Metabolomic Profiling of Statin Use and Genetic Inhibition of HMG-CoA Reductase
Open accessAbstract
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.
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Using randomization to a statin in an RCT to determine the causal effect of LDLc on CHD might have the same source of violation of the exclusion restriction criteria as an MR study that uses genetic variant(s) which influence the same biological path as that which statins act on.
“For example, in Figures 1a–d, we show how using randomization to a statin in an RCT to determine the causal effect of low-density lipoprotein cholesterol (LDLc) on coronary heart disease (CHD) might have the same source of violation of this criterion as an MR study that uses (a) genetic variant(s) which influence(s) the same biological path as that which statins act on.46”
From Triangulation in aetiological epidemiology (2017) · cites this paper as [46]
The effects on disease risk of different pharmacological and surgical approaches to modifying BMI may potentially differ.
“Therefore, the effects on disease risk of different pharmacological (and surgical 71,72 ) approaches to modifying BMI, may potentially differ.”
From Integrating genomics with biomarkers and therapeutic targets to invigorate cardiovascular drug development (2021) · cites this paper as [72]
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References 40 · Cited by 188
Research works printed but not linked: 1
- [2]National Center for Health Statistics (US) Health, United States, With Special Feature on Prescription Drugs 2014 National Center for Health Statistics Hyattsville, MD 24967476
- 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., & Ala-Korpela, M.
- Affiliations
- University of Oulu (FI)
- University of Eastern Finland (FI)
- London School of Hygiene & Tropical Medicine (GB)
- University of Helsinki (FI)
- University College London (GB)
- Tampere University Hospital (FI)
- Tampere University (FI)
- University of Glasgow (GB)
- Finnish Institute for Health and Welfare (FI)
- Oulu University Hospital (FI)
- University of Bristol (GB)
- University of Turku (FI)
- Corresponding author
- Würtz, Peter
- ORCID
- Würtz, Peter
- Wang, Qin
- Kangas, Antti J.
- Fatemifar, Ghazaleh
- Tynkkynen, Tuulia
- Tiainen, Mika
- Perola, Markus
- Tillin, Therese
- Hughes, Alun D.
- Mäntyselkä, Pekka
- Kähönen, Mika
- Lehtimäki, Terho
- Sattar, Naveed
- Hingorani, Aroon D.
- Casas, Juan-Pablo
- Salomaa, Veikko
- Järvelin, Marjo-Riitta
- Vanhala, Mauno
- Lawlor, Debbie A.
- Raitakari, Olli T.
- Chaturvedi, Nish
- Kettunen, Johannes
- Venue
- Journal of the American College of Cardiology
- Publisher
- Elsevier BV
- Published
- 2016-03
- Volume
- 67
- Issue
- 10
- Pages
- 1200-1210
- ISSN
- 0735-1097 (ISSN-L)
- PMC
- PMC4783625
- OpenAlex
- W2296625401
- Cited by
- 188
- References
- 40
- Citations by year
- 2026: 7 · 2025: 7 · 2024: 15 · 2023: 24 · 2022: 19 · 2021: 25 · 2020: 19 · 2019: 23 · 2018: 20 · 2017: 21 · 2016: 8
- FWCI
- 26.57
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Journal of the American College of Cardiology (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Bristol Research (University of Bristol) (publishedVersion, cc-by)
- ENLIGHTEN (Jurnal Bimbingan dan Konseling Islam) (acceptedVersion)
- Explore Bristol Research (acceptedVersion, cc-by)
- LSHTM Research Online (London School of Hygiene and Tropical Medicine) (acceptedVersion)
- UEF eRepo (University of Eastern Finland) (submittedVersion, cc-by)
- Adelaide Research & Scholarship (AR&S) (University of Adelaide) (submittedVersion, cc-by-nc-nd)
- UCL Discovery (University College London) (submittedVersion)
- Työväentutkimus Vuosikirja (submittedVersion, other-oa)
- Spiral (Imperial College London) (submittedVersion, other-oa)
- STM:n Hallinnonalan avoin julkaisuarkisto (Julkari) (submittedVersion)
- Funders
- Wellcome Trust (WT092830M, 102215/2/13/2), 102215, WT088806)
- National Institute for Health and Care Research (NF-SI-0515-10091, NF-SI-0611-10196)
- British Heart Foundation (PG/12/71/29684, SP/07/008/24066, RG/10/12/28456, PG/13/66/30442, CS/13/1/30327, RG/13/2/30098, SP/13/6/30554)
- European Commission (633595)
- Novo Nordisk Fonden (NNF15OC0015998)
- National Institutes of Health (6r01hl087679-03, 5rl1mh083268-05)
- Medical Research Council (MR/K013351/1, MR/K006584/1, MC_PC_15018)
- National Heart, Lung, and Blood Institute (5R01 HL087679-02, R01 HL087679, R01HL036310)
- National Institute of Mental Health (R01MH063706, RL1-MH083268, 1RL1MH083268-01, 5R01 MH63706:02)
- Topics
- Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolomics and Mass Spectrometry Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
- Keywords
- statins, HMG-CoA reductase inhibition, remnant cholesterol, lipoproteins, fatty acids, omega-6 fatty acids, triglycerides, circulating amino acids, ketones, serum metabolomics, Mendelian randomization, cardiovascular disease prevention
- MeSH terms
- Adult, Cardiovascular Diseases, Female, Finland, Forecasting, United Kingdom, Humans, Hydroxymethylglutaryl CoA Reductases, Male, Middle Aged, Magnetic Resonance Spectroscopy, Retrospective Studies, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Metabolomics, Mendelian Randomization Analysis
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