Metabolomic Profiling of Statin Use and Genetic Inhibition of HMG-CoA Reductase

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Wurtz , P , Wang , Q , Soininen , P , Kangas , A J , Fatemifar , G , Tynkkynen , T , Tiainen , M , Perola , M , Tillin , T , Hughes , A D , Mantyselka , P , Kahonen , M , Lehtimaki , T , Sattar , N , Hingorani , A D , Casas , J-P , Salomaa , V , Kivimaki , M , Jarvelin , M-R , Smith , G D , Vanhala , M , Lawlor , D A , Raitakari , O T , Chaturvedi , N , Kettunen , J & Ala-Korpela , M 2016 , ' Metabolomic Profiling of Statin Use and Genetic Inhibition of HMG-CoA Reductase ' Journal of the American College of Cardiology , vol. 67 , no. 10 , pp. 1200-1210 . DOI: 10.1016/j.jacc.2015.12.060

Title: Metabolomic Profiling of Statin Use and Genetic Inhibition of HMG-CoA Reductase
Author: Wurtz, Peter; Wang, Qin; Soininen, Pasi; Kangas, Antti J.; Fatemifar, Ghazaleh; Tynkkynen, Tuulia; Tiainen, Mika; Perola, Markus; Tillin, Therese; Hughes, Alun D.; Mantyselka, Pekka; Kahonen, Mika; Lehtimaki, Terho; Sattar, Naveed; Hingorani, Aroon D.; Casas, Juan-Pablo; Salomaa, Veikko; Kivimaki, Mika; Jarvelin, Marjo-Riitta; Smith, George Davey; Vanhala, Mauno; Lawlor, Debbie A.; Raitakari, Olli T.; Chaturvedi, Nish; Kettunen, Johannes; Ala-Korpela, Mika
Contributor: University of Helsinki, Institute for Molecular Medicine Finland
University of Helsinki, Department of Public Health
Date: 2016-03-15
Language: eng
Number of pages: 11
Belongs to series: Journal of the American College of Cardiology
ISSN: 0735-1097
URI: http://hdl.handle.net/10138/161088
Abstract: 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 (R-2 = 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. (C) 2016 by the American College of Cardiology Foundation.
Subject: cholesterol lowering
drug development
lipoproteins
Mendelian randomization
metabolomics
GENOME-WIDE ASSOCIATION
CORONARY-HEART-DISEASE
FATTY-ACID-COMPOSITION
LDL CHOLESTEROL
MENDELIAN RANDOMIZATION
CARDIOVASCULAR-DISEASE
COHORT PROFILE
RISK
TRIGLYCERIDES
EPIDEMIOLOGY
3121 Internal medicine
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