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


BACKGROUND
ClinicalTrials.gov NCT00451828.
Bioinformatics Research Group, AI Center, SRI International, Menlo Park, California, United States of America.
Miles
M
Trupp
Hongjie
H
Zhu
William R
WR
Wikoff
Rebecca A
RA
Baillie
Zhao-Bang
ZB
Zeng
Peter D
PD
Karp
Oliver
O
Fiehn
Ronald M
RM
Krauss
Rima
R
Kaddurah-Daouk
D000328:Adult; D000601:Amino Acids, Essential / Q000097:blood*; D054316:Biomarkers, Pharmacological / Q000097:blood*; D008078:Cholesterol, LDL / Q000097:blood*; D002956:Citrulline / Q000097:blood; D003553:Cystine / Q000097:blood; D005260:Female; D005632:Fructose / Q000097:blood; D008401:Gas Chromatography-Mass Spectrometry; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D007850:Lauric Acids / Q000097:blood; D008297:Male; D055432:Metabolomics; D019001:Nitric Oxide Synthase / Q000097:blood; D009952:Ornithine / Q000097:blood; D019821:Simvastatin / Q000494:pharmacology* / Q000627:therapeutic use; D013229:Stearic Acids / Q000097:blood; D019802:Succinic Acid / Q000097:blood; D019820:Xanthine / Q000097:blood; D024502:alpha-Tocopherol / Q000097:blood
D000601:Amino Acids, Essential; D054316:Biomarkers, Pharmacological; D008078:Cholesterol, LDL; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007850:Lauric Acids; D013229:Stearic Acids; C030358:lauric acid; D019820:Xanthine; D002956:Citrulline; D005632:Fructose; D003553:Cystine; C031183:stearic acid; D019802:Succinic Acid; D019821:Simvastatin; D009952:Ornithine; D019001:Nitric Oxide Synthase; D024502:alpha-Tocopherol