Metabolomic Profiling of Statin Use and Genetic Inhibition of HMG-CoA Reductase
| Autor: | Mika Tiainen, George Davey Smith, Veikko Salomaa, Antti J. Kangas, Pasi Soininen, Qin Wang, Pekka Mäntyselkä, Marjo-Riitta Järvelin, Tuulia Tynkkynen, Mika Kähönen, Mika Ala-Korpela, Johannes Kettunen, Markus Perola, Mika Kivimäki, Mauno Vanhala, Peter Würtz, Ghazaleh Fatemifar, Alun D. Hughes, Therese Tillin, Juan-Pablo Casas, Terho Lehtimäki, Aroon D. Hingorani, Nish Chaturvedi, Olli T. Raitakari, Naveed Sattar, Debbie A Lawlor |
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| Přispěvatelé: | Institute for Molecular Medicine Finland, Clinicum, Department of Public Health, Quantitative Genetics, Faculty of Health Sciences, School of Pharmacy, Activities, School of Medicine / Public Health |
| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Male Very low-density lipoprotein Cardiac & Cardiovascular Systems Magnetic Resonance Spectroscopy cholesterol lowering Genome-wide association study 030204 cardiovascular system & hematology FATTY-ACID-COMPOSITION 0302 clinical medicine IDL intermediate-density lipoprotein Medicine EPIDEMIOLOGY HMGCR HMG-CoA reductase Finland Original Investigation RISK biology Great Britain Middle Aged Hydroxymethylglutaryl-CoA reductase metabolomics 3. Good health 1117 Public Health And Health Services Drug development CARDIOVASCULAR-DISEASE Cardiovascular Diseases HMG-CoA reductase lipids (amino acids peptides and proteins) Female Cardiology and Cardiovascular Medicine Life Sciences & Biomedicine TRIGLYCERIDES Adult medicine.medical_specialty HDL high-density lipoprotein CVD cardiovascular disease 1102 Cardiovascular Medicine And Haematology 03 medical and health sciences Metabolomics Internal medicine Mendelian randomization Humans CORONARY-HEART-DISEASE GENOME-WIDE ASSOCIATION NMR nuclear magnetic resonance Retrospective Studies Science & Technology business.industry VLDL very-low-density lipoprotein Mendelian Randomization Analysis ta3121 drug development United Kingdom lipoproteins 030104 developmental biology Endocrinology Cardiovascular System & Hematology 3121 General medicine internal medicine and other clinical medicine Cardiovascular System & Cardiology biology.protein COHORT PROFILE LDL-C low-density lipoprotein cholesterol Hydroxymethylglutaryl CoA Reductases LDL CHOLESTEROL Hydroxymethylglutaryl-CoA Reductase Inhibitors business Lipoprotein Forecasting |
| Zdroj: | Journal of the American College of Cardiology 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 & Ala-Korpela, M J 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 . https://doi.org/10.1016/j.jacc.2015.12.060 |
| ISSN: | 0735-1097 |
| DOI: | 10.1016/j.jacc.2015.12.060 |
| Popis: | Article 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. published version http://purl.org/eprint/status/PeerReviewed |
| Databáze: | OpenAIRE |
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