Distribution; Smoking - blood; Smoking - epidemiology; United Kingdom - epidemiology; United States - epidemiology; Young Adult; United States; United Kingdom; Finland; biological markers; risk factors; fatty acids; metabolomics; amino acids
• ISSN: 0009-7322; 1524-4539
• DOI: 10.1161/CIRCULATIONAHA.114.013116

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-analyseshigher serum phenylalanine (hazard ratio per standard deviation, 1.18; 95% confidence interval, 1.12–1.24; P=4×10) and monounsaturated fatty acid levels (1.17; 1.11–1.24; P=1×10) were associated with increased cardiovascular risk, while higher omega-6 fatty acids (0.89; 0.84–0.94; P=6×10) and docosahexaenoic acid levels (0.90; 0.86–0.95; P=5×10) 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.