Association of Circulating Metabolites With Risk of Coronary Heart Disease in a European Population: Results From the Biomarkers for Cardiovascular Risk Assessment in Europe (BiomarCaRE) Consortium

, Ersin Cavus, Mahir Karakas, Francisco M Ojeda, Jukka Kontto, Giovanni Veronesi, Marco Mario Ferrario, Allan Linneberg, Torben Jørgensen, Christa Meisinger, Barbara Thorand, Licia Iacoviello, Daniela Börnigen, Mark Woodward, Renate Schnabel, Simona Costanzo, Hugh Tunstall-Pedoe, Wolfgang Koenig, Kari Kuulasmaa, Veikko SalomaaStefan Blankenberg, Tanja Zeller

Research output: Contribution to journalArticle

Abstract

Importance: Risk stratification for coronary heart disease (CHD) remains challenging because of the complex causative mechanism of the disease. Metabolomic profiling offers the potential to detect new biomarkers and improve CHD risk assessment.

Objective: To evaluate the association between circulating metabolites and incident CHD in a large European cohort.

Design, Setting, and Participants: This population-based study used the Biomarkers for Cardiovascular Risk Assessment in Europe (BiomarCaRE) case-cohort to measure circulating metabolites using a targeted approach in serum samples from 10 741 individuals without prevalent CHD. The cohort consisted of a weighted, random subcohort of the original cohort of more than 70 000 individuals. The case-cohort design was applied to 6 European cohorts: FINRISK97 (Finland), Monitoring of Trends and Determinants in Cardiovascular Diseases/Cooperative Health Research in the Region of Augsburg (MONICA/KORA; Germany), MONICA-Brianza and Moli-Sani (Italy), DanMONICA (Denmark), and the Scottish Heart Health Extended Cohort (United Kingdom).

Main Outcomes and Measures: Associations with time to CHD onset were assessed individually by applying weighted and adjusted Cox proportional hazard models. The association of metabolites with CHD onset was examined by C indices.

Results: In 10 741 individuals (4157 women [38.7%]; median [interquartile range] age, 56.5 [49.2-62.2] years), 2166 incident CHD events (20.2%) occurred over a median (interquartile range) follow-up time of 9.2 (4.5-15.0) years. Among the 141 metabolites analyzed, 24 were significantly associated with incident CHD at a nominal P value of .05, including phosphatidylcholines (PCs), lysoPCs, amino acids, and sphingolipids. Five PCs remained significant after correction for multiple testing: acyl-alkyl-PC C40:6 (hazard ratio [HR], 1.13 [95% CI, 1.07-1.18]), diacyl-PC C40:6 (HR, 1.10 [95% CI, 1.04-1.15]), acyl-alkyl-PC C38:6 (HR, 1.11 [95% CI, 1.05-1.16]), diacyl-PC C38:6 (HR, 1.09 [95% CI, 1.04-1.14]) and diacyl-PC C38:5 (HR, 1.10 [95% CI, 1.05-1.16]). Lower levels of these metabolites were associated with increased risk of incident CHD. The strength of the associations competes with those of classic risk factors (C statistics: acyl-alkyl-PC C40:6, 0.756 [95% CI, 0.738-0.774], diacyl-PC C40:6, 0.754 [95% CI, 0.736-0.772], acyl-alkyl-PC C38:6, 0.755 [95% CI, 0.736-0.773], diacyl-PC C38:6, 0.754 [95% CI, 0.736-0.772]), diacyl-PC C38:5, 0.754 [95% CI, 0.736-0.772]). Adding metabolites to a base risk model including classic risk factors high-sensitivity C-reactive protein and high-sensitivity troponin I did not improve discrimination by C statistics.

Conclusions and Relevance: Five PCs were significantly associated with increased risk of incident CHD and showed comparable discrimination with individual classic risk factors. Although these metabolites do not improve CHD risk assessment beyond that of classic risk factors, these findings hold promise for an improved understanding of the pathophysiology of CHD.

Original languageEnglish
JournalJAMA cardiology
DOIs
Publication statusE-pub ahead of print - 30 Oct 2019

Fingerprint

Phosphatidylcholines
Coronary Disease
Biomarkers
Population
Sphingolipids
Troponin I
Metabolomics
Health
Denmark
Finland
Proportional Hazards Models
C-Reactive Protein
Italy
Germany
Cardiovascular Diseases
Outcome Assessment (Health Care)

Keywords

  • Cardiology
  • Ischemic Heart Disease
  • Cardiovascular Risk Factors

Cite this

Cavus, Ersin ; Karakas, Mahir ; Ojeda, Francisco M ; Kontto, Jukka ; Veronesi, Giovanni ; Ferrario, Marco Mario ; Linneberg, Allan ; Jørgensen, Torben ; Meisinger, Christa ; Thorand, Barbara ; Iacoviello, Licia ; Börnigen, Daniela ; Woodward, Mark ; Schnabel, Renate ; Costanzo, Simona ; Tunstall-Pedoe, Hugh ; Koenig, Wolfgang ; Kuulasmaa, Kari ; Salomaa, Veikko ; Blankenberg, Stefan ; Zeller, Tanja. / Association of Circulating Metabolites With Risk of Coronary Heart Disease in a European Population : Results From the Biomarkers for Cardiovascular Risk Assessment in Europe (BiomarCaRE) Consortium. In: JAMA cardiology. 2019.
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title = "Association of Circulating Metabolites With Risk of Coronary Heart Disease in a European Population: Results From the Biomarkers for Cardiovascular Risk Assessment in Europe (BiomarCaRE) Consortium",
abstract = "Importance: Risk stratification for coronary heart disease (CHD) remains challenging because of the complex causative mechanism of the disease. Metabolomic profiling offers the potential to detect new biomarkers and improve CHD risk assessment.Objective: To evaluate the association between circulating metabolites and incident CHD in a large European cohort.Design, Setting, and Participants: This population-based study used the Biomarkers for Cardiovascular Risk Assessment in Europe (BiomarCaRE) case-cohort to measure circulating metabolites using a targeted approach in serum samples from 10 741 individuals without prevalent CHD. The cohort consisted of a weighted, random subcohort of the original cohort of more than 70 000 individuals. The case-cohort design was applied to 6 European cohorts: FINRISK97 (Finland), Monitoring of Trends and Determinants in Cardiovascular Diseases/Cooperative Health Research in the Region of Augsburg (MONICA/KORA; Germany), MONICA-Brianza and Moli-Sani (Italy), DanMONICA (Denmark), and the Scottish Heart Health Extended Cohort (United Kingdom).Main Outcomes and Measures: Associations with time to CHD onset were assessed individually by applying weighted and adjusted Cox proportional hazard models. The association of metabolites with CHD onset was examined by C indices.Results: In 10 741 individuals (4157 women [38.7{\%}]; median [interquartile range] age, 56.5 [49.2-62.2] years), 2166 incident CHD events (20.2{\%}) occurred over a median (interquartile range) follow-up time of 9.2 (4.5-15.0) years. Among the 141 metabolites analyzed, 24 were significantly associated with incident CHD at a nominal P value of .05, including phosphatidylcholines (PCs), lysoPCs, amino acids, and sphingolipids. Five PCs remained significant after correction for multiple testing: acyl-alkyl-PC C40:6 (hazard ratio [HR], 1.13 [95{\%} CI, 1.07-1.18]), diacyl-PC C40:6 (HR, 1.10 [95{\%} CI, 1.04-1.15]), acyl-alkyl-PC C38:6 (HR, 1.11 [95{\%} CI, 1.05-1.16]), diacyl-PC C38:6 (HR, 1.09 [95{\%} CI, 1.04-1.14]) and diacyl-PC C38:5 (HR, 1.10 [95{\%} CI, 1.05-1.16]). Lower levels of these metabolites were associated with increased risk of incident CHD. The strength of the associations competes with those of classic risk factors (C statistics: acyl-alkyl-PC C40:6, 0.756 [95{\%} CI, 0.738-0.774], diacyl-PC C40:6, 0.754 [95{\%} CI, 0.736-0.772], acyl-alkyl-PC C38:6, 0.755 [95{\%} CI, 0.736-0.773], diacyl-PC C38:6, 0.754 [95{\%} CI, 0.736-0.772]), diacyl-PC C38:5, 0.754 [95{\%} CI, 0.736-0.772]). Adding metabolites to a base risk model including classic risk factors high-sensitivity C-reactive protein and high-sensitivity troponin I did not improve discrimination by C statistics.Conclusions and Relevance: Five PCs were significantly associated with increased risk of incident CHD and showed comparable discrimination with individual classic risk factors. Although these metabolites do not improve CHD risk assessment beyond that of classic risk factors, these findings hold promise for an improved understanding of the pathophysiology of CHD.",
keywords = "Cardiology, Ischemic Heart Disease, Cardiovascular Risk Factors",
author = "Ersin Cavus and Mahir Karakas and Ojeda, {Francisco M} and Jukka Kontto and Giovanni Veronesi and Ferrario, {Marco Mario} and Allan Linneberg and Torben J{\o}rgensen and Christa Meisinger and Barbara Thorand and Licia Iacoviello and Daniela B{\"o}rnigen and Mark Woodward and Renate Schnabel and Simona Costanzo and Hugh Tunstall-Pedoe and Wolfgang Koenig and Kari Kuulasmaa and Veikko Salomaa and Stefan Blankenberg and Tanja Zeller",
year = "2019",
month = "10",
day = "30",
doi = "10.1001/jamacardio.2019.4130",
language = "English",

}

Cavus, E, Karakas, M, Ojeda, FM, Kontto, J, Veronesi, G, Ferrario, MM, Linneberg, A, Jørgensen, T, Meisinger, C, Thorand, B, Iacoviello, L, Börnigen, D, Woodward, M, Schnabel, R, Costanzo, S, Tunstall-Pedoe, H, Koenig, W, Kuulasmaa, K, Salomaa, V & Blankenberg, S & Zeller, T 2019, 'Association of Circulating Metabolites With Risk of Coronary Heart Disease in a European Population: Results From the Biomarkers for Cardiovascular Risk Assessment in Europe (BiomarCaRE) Consortium', JAMA cardiology. https://doi.org/10.1001/jamacardio.2019.4130

Association of Circulating Metabolites With Risk of Coronary Heart Disease in a European Population : Results From the Biomarkers for Cardiovascular Risk Assessment in Europe (BiomarCaRE) Consortium. /; Cavus, Ersin; Karakas, Mahir; Ojeda, Francisco M; Kontto, Jukka; Veronesi, Giovanni; Ferrario, Marco Mario; Linneberg, Allan; Jørgensen, Torben; Meisinger, Christa; Thorand, Barbara; Iacoviello, Licia; Börnigen, Daniela; Woodward, Mark; Schnabel, Renate; Costanzo, Simona; Tunstall-Pedoe, Hugh; Koenig, Wolfgang; Kuulasmaa, Kari; Salomaa, Veikko; Blankenberg, Stefan; Zeller, Tanja.

In: JAMA cardiology, 30.10.2019.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Association of Circulating Metabolites With Risk of Coronary Heart Disease in a European Population

T2 - Results From the Biomarkers for Cardiovascular Risk Assessment in Europe (BiomarCaRE) Consortium

AU - Cavus, Ersin

AU - Karakas, Mahir

AU - Ojeda, Francisco M

AU - Kontto, Jukka

AU - Veronesi, Giovanni

AU - Ferrario, Marco Mario

AU - Linneberg, Allan

AU - Jørgensen, Torben

AU - Meisinger, Christa

AU - Thorand, Barbara

AU - Iacoviello, Licia

AU - Börnigen, Daniela

AU - Woodward, Mark

AU - Schnabel, Renate

AU - Costanzo, Simona

AU - Tunstall-Pedoe, Hugh

AU - Koenig, Wolfgang

AU - Kuulasmaa, Kari

AU - Salomaa, Veikko

AU - Blankenberg, Stefan

AU - Zeller, Tanja

PY - 2019/10/30

Y1 - 2019/10/30

N2 - Importance: Risk stratification for coronary heart disease (CHD) remains challenging because of the complex causative mechanism of the disease. Metabolomic profiling offers the potential to detect new biomarkers and improve CHD risk assessment.Objective: To evaluate the association between circulating metabolites and incident CHD in a large European cohort.Design, Setting, and Participants: This population-based study used the Biomarkers for Cardiovascular Risk Assessment in Europe (BiomarCaRE) case-cohort to measure circulating metabolites using a targeted approach in serum samples from 10 741 individuals without prevalent CHD. The cohort consisted of a weighted, random subcohort of the original cohort of more than 70 000 individuals. The case-cohort design was applied to 6 European cohorts: FINRISK97 (Finland), Monitoring of Trends and Determinants in Cardiovascular Diseases/Cooperative Health Research in the Region of Augsburg (MONICA/KORA; Germany), MONICA-Brianza and Moli-Sani (Italy), DanMONICA (Denmark), and the Scottish Heart Health Extended Cohort (United Kingdom).Main Outcomes and Measures: Associations with time to CHD onset were assessed individually by applying weighted and adjusted Cox proportional hazard models. The association of metabolites with CHD onset was examined by C indices.Results: In 10 741 individuals (4157 women [38.7%]; median [interquartile range] age, 56.5 [49.2-62.2] years), 2166 incident CHD events (20.2%) occurred over a median (interquartile range) follow-up time of 9.2 (4.5-15.0) years. Among the 141 metabolites analyzed, 24 were significantly associated with incident CHD at a nominal P value of .05, including phosphatidylcholines (PCs), lysoPCs, amino acids, and sphingolipids. Five PCs remained significant after correction for multiple testing: acyl-alkyl-PC C40:6 (hazard ratio [HR], 1.13 [95% CI, 1.07-1.18]), diacyl-PC C40:6 (HR, 1.10 [95% CI, 1.04-1.15]), acyl-alkyl-PC C38:6 (HR, 1.11 [95% CI, 1.05-1.16]), diacyl-PC C38:6 (HR, 1.09 [95% CI, 1.04-1.14]) and diacyl-PC C38:5 (HR, 1.10 [95% CI, 1.05-1.16]). Lower levels of these metabolites were associated with increased risk of incident CHD. The strength of the associations competes with those of classic risk factors (C statistics: acyl-alkyl-PC C40:6, 0.756 [95% CI, 0.738-0.774], diacyl-PC C40:6, 0.754 [95% CI, 0.736-0.772], acyl-alkyl-PC C38:6, 0.755 [95% CI, 0.736-0.773], diacyl-PC C38:6, 0.754 [95% CI, 0.736-0.772]), diacyl-PC C38:5, 0.754 [95% CI, 0.736-0.772]). Adding metabolites to a base risk model including classic risk factors high-sensitivity C-reactive protein and high-sensitivity troponin I did not improve discrimination by C statistics.Conclusions and Relevance: Five PCs were significantly associated with increased risk of incident CHD and showed comparable discrimination with individual classic risk factors. Although these metabolites do not improve CHD risk assessment beyond that of classic risk factors, these findings hold promise for an improved understanding of the pathophysiology of CHD.

AB - Importance: Risk stratification for coronary heart disease (CHD) remains challenging because of the complex causative mechanism of the disease. Metabolomic profiling offers the potential to detect new biomarkers and improve CHD risk assessment.Objective: To evaluate the association between circulating metabolites and incident CHD in a large European cohort.Design, Setting, and Participants: This population-based study used the Biomarkers for Cardiovascular Risk Assessment in Europe (BiomarCaRE) case-cohort to measure circulating metabolites using a targeted approach in serum samples from 10 741 individuals without prevalent CHD. The cohort consisted of a weighted, random subcohort of the original cohort of more than 70 000 individuals. The case-cohort design was applied to 6 European cohorts: FINRISK97 (Finland), Monitoring of Trends and Determinants in Cardiovascular Diseases/Cooperative Health Research in the Region of Augsburg (MONICA/KORA; Germany), MONICA-Brianza and Moli-Sani (Italy), DanMONICA (Denmark), and the Scottish Heart Health Extended Cohort (United Kingdom).Main Outcomes and Measures: Associations with time to CHD onset were assessed individually by applying weighted and adjusted Cox proportional hazard models. The association of metabolites with CHD onset was examined by C indices.Results: In 10 741 individuals (4157 women [38.7%]; median [interquartile range] age, 56.5 [49.2-62.2] years), 2166 incident CHD events (20.2%) occurred over a median (interquartile range) follow-up time of 9.2 (4.5-15.0) years. Among the 141 metabolites analyzed, 24 were significantly associated with incident CHD at a nominal P value of .05, including phosphatidylcholines (PCs), lysoPCs, amino acids, and sphingolipids. Five PCs remained significant after correction for multiple testing: acyl-alkyl-PC C40:6 (hazard ratio [HR], 1.13 [95% CI, 1.07-1.18]), diacyl-PC C40:6 (HR, 1.10 [95% CI, 1.04-1.15]), acyl-alkyl-PC C38:6 (HR, 1.11 [95% CI, 1.05-1.16]), diacyl-PC C38:6 (HR, 1.09 [95% CI, 1.04-1.14]) and diacyl-PC C38:5 (HR, 1.10 [95% CI, 1.05-1.16]). Lower levels of these metabolites were associated with increased risk of incident CHD. The strength of the associations competes with those of classic risk factors (C statistics: acyl-alkyl-PC C40:6, 0.756 [95% CI, 0.738-0.774], diacyl-PC C40:6, 0.754 [95% CI, 0.736-0.772], acyl-alkyl-PC C38:6, 0.755 [95% CI, 0.736-0.773], diacyl-PC C38:6, 0.754 [95% CI, 0.736-0.772]), diacyl-PC C38:5, 0.754 [95% CI, 0.736-0.772]). Adding metabolites to a base risk model including classic risk factors high-sensitivity C-reactive protein and high-sensitivity troponin I did not improve discrimination by C statistics.Conclusions and Relevance: Five PCs were significantly associated with increased risk of incident CHD and showed comparable discrimination with individual classic risk factors. Although these metabolites do not improve CHD risk assessment beyond that of classic risk factors, these findings hold promise for an improved understanding of the pathophysiology of CHD.

KW - Cardiology

KW - Ischemic Heart Disease

KW - Cardiovascular Risk Factors

U2 - 10.1001/jamacardio.2019.4130

DO - 10.1001/jamacardio.2019.4130

M3 - Article

C2 - 31664431

ER -