title: Metabolomic Profiling of Statin Use and Genetic Inhibition of HMG-CoA Reductase.
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.
  
  
  OBJECTIVE
  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.
authors.affiliation: Computational Medicine, Institute of Health Sciences, University of Oulu and Biocenter Oulu, Oulu, Finland. Electronic address: peter.wurtz@computationalmedicine.fi.
authors.forename: Peter
authors.initials: P
authors.lastname: Würtz
authors.affiliation: Computational Medicine, Institute of Health Sciences, University of Oulu and Biocenter Oulu, Oulu, Finland; NMR Metabolomics Laboratory, School of Pharmacy, University of Eastern Finland, Kuopio, Finland.
authors.forename: Qin
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Computational Medicine, Institute of Health Sciences, University of Oulu and Biocenter Oulu, Oulu, Finland; NMR Metabolomics Laboratory, School of Pharmacy, University of Eastern Finland, Kuopio, Finland.
authors.forename: Pasi
authors.initials: P
authors.lastname: Soininen
authors.affiliation: Computational Medicine, Institute of Health Sciences, University of Oulu and Biocenter Oulu, Oulu, Finland.
authors.forename: Antti J
authors.initials: AJ
authors.lastname: Kangas
authors.affiliation: Faculty of Epidemiology and Public Health, London School of Hygiene and Tropical Medicine, London, United Kingdom.
authors.forename: Ghazaleh
authors.initials: G
authors.lastname: Fatemifar
authors.affiliation: Computational Medicine, Institute of Health Sciences, University of Oulu and Biocenter Oulu, Oulu, Finland; NMR Metabolomics Laboratory, School of Pharmacy, University of Eastern Finland, Kuopio, Finland.
authors.forename: Tuulia
authors.initials: T
authors.lastname: Tynkkynen
authors.affiliation: Computational Medicine, Institute of Health Sciences, University of Oulu and Biocenter Oulu, Oulu, Finland; NMR Metabolomics Laboratory, School of Pharmacy, University of Eastern Finland, Kuopio, Finland.
authors.forename: Mika
authors.initials: M
authors.lastname: Tiainen
authors.affiliation: National Institute for Health and Welfare, Helsinki, Finland; Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland; University of Tartu, Estonian Genome Center, Tartu, Estonia.
authors.forename: Markus
authors.initials: M
authors.lastname: Perola
authors.affiliation: Institute of Cardiovascular Science, University College London, London, United Kingdom.
authors.forename: Therese
authors.initials: T
authors.lastname: Tillin
authors.affiliation: Institute of Cardiovascular Science, University College London, London, United Kingdom.
authors.forename: Alun D
authors.initials: AD
authors.lastname: Hughes
authors.affiliation: Primary Health Care, School of Medicine, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland.
authors.forename: Pekka
authors.initials: P
authors.lastname: Mäntyselkä
authors.affiliation: Department of Clinical Physiology, University of Tampere and Tampere University Hospital, Tampere, Finland.
authors.forename: Mika
authors.initials: M
authors.lastname: Kähönen
authors.affiliation: Department of Clinical Chemistry, Fimlab Laboratories, and School of Medicine, University of Tampere, Tampere, Finland.
authors.forename: Terho
authors.initials: T
authors.lastname: Lehtimäki
authors.affiliation: Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom.
authors.forename: Naveed
authors.initials: N
authors.lastname: Sattar
authors.affiliation: Institute of Cardiovascular Science, University College London, London, United Kingdom.
authors.forename: Aroon D
authors.initials: AD
authors.lastname: Hingorani
authors.affiliation: Faculty of Epidemiology and Public Health, London School of Hygiene and Tropical Medicine, London, United Kingdom; Institute of Cardiovascular Science, University College London, London, United Kingdom.
authors.forename: Juan-Pablo
authors.initials: JP
authors.lastname: Casas
authors.affiliation: National Institute for Health and Welfare, Helsinki, Finland.
authors.forename: Veikko
authors.initials: V
authors.lastname: Salomaa
authors.affiliation: Department of Epidemiology and Public Health, University College London, London, United Kingdom; Clinicum, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
authors.forename: Mika
authors.initials: M
authors.lastname: Kivimäki
authors.affiliation: Institute of Health Sciences and Biocenter Oulu, University of Oulu, Oulu, Helsinki, Finland; Department of Epidemiology and Biostatistics, MRC-PHE Centre for Environment and Health, Imperial College London, London, United Kingdom; Oulu University Hospital, Oulu, Finland.
authors.forename: Marjo-Riitta
authors.initials: MR
authors.lastname: Järvelin
authors.affiliation: Medical Research Council Integrative Epidemiology Unit at the University of Bristol, Bristol, United Kingdom; School of Social and Community Medicine, University of Bristol, Bristol, United Kingdom.
authors.forename: George
authors.initials: G
authors.lastname: Davey Smith
authors.affiliation: Primary Health Care, School of Medicine, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland; Primary Health Care, Central Finland Central Hospital, Jyväskylä, Finland.
authors.forename: Mauno
authors.initials: M
authors.lastname: Vanhala
authors.affiliation: Medical Research Council Integrative Epidemiology Unit at the University of Bristol, Bristol, United Kingdom; School of Social and Community Medicine, University of Bristol, Bristol, United Kingdom.
authors.forename: Debbie A
authors.initials: DA
authors.lastname: Lawlor
authors.affiliation: Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland; Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Turku, Finland.
authors.forename: Olli T
authors.initials: OT
authors.lastname: Raitakari
authors.affiliation: Institute of Cardiovascular Science, University College London, London, United Kingdom.
authors.forename: Nish
authors.initials: N
authors.lastname: Chaturvedi
authors.affiliation: Computational Medicine, Institute of Health Sciences, University of Oulu and Biocenter Oulu, Oulu, Finland; NMR Metabolomics Laboratory, School of Pharmacy, University of Eastern Finland, Kuopio, Finland.
authors.forename: Johannes
authors.initials: J
authors.lastname: Kettunen
authors.affiliation: Computational Medicine, Institute of Health Sciences, University of Oulu and Biocenter Oulu, Oulu, Finland; NMR Metabolomics Laboratory, School of Pharmacy, University of Eastern Finland, Kuopio, Finland; Oulu University Hospital, Oulu, Finland; Medical Research Council Integrative Epidemiology Unit at the University of Bristol, Bristol, United Kingdom; Computational Medicine, School of Social and Community Medicine, University of Bristol, Bristol, United Kingdom. Electronic address: mika.ala-korpela@computationalmedicine.fi.
authors.forename: Mika
authors.initials: M
authors.lastname: Ala-Korpela
mesh_terms: D000328:Adult; D002318:Cardiovascular Diseases / Q000097:blood / Q000235:genetics / Q000517:prevention & control*; D005260:Female; D005387:Finland; D005544:Forecasting; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases / Q000097:blood / Q000187:drug effects / Q000235:genetics*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use*; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D008297:Male; D057182:Mendelian Randomization Analysis / Q000379:methods*; D055432:Metabolomics / Q000379:methods*; D008875:Middle Aged; D012189:Retrospective Studies; D006113:United Kingdom
chemical_list: D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D006903:Hydroxymethylglutaryl CoA Reductases
keywords: Mendelian randomization; cholesterol lowering; drug development; lipoproteins; metabolomics