A prospective study of serum metabolites and risk of ischemic stroke

Daokun Sun, Steffen Tiedt, Bing Yu, Xueqiu Jian, Rebecca F Gottesman, Thomas H. Mosley, Eric Boerwinkle, Martin Dichgans, Myriam Fornage

Research output: Contribution to journalArticle

Abstract

OBJECTIVE: To identify promising blood-based biomarkers and novel etiologic pathways of disease risk, we applied an untargeted serum metabolomics profiling in a community-based prospective study of ischemic stroke (IS). METHODS: In 3,904 men and women from the Atherosclerosis Risk In Communities study, Cox proportional hazard models were used to estimate the association of incident IS with the standardized level of 245 fasting serum metabolites individually, adjusting for age, sex, race, field center, batch, diabetes, hypertension, current smoking status, body mass index, and estimated glomerular filtration rate. Validation of results was carried out in an independent sample of 114 IS cases and 112 healthy controls. RESULTS: Serum levels of 2 long-chain dicarboxylic acids, tetradecanedioate and hexadecanedioate, were strongly correlated (r = 0.88) and were associated with incident IS after adjusting for covariates (hazard ratio [95% confidence interval (CI)] 1.11 [1.06-1.16] and 1.12 [1.07-1.17], respectively; p < 0.0001). Analyses by IS subtypes suggested that these associations were specific to cardioembolic stroke (CES). Associations of tetradecanedioate and hexadecanedioate with IS were independently confirmed (odds ratio [95% CI] 1.76 [1.21; 2.56] and 1.60 [1.11; 2.32], respectively). CONCLUSION: Two serum long-chain dicarboxylic acids, metabolic products of ω-oxidation of fatty acids, were associated with IS and CES independently of known risk factors. Pathways related to intracellular hexadecanedioate synthesis or those involved in its clearance from the circulation may mediate IS risk. These results highlight the potential of metabolomics to discover novel circulating biomarkers for stroke and to unravel novel pathways for IS and its subtypes.

Original languageEnglish (US)
Pages (from-to)e1890-e1898
JournalNeurology
Volume92
Issue number16
DOIs
StatePublished - Apr 16 2019
Externally publishedYes

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Stroke
Prospective Studies
Serum
Dicarboxylic Acids
Metabolomics
Biomarkers
Confidence Intervals
Glomerular Filtration Rate
Proportional Hazards Models
Fasting
Atherosclerosis
Body Mass Index
Fatty Acids
Smoking
Odds Ratio
Hypertension

ASJC Scopus subject areas

  • Clinical Neurology

Cite this

Sun, D., Tiedt, S., Yu, B., Jian, X., Gottesman, R. F., Mosley, T. H., ... Fornage, M. (2019). A prospective study of serum metabolites and risk of ischemic stroke. Neurology, 92(16), e1890-e1898. https://doi.org/10.1212/WNL.0000000000007279

A prospective study of serum metabolites and risk of ischemic stroke. / Sun, Daokun; Tiedt, Steffen; Yu, Bing; Jian, Xueqiu; Gottesman, Rebecca F; Mosley, Thomas H.; Boerwinkle, Eric; Dichgans, Martin; Fornage, Myriam.

In: Neurology, Vol. 92, No. 16, 16.04.2019, p. e1890-e1898.

Research output: Contribution to journalArticle

Sun, D, Tiedt, S, Yu, B, Jian, X, Gottesman, RF, Mosley, TH, Boerwinkle, E, Dichgans, M & Fornage, M 2019, 'A prospective study of serum metabolites and risk of ischemic stroke', Neurology, vol. 92, no. 16, pp. e1890-e1898. https://doi.org/10.1212/WNL.0000000000007279
Sun, Daokun ; Tiedt, Steffen ; Yu, Bing ; Jian, Xueqiu ; Gottesman, Rebecca F ; Mosley, Thomas H. ; Boerwinkle, Eric ; Dichgans, Martin ; Fornage, Myriam. / A prospective study of serum metabolites and risk of ischemic stroke. In: Neurology. 2019 ; Vol. 92, No. 16. pp. e1890-e1898.
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abstract = "OBJECTIVE: To identify promising blood-based biomarkers and novel etiologic pathways of disease risk, we applied an untargeted serum metabolomics profiling in a community-based prospective study of ischemic stroke (IS). METHODS: In 3,904 men and women from the Atherosclerosis Risk In Communities study, Cox proportional hazard models were used to estimate the association of incident IS with the standardized level of 245 fasting serum metabolites individually, adjusting for age, sex, race, field center, batch, diabetes, hypertension, current smoking status, body mass index, and estimated glomerular filtration rate. Validation of results was carried out in an independent sample of 114 IS cases and 112 healthy controls. RESULTS: Serum levels of 2 long-chain dicarboxylic acids, tetradecanedioate and hexadecanedioate, were strongly correlated (r = 0.88) and were associated with incident IS after adjusting for covariates (hazard ratio [95{\%} confidence interval (CI)] 1.11 [1.06-1.16] and 1.12 [1.07-1.17], respectively; p < 0.0001). Analyses by IS subtypes suggested that these associations were specific to cardioembolic stroke (CES). Associations of tetradecanedioate and hexadecanedioate with IS were independently confirmed (odds ratio [95{\%} CI] 1.76 [1.21; 2.56] and 1.60 [1.11; 2.32], respectively). CONCLUSION: Two serum long-chain dicarboxylic acids, metabolic products of ω-oxidation of fatty acids, were associated with IS and CES independently of known risk factors. Pathways related to intracellular hexadecanedioate synthesis or those involved in its clearance from the circulation may mediate IS risk. These results highlight the potential of metabolomics to discover novel circulating biomarkers for stroke and to unravel novel pathways for IS and its subtypes.",
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AU - Mosley, Thomas H.

AU - Boerwinkle, Eric

AU - Dichgans, Martin

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N2 - OBJECTIVE: To identify promising blood-based biomarkers and novel etiologic pathways of disease risk, we applied an untargeted serum metabolomics profiling in a community-based prospective study of ischemic stroke (IS). METHODS: In 3,904 men and women from the Atherosclerosis Risk In Communities study, Cox proportional hazard models were used to estimate the association of incident IS with the standardized level of 245 fasting serum metabolites individually, adjusting for age, sex, race, field center, batch, diabetes, hypertension, current smoking status, body mass index, and estimated glomerular filtration rate. Validation of results was carried out in an independent sample of 114 IS cases and 112 healthy controls. RESULTS: Serum levels of 2 long-chain dicarboxylic acids, tetradecanedioate and hexadecanedioate, were strongly correlated (r = 0.88) and were associated with incident IS after adjusting for covariates (hazard ratio [95% confidence interval (CI)] 1.11 [1.06-1.16] and 1.12 [1.07-1.17], respectively; p < 0.0001). Analyses by IS subtypes suggested that these associations were specific to cardioembolic stroke (CES). Associations of tetradecanedioate and hexadecanedioate with IS were independently confirmed (odds ratio [95% CI] 1.76 [1.21; 2.56] and 1.60 [1.11; 2.32], respectively). CONCLUSION: Two serum long-chain dicarboxylic acids, metabolic products of ω-oxidation of fatty acids, were associated with IS and CES independently of known risk factors. Pathways related to intracellular hexadecanedioate synthesis or those involved in its clearance from the circulation may mediate IS risk. These results highlight the potential of metabolomics to discover novel circulating biomarkers for stroke and to unravel novel pathways for IS and its subtypes.

AB - OBJECTIVE: To identify promising blood-based biomarkers and novel etiologic pathways of disease risk, we applied an untargeted serum metabolomics profiling in a community-based prospective study of ischemic stroke (IS). METHODS: In 3,904 men and women from the Atherosclerosis Risk In Communities study, Cox proportional hazard models were used to estimate the association of incident IS with the standardized level of 245 fasting serum metabolites individually, adjusting for age, sex, race, field center, batch, diabetes, hypertension, current smoking status, body mass index, and estimated glomerular filtration rate. Validation of results was carried out in an independent sample of 114 IS cases and 112 healthy controls. RESULTS: Serum levels of 2 long-chain dicarboxylic acids, tetradecanedioate and hexadecanedioate, were strongly correlated (r = 0.88) and were associated with incident IS after adjusting for covariates (hazard ratio [95% confidence interval (CI)] 1.11 [1.06-1.16] and 1.12 [1.07-1.17], respectively; p < 0.0001). Analyses by IS subtypes suggested that these associations were specific to cardioembolic stroke (CES). Associations of tetradecanedioate and hexadecanedioate with IS were independently confirmed (odds ratio [95% CI] 1.76 [1.21; 2.56] and 1.60 [1.11; 2.32], respectively). CONCLUSION: Two serum long-chain dicarboxylic acids, metabolic products of ω-oxidation of fatty acids, were associated with IS and CES independently of known risk factors. Pathways related to intracellular hexadecanedioate synthesis or those involved in its clearance from the circulation may mediate IS risk. These results highlight the potential of metabolomics to discover novel circulating biomarkers for stroke and to unravel novel pathways for IS and its subtypes.

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