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Metabolomics reveals amino acids contribute to variation in response to simvastatin treatment.

Publication ,  Journal Article
Trupp, M; Zhu, H; Wikoff, WR; Baillie, RA; Zeng, Z-B; Karp, PD; Fiehn, O; Krauss, RM; Kaddurah-Daouk, R
Published in: PLoS One
2012

UNLABELLED: Statins are widely prescribed for reducing LDL-cholesterol (C) and risk for cardiovascular disease (CVD), but there is considerable variation in therapeutic response. We used a gas chromatography-time-of-flight mass-spectrometry-based metabolomics platform to evaluate global effects of simvastatin on intermediary metabolism. Analyses were conducted in 148 participants in the Cholesterol and Pharmacogenetics study who were profiled pre and six weeks post treatment with 40 mg/day simvastatin: 100 randomly selected from the full range of the LDL-C response distribution and 24 each from the top and bottom 10% of this distribution ("good" and "poor" responders, respectively). The metabolic signature of drug exposure in the full range of responders included essential amino acids, lauric acid (p<0.0055, q<0.055), and alpha-tocopherol (p<0.0003, q<0.017). Using the HumanCyc database and pathway enrichment analysis, we observed that the metabolites of drug exposure were enriched for the pathway class amino acid degradation (p<0.0032). Metabolites whose change correlated with LDL-C lowering response to simvastatin in the full range responders included cystine, urea cycle intermediates, and the dibasic amino acids ornithine, citrulline and lysine. These dibasic amino acids share plasma membrane transporters with arginine, the rate-limiting substrate for nitric oxide synthase (NOS), a critical mediator of cardiovascular health. Baseline metabolic profiles of the good and poor responders were analyzed by orthogonal partial least square discriminant analysis so as to determine the metabolites that best separated the two response groups and could be predictive of LDL-C response. Among these were xanthine, 2-hydroxyvaleric acid, succinic acid, stearic acid, and fructose. Together, the findings from this study indicate that clusters of metabolites involved in multiple pathways not directly connected with cholesterol metabolism may play a role in modulating the response to simvastatin treatment. TRIAL REGISTRATION: ClinicalTrials.gov NCT00451828.

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Published In

PLoS One

DOI

EISSN

1932-6203

Publication Date

2012

Volume

7

Issue

7

Start / End Page

e38386

Location

United States

Related Subject Headings

  • alpha-Tocopherol
  • Xanthine
  • Succinic Acid
  • Stearic Acids
  • Simvastatin
  • Ornithine
  • Nitric Oxide Synthase
  • Metabolomics
  • Male
  • Lauric Acids
 

Citation

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Trupp, M., Zhu, H., Wikoff, W. R., Baillie, R. A., Zeng, Z.-B., Karp, P. D., … Kaddurah-Daouk, R. (2012). Metabolomics reveals amino acids contribute to variation in response to simvastatin treatment. PLoS One, 7(7), e38386. https://doi.org/10.1371/journal.pone.0038386
Trupp, Miles, Hongjie Zhu, William R. Wikoff, Rebecca A. Baillie, Zhao-Bang Zeng, Peter D. Karp, Oliver Fiehn, Ronald M. Krauss, and Rima Kaddurah-Daouk. “Metabolomics reveals amino acids contribute to variation in response to simvastatin treatment.PLoS One 7, no. 7 (2012): e38386. https://doi.org/10.1371/journal.pone.0038386.
Trupp M, Zhu H, Wikoff WR, Baillie RA, Zeng Z-B, Karp PD, et al. Metabolomics reveals amino acids contribute to variation in response to simvastatin treatment. PLoS One. 2012;7(7):e38386.
Trupp, Miles, et al. “Metabolomics reveals amino acids contribute to variation in response to simvastatin treatment.PLoS One, vol. 7, no. 7, 2012, p. e38386. Pubmed, doi:10.1371/journal.pone.0038386.
Trupp M, Zhu H, Wikoff WR, Baillie RA, Zeng Z-B, Karp PD, Fiehn O, Krauss RM, Kaddurah-Daouk R. Metabolomics reveals amino acids contribute to variation in response to simvastatin treatment. PLoS One. 2012;7(7):e38386.

Published In

PLoS One

DOI

EISSN

1932-6203

Publication Date

2012

Volume

7

Issue

7

Start / End Page

e38386

Location

United States

Related Subject Headings

  • alpha-Tocopherol
  • Xanthine
  • Succinic Acid
  • Stearic Acids
  • Simvastatin
  • Ornithine
  • Nitric Oxide Synthase
  • Metabolomics
  • Male
  • Lauric Acids