title: Pharmacometabolomics reveals that serotonin is implicated in aspirin response variability.
abstract: While aspirin is generally effective for prevention of cardiovascular disease, considerable variation in drug response exists, resulting in some individuals displaying high on-treatment platelet reactivity. We used pharmacometabolomics to define pathways implicated in variation of response to treatment. We profiled serum samples from healthy subjects pre- and postaspirin (14 days, 81 mg/day) using mass spectrometry. We established a strong signature of aspirin exposure independent of response (15/34 metabolites changed). In our discovery (N = 80) and replication (N = 125) cohorts, higher serotonin levels pre- and postaspirin correlated with high, postaspirin, collagen-induced platelet aggregation. In a third cohort, platelets from subjects with the highest levels of serotonin preaspirin retained higher reactivity after incubation with aspirin than platelets from subjects with the lowest serotonin levels preaspirin (72 ± 8 vs. 61 ± 11%, P = 0.02, N = 20). Finally, ex vivo, serotonin strongly increased platelet reactivity after platelet incubation with aspirin (+20%, P = 4.9 × 10(-4), N = 12). These results suggest that serotonin is implicated in aspirin response variability.
authors.affiliation: 1] Division of Analytical Biosciences, Leiden Academic Centre for Drug Research, Leiden, The Netherlands [2] Netherlands Metabolomics Centre, Leiden, The Netherlands.
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authors.initials: S
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authors.affiliation: Program in Personalized and Genomic Medicine, Division of Endocrinology, Diabetes, and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland, USA.
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authors.initials: JP
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authors.affiliation: Duke University Medical Center, Durham, North Carolina, USA.
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authors.affiliation: Program in Personalized and Genomic Medicine, Division of Endocrinology, Diabetes, and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland, USA.
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authors.initials: LM
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authors.affiliation: Program in Personalized and Genomic Medicine, Division of Endocrinology, Diabetes, and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland, USA.
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authors.affiliation: Program in Personalized and Genomic Medicine, Division of Endocrinology, Diabetes, and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland, USA.
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authors.affiliation: 1] Division of Analytical Biosciences, Leiden Academic Centre for Drug Research, Leiden, The Netherlands [2] Netherlands Metabolomics Centre, Leiden, The Netherlands.
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authors.affiliation: 1] Division of Analytical Biosciences, Leiden Academic Centre for Drug Research, Leiden, The Netherlands [2] Netherlands Metabolomics Centre, Leiden, The Netherlands.
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authors.affiliation: 1] Division of Analytical Biosciences, Leiden Academic Centre for Drug Research, Leiden, The Netherlands [2] Netherlands Metabolomics Centre, Leiden, The Netherlands.
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authors.lastname: Ramaker
authors.affiliation: 1] Division of Analytical Biosciences, Leiden Academic Centre for Drug Research, Leiden, The Netherlands [2] Netherlands Metabolomics Centre, Leiden, The Netherlands.
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authors.initials: RJ
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authors.affiliation: Program in Personalized and Genomic Medicine, Division of Endocrinology, Diabetes, and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland, USA.
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authors.initials: CG
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authors.affiliation: Duke University Medical Center, Durham, North Carolina, USA.
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authors.initials: H
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authors.affiliation: 1] Duke University Medical Center, Durham, North Carolina, USA [2] Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, RWTH Aachen University, Aachen, Germany.
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authors.initials: CL
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authors.affiliation: Duke University Medical Center, Durham, North Carolina, USA.
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authors.affiliation: Duke University Medical Center, Durham, North Carolina, USA.
authors.forename: T L
authors.initials: TL
authors.lastname: Ortel
authors.affiliation: Program in Personalized and Genomic Medicine, Division of Endocrinology, Diabetes, and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland, USA.
authors.forename: A R
authors.initials: AR
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authors.affiliation: 1] Division of Analytical Biosciences, Leiden Academic Centre for Drug Research, Leiden, The Netherlands [2] Netherlands Metabolomics Centre, Leiden, The Netherlands.
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authors.initials: T
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authors.affiliation: 1] Department of Psychiatry and Behavioral Sciences, Duke University, Durham, North Carolina, USA [2] Duke Institute for Brain Sciences, Duke University, Durham, North Carolina, USA [3] Institute of Genome Science and Policy, Duke University, Durham, North Carolina, USA.
authors.forename: R
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authors.lastname: Kaddurah-Daouk