Metabolomic profiling of statin use and genetic inhibition of HMG-CoA reductase

Würtz, P. et al. (2016) Metabolomic profiling of statin use and genetic inhibition of HMG-CoA reductase. Journal of the American College of Cardiology, 67(10), pp. 1200-1210. (doi: 10.1016/j.jacc.2015.12.060) (PMID:26965542) (PMCID:PMC4783625)

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Background: Statins are first-line therapy for cardiovascular disease prevention, but their systemic effects across lipoprotein subclasses, fatty acids, and circulating metabolites remain incompletely characterized. Objectives: This study sought to determine the molecular effects of statin therapy on multiple metabolic pathways. Methods: Metabolic profiles based on serum nuclear magnetic resonance metabolomics were quantified at 2 time points in 4 population-based cohorts from the United Kingdom and Finland (N = 5,590; 2.5 to 23.0 years of follow-up). Concentration changes in 80 lipid and metabolite measures during follow-up were compared between 716 individuals who started statin therapy and 4,874 persistent nonusers. To further understand the pharmacological effects of statins, we used Mendelian randomization to assess associations of a genetic variant known to mimic inhibition of HMG-CoA reductase (the intended drug target) with the same lipids and metabolites for 27,914 individuals from 8 population-based cohorts. Results: Starting statin therapy was associated with numerous lipoprotein and fatty acid changes, including substantial lowering of remnant cholesterol (80% relative to low-density lipoprotein cholesterol [LDL-C]), but only modest lowering of triglycerides (25% relative to LDL-C). Among fatty acids, omega-6 levels decreased the most (68% relative to LDL-C); other fatty acids were only modestly affected. No robust changes were observed for circulating amino acids, ketones, or glycolysis-related metabolites. The intricate metabolic changes associated with statin use closely matched the association pattern with rs12916 in the HMGCR gene (R2 = 0.94, slope 1.00 ± 0.03). Conclusions: Statin use leads to extensive lipid changes beyond LDL-C and appears efficacious for lowering remnant cholesterol. Metabolomic profiling, however, suggested minimal effects on amino acids. The results exemplify how detailed metabolic characterization of genetic proxies for drug targets can inform indications, pleiotropic effects, and pharmacological mechanisms.

Item Type:Articles
Glasgow Author(s) Enlighten ID:Sattar, Professor Naveed
Authors: Würtz, P., Wang, Q., Soininen, P., Kangas, A. J., Fatemifar, G., Tynkkynen, T., Tiainen, M., Perola, M., Tillin, T., Hughes, A. D., Mäntyselkä, P., Kähönen, M., Lehtimäki, T., Sattar, N., Hingorani, A. D., Casas, J.-P., Salomaa, V., Kivimäki, M., Järvelin, M.-R., Davey Smith, G., Vanhala, M., Lawlor, D. A., Raitakari, O. T., Chaturvedi, N., Kettunen, J., and Ala-Korpela, M.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
Journal Name:Journal of the American College of Cardiology
Publisher:Elsevier for American College of Cardiology
ISSN (Online):1558-3597
Published Online:07 March 2016
Copyright Holders:Copyright © 2016 American College of Cardiology Foundation
First Published:First published in Journal of the American College of Cardiology 67(10:1200-1210
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
514682Obstetric, lifestyle and genetic determinants of atherosclerosis, fat mass, insulin, glucose and lipid levels in women in early middle-ageNaveed SattarBritish Heart Foundation (BHF)SP/07/008/24066RI CARDIOVASCULAR & MEDICAL SCIENCES