Purine pathway implicated in mechanism of resistance to aspirin therapy

Pharmacometabolomics-informed pharmacogenomics

L. M. Yerges-Armstrong, S. Ellero-Simatos, A. Georgiades, H. Zhu, J. P. Lewis, R. B. Horenstein, A. L. Beitelshees, A. Dane, T. Reijmers, T. Hankemeier, O. Fiehn, A. R. Shuldiner, R. Kaddurah-Daouk

Research output: Contribution to journalArticle

45 Citations (Scopus)

Abstract

Although aspirin is a well-established antiplatelet agent, the mechanisms of aspirin resistance remain poorly understood. Metabolomics allows for measurement of hundreds of small molecules in biological samples, enabling detailed mapping of pathways involved in drug response. We defined the metabolic signature of aspirin exposure in subjects from the Heredity and Phenotype Intervention Heart Study. Many metabolites, including known aspirin catabolites, changed on exposure to aspirin, and pathway enrichment analysis identified purine metabolism as significantly affected by drug exposure. Furthermore, purines were associated with aspirin response, and poor responders had higher postaspirin adenosine and inosine levels than did good responders (n = 76; both P < 4 × 10-3). Using our established " pharmacometabolomics-informed pharmacogenomics" approach, we identified genetic variants in adenosine kinase associated with aspirin response. Combining metabolomics and genomics allowed for more comprehensive interrogation of mechanisms of variation in aspirin response-an important step toward personalized treatment approaches for cardiovascular disease.

Original languageEnglish (US)
Pages (from-to)525-532
Number of pages8
JournalClinical Pharmacology and Therapeutics
Volume94
Issue number4
DOIs
StatePublished - Oct 2013

Fingerprint

Pharmacogenetics
Aspirin
Metabolomics
Therapeutics
Adenosine Kinase
Inosine
Purines
Heredity
purine
Platelet Aggregation Inhibitors
Genomics
Pharmaceutical Preparations
Adenosine
Cardiovascular Diseases
Phenotype

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)

Cite this

Yerges-Armstrong, L. M., Ellero-Simatos, S., Georgiades, A., Zhu, H., Lewis, J. P., Horenstein, R. B., ... Kaddurah-Daouk, R. (2013). Purine pathway implicated in mechanism of resistance to aspirin therapy: Pharmacometabolomics-informed pharmacogenomics. Clinical Pharmacology and Therapeutics, 94(4), 525-532. https://doi.org/10.1038/clpt.2013.119

Purine pathway implicated in mechanism of resistance to aspirin therapy : Pharmacometabolomics-informed pharmacogenomics. / Yerges-Armstrong, L. M.; Ellero-Simatos, S.; Georgiades, A.; Zhu, H.; Lewis, J. P.; Horenstein, R. B.; Beitelshees, A. L.; Dane, A.; Reijmers, T.; Hankemeier, T.; Fiehn, O.; Shuldiner, A. R.; Kaddurah-Daouk, R.

In: Clinical Pharmacology and Therapeutics, Vol. 94, No. 4, 10.2013, p. 525-532.

Research output: Contribution to journalArticle

Yerges-Armstrong, LM, Ellero-Simatos, S, Georgiades, A, Zhu, H, Lewis, JP, Horenstein, RB, Beitelshees, AL, Dane, A, Reijmers, T, Hankemeier, T, Fiehn, O, Shuldiner, AR & Kaddurah-Daouk, R 2013, 'Purine pathway implicated in mechanism of resistance to aspirin therapy: Pharmacometabolomics-informed pharmacogenomics', Clinical Pharmacology and Therapeutics, vol. 94, no. 4, pp. 525-532. https://doi.org/10.1038/clpt.2013.119
Yerges-Armstrong, L. M. ; Ellero-Simatos, S. ; Georgiades, A. ; Zhu, H. ; Lewis, J. P. ; Horenstein, R. B. ; Beitelshees, A. L. ; Dane, A. ; Reijmers, T. ; Hankemeier, T. ; Fiehn, O. ; Shuldiner, A. R. ; Kaddurah-Daouk, R. / Purine pathway implicated in mechanism of resistance to aspirin therapy : Pharmacometabolomics-informed pharmacogenomics. In: Clinical Pharmacology and Therapeutics. 2013 ; Vol. 94, No. 4. pp. 525-532.
@article{907b0a5282614bbca2b8fd8637211004,
title = "Purine pathway implicated in mechanism of resistance to aspirin therapy: Pharmacometabolomics-informed pharmacogenomics",
abstract = "Although aspirin is a well-established antiplatelet agent, the mechanisms of aspirin resistance remain poorly understood. Metabolomics allows for measurement of hundreds of small molecules in biological samples, enabling detailed mapping of pathways involved in drug response. We defined the metabolic signature of aspirin exposure in subjects from the Heredity and Phenotype Intervention Heart Study. Many metabolites, including known aspirin catabolites, changed on exposure to aspirin, and pathway enrichment analysis identified purine metabolism as significantly affected by drug exposure. Furthermore, purines were associated with aspirin response, and poor responders had higher postaspirin adenosine and inosine levels than did good responders (n = 76; both P < 4 × 10-3). Using our established {"} pharmacometabolomics-informed pharmacogenomics{"} approach, we identified genetic variants in adenosine kinase associated with aspirin response. Combining metabolomics and genomics allowed for more comprehensive interrogation of mechanisms of variation in aspirin response-an important step toward personalized treatment approaches for cardiovascular disease.",
author = "Yerges-Armstrong, {L. M.} and S. Ellero-Simatos and A. Georgiades and H. Zhu and Lewis, {J. P.} and Horenstein, {R. B.} and Beitelshees, {A. L.} and A. Dane and T. Reijmers and T. Hankemeier and O. Fiehn and Shuldiner, {A. R.} and R. Kaddurah-Daouk",
year = "2013",
month = "10",
doi = "10.1038/clpt.2013.119",
language = "English (US)",
volume = "94",
pages = "525--532",
journal = "Clinical Pharmacology and Therapeutics",
issn = "0009-9236",
publisher = "Nature Publishing Group",
number = "4",

}

TY - JOUR

T1 - Purine pathway implicated in mechanism of resistance to aspirin therapy

T2 - Pharmacometabolomics-informed pharmacogenomics

AU - Yerges-Armstrong, L. M.

AU - Ellero-Simatos, S.

AU - Georgiades, A.

AU - Zhu, H.

AU - Lewis, J. P.

AU - Horenstein, R. B.

AU - Beitelshees, A. L.

AU - Dane, A.

AU - Reijmers, T.

AU - Hankemeier, T.

AU - Fiehn, O.

AU - Shuldiner, A. R.

AU - Kaddurah-Daouk, R.

PY - 2013/10

Y1 - 2013/10

N2 - Although aspirin is a well-established antiplatelet agent, the mechanisms of aspirin resistance remain poorly understood. Metabolomics allows for measurement of hundreds of small molecules in biological samples, enabling detailed mapping of pathways involved in drug response. We defined the metabolic signature of aspirin exposure in subjects from the Heredity and Phenotype Intervention Heart Study. Many metabolites, including known aspirin catabolites, changed on exposure to aspirin, and pathway enrichment analysis identified purine metabolism as significantly affected by drug exposure. Furthermore, purines were associated with aspirin response, and poor responders had higher postaspirin adenosine and inosine levels than did good responders (n = 76; both P < 4 × 10-3). Using our established " pharmacometabolomics-informed pharmacogenomics" approach, we identified genetic variants in adenosine kinase associated with aspirin response. Combining metabolomics and genomics allowed for more comprehensive interrogation of mechanisms of variation in aspirin response-an important step toward personalized treatment approaches for cardiovascular disease.

AB - Although aspirin is a well-established antiplatelet agent, the mechanisms of aspirin resistance remain poorly understood. Metabolomics allows for measurement of hundreds of small molecules in biological samples, enabling detailed mapping of pathways involved in drug response. We defined the metabolic signature of aspirin exposure in subjects from the Heredity and Phenotype Intervention Heart Study. Many metabolites, including known aspirin catabolites, changed on exposure to aspirin, and pathway enrichment analysis identified purine metabolism as significantly affected by drug exposure. Furthermore, purines were associated with aspirin response, and poor responders had higher postaspirin adenosine and inosine levels than did good responders (n = 76; both P < 4 × 10-3). Using our established " pharmacometabolomics-informed pharmacogenomics" approach, we identified genetic variants in adenosine kinase associated with aspirin response. Combining metabolomics and genomics allowed for more comprehensive interrogation of mechanisms of variation in aspirin response-an important step toward personalized treatment approaches for cardiovascular disease.

UR - http://www.scopus.com/inward/record.url?scp=84884502711&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84884502711&partnerID=8YFLogxK

U2 - 10.1038/clpt.2013.119

DO - 10.1038/clpt.2013.119

M3 - Article

VL - 94

SP - 525

EP - 532

JO - Clinical Pharmacology and Therapeutics

JF - Clinical Pharmacology and Therapeutics

SN - 0009-9236

IS - 4

ER -