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

Peter Würtz; Aki S Havulinna; Pasi Soininen; Tuulia Tynkkynen; David Prieto-Merino; Therese Tillin; Anahita Ghorbani; Anna Artati; Qin Wang; Mika Tiainen; Antti J Kangas; Johannes Kettunen; Jari Kaikkonen; Vera Mikkilä; Antti Jula; Mika Kähönen; Terho Lehtimäki; Debbie A Lawlor; Tom R Gaunt; Alun D Hughes; Naveed Sattar; Thomas Illig; Jerzy Adamski; Thomas J Wang; Markus Perola; Samuli Ripatti; Ramachandran S Vasan; Olli T Raitakari; Robert E Gerszten; Juan-Pablo Casas; Nish Chaturvedi; Mika Ala-Korpela; Veikko Salomaa

doi:10.1161/CIRCULATIONAHA.114.013116

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

Peter Würtz, Aki S Havulinna, Pasi Soininen, Tuulia Tynkkynen, David Prieto-Merino, Therese Tillin, Anahita Ghorbani, Anna Artati, Qin Wang, Mika Tiainen, Antti J Kangas, Johannes Kettunen, Jari Kaikkonen, Vera Mikkilä, Antti Jula, Mika Kähönen, Terho Lehtimäki, Debbie A Lawlor, Tom R Gaunt, Alun D HughesNaveed Sattar, Thomas Illig, Jerzy Adamski, Thomas J Wang, Markus Perola, Samuli Ripatti, Ramachandran S Vasan, Olli T Raitakari, Robert E Gerszten, Juan-Pablo Casas, Nish Chaturvedi, Mika Ala-Korpela, Veikko Salomaa

Research output: Contribution to journal › Article (Academic Journal) › peer-review

551 Citations (Scopus)

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.

Original language	English
Pages (from-to)	774-85
Number of pages	12
Journal	Circulation
Volume	131
Issue number	9
Early online date	8 Jan 2015
DOIs	https://doi.org/10.1161/CIRCULATIONAHA.114.013116
Publication status	Published - 3 Mar 2015

Keywords

Adolescent
Adult
Age Distribution
Aged
Biomarkers
Blood Pressure
Cardiovascular Agents
Cardiovascular Diseases
Child
Comorbidity
Diabetes Mellitus
Docosahexaenoic Acids
Endophenotypes
Fatty Acids, Monounsaturated
Fatty Acids, Omega-6
Female
Finland
Great Britain
Health Surveys
High-Throughput Screening Assays
Humans
Male
Mass Spectrometry
Metabolomics
Middle Aged
Nuclear Magnetic Resonance, Biomolecular
Phenylalanine
Prospective Studies
Risk Assessment
Risk Factors
Sex Distribution
Smoking
United States
Young Adult

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1161/CIRCULATIONAHA.114.013116

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IEU Theme 2
Flach, P. A. (Principal Investigator), Gaunt, T. R. (Principal Investigator) & Gaunt, T. R. (Principal Investigator)
1/06/13 → 31/03/18
Project: Research
MRC UoB UNITE Unit - Programme 5
Lawlor, D. A. (Principal Investigator) & Lawlor, D. A. (Principal Investigator)
1/06/13 → 31/03/18
Project: Research
A systems approach to the classification of genes impacting the cardiovascular phenome
Gaunt, T. R. (Principal Investigator)
1/02/11 → 1/05/14
Project: Research

Professor Tom R Gaunt
- Tom.Gauntbristol.acuk
- Bristol Medical School (PHS) - Professor of Health and Biomedical Informatics and MRC Investigator
- Bristol Population Health Science Institute
- MRC Integrative Epidemiology Unit - Programme lead
Person: Academic , Member

Cite this

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., ... Salomaa, V. (2015). Metabolite profiling and cardiovascular event risk: a prospective study of 3 population-based cohorts. Circulation, 131(9), 774-85. https://doi.org/10.1161/CIRCULATIONAHA.114.013116

@article{9f74a888f9954a948b5d7d7118e3b190,

title = "Metabolite profiling and cardiovascular event risk: a prospective study of 3 population-based cohorts",

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 = "Adolescent, Adult, Age Distribution, Aged, Biomarkers, Blood Pressure, Cardiovascular Agents, Cardiovascular Diseases, Child, Comorbidity, Diabetes Mellitus, Docosahexaenoic Acids, Endophenotypes, Fatty Acids, Monounsaturated, Fatty Acids, Omega-6, Female, Finland, Great Britain, Health Surveys, High-Throughput Screening Assays, Humans, Male, Mass Spectrometry, Metabolomics, Middle Aged, Nuclear Magnetic Resonance, Biomolecular, Phenylalanine, Prospective Studies, Risk Assessment, Risk Factors, Sex Distribution, Smoking, United States, Young Adult",

author = "Peter W{\"u}rtz and Havulinna, \{Aki S\} and Pasi Soininen and Tuulia Tynkkynen and David Prieto-Merino and Therese Tillin and Anahita Ghorbani and Anna Artati and Qin Wang and Mika Tiainen and Kangas, \{Antti J\} and Johannes Kettunen and Jari Kaikkonen and Vera Mikkil{\"a} and Antti Jula and Mika K{\"a}h{\"o}nen and Terho Lehtim{\"a}ki and Lawlor, \{Debbie A\} and Gaunt, \{Tom R\} and Hughes, \{Alun D\} and Naveed Sattar and Thomas Illig and Jerzy Adamski and Wang, \{Thomas J\} and Markus Perola and Samuli Ripatti and Vasan, \{Ramachandran S\} and Raitakari, \{Olli T\} and Gerszten, \{Robert E\} and Juan-Pablo Casas and Nish Chaturvedi and Mika Ala-Korpela and Veikko Salomaa",

note = "{\textcopyright} 2015 American Heart Association, Inc.",

year = "2015",

month = mar,

day = "3",

doi = "10.1161/CIRCULATIONAHA.114.013116",

language = "English",

volume = "131",

pages = "774--85",

journal = "Circulation",

issn = "0009-7322",

publisher = "Lippincott Williams and Wilkins",

number = "9",

}

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, J-P, Chaturvedi, N, Ala-Korpela, M & Salomaa, V 2015, 'Metabolite profiling and cardiovascular event risk: a prospective study of 3 population-based cohorts', Circulation, vol. 131, no. 9, pp. 774-85. https://doi.org/10.1161/CIRCULATIONAHA.114.013116

TY - JOUR

T1 - Metabolite profiling and cardiovascular event risk

T2 - a prospective study of 3 population-based cohorts

AU - Würtz, Peter

AU - Havulinna, Aki S

AU - Soininen, Pasi

AU - Tynkkynen, Tuulia

AU - Prieto-Merino, David

AU - Tillin, Therese

AU - Ghorbani, Anahita

AU - Artati, Anna

AU - Wang, Qin

AU - Tiainen, Mika

AU - Kangas, Antti J

AU - Kettunen, Johannes

AU - Kaikkonen, Jari

AU - Mikkilä, Vera

AU - Jula, Antti

AU - Kähönen, Mika

AU - Lehtimäki, Terho

AU - Lawlor, Debbie A

AU - Gaunt, Tom R

AU - Hughes, Alun D

AU - Sattar, Naveed

AU - Illig, Thomas

AU - Adamski, Jerzy

AU - Wang, Thomas J

AU - Perola, Markus

AU - Ripatti, Samuli

AU - Vasan, Ramachandran S

AU - Raitakari, Olli T

AU - Gerszten, Robert E

AU - Casas, Juan-Pablo

AU - Chaturvedi, Nish

AU - Ala-Korpela, Mika

AU - Salomaa, Veikko

PY - 2015/3/3

Y1 - 2015/3/3

N2 - 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.

AB - 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.

KW - Adolescent

KW - Adult

KW - Age Distribution

KW - Aged

KW - Biomarkers

KW - Blood Pressure

KW - Cardiovascular Agents

KW - Cardiovascular Diseases

KW - Child

KW - Comorbidity

KW - Diabetes Mellitus

KW - Docosahexaenoic Acids

KW - Endophenotypes

KW - Fatty Acids, Monounsaturated

KW - Fatty Acids, Omega-6

KW - Female

KW - Finland

KW - Great Britain

KW - Health Surveys

KW - High-Throughput Screening Assays

KW - Humans

KW - Male

KW - Mass Spectrometry

KW - Metabolomics

KW - Middle Aged

KW - Nuclear Magnetic Resonance, Biomolecular

KW - Phenylalanine

KW - Prospective Studies

KW - Risk Assessment

KW - Risk Factors

KW - Sex Distribution

KW - Smoking

KW - United States

KW - Young Adult

U2 - 10.1161/CIRCULATIONAHA.114.013116

DO - 10.1161/CIRCULATIONAHA.114.013116

M3 - Article (Academic Journal)

C2 - 25573147

SN - 0009-7322

VL - 131

SP - 774

EP - 785

JO - Circulation

JF - Circulation

IS - 9

ER -

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

Abstract

Keywords

UN SDGs

Access to Document

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Projects

IEU Theme 2

MRC UoB UNITE Unit - Programme 5

A systems approach to the classification of genes impacting the cardiovascular phenome

Profiles

Professor Tom R Gaunt

Cite this