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

Peter Würtz; Qin Wang; Pasi Soininen; Antti J. Kangas; Ghazaleh Fatemifar; Tuulia Tynkkynen; Mika Tiainen; Markus Perola; Therese Tillin; Alun D. Hughes; Pekka Mäntyselkä; Mika Kähönen; Terho Lehtimäki; Naveed Sattar; Aroon D. Hingorani; Juan-Pablo Casas; Veikko Salomaa; Mika Kivimäki; Marjo-Riitta Järvelin; George Davey Smith; Mauno Vanhala; Debbie A. Lawlor; Olli T. Raitakari; Nish Chaturvedi; Johannes Kettunen; Mika J Ala-Korpela

doi:10.1016/j.jacc.2015.12.060

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

Peter Würtz, Qin Wang, Pasi Soininen, Antti J. Kangas, Ghazaleh Fatemifar, Tuulia Tynkkynen, Mika Tiainen, Markus Perola, Therese Tillin, Alun D. Hughes, Pekka Mäntyselkä, Mika Kähönen, Terho Lehtimäki, Naveed Sattar, Aroon D. Hingorani, Juan-Pablo Casas, Veikko Salomaa, Mika Kivimäki, Marjo-Riitta Järvelin, George Davey SmithMauno Vanhala, Debbie A. Lawlor, Olli T. Raitakari, Nish Chaturvedi, Johannes Kettunen, Mika J Ala-Korpela

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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 (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.

Original language	English
Pages (from-to)	1200-1210
Number of pages	11
Journal	Journal of the American College of Cardiology
Volume	67
Issue number	10
Early online date	7 Mar 2016
DOIs	https://doi.org/10.1016/j.jacc.2015.12.060
Publication status	Published - 15 Mar 2016

Keywords

cholesterol lowering
drug development
lipoproteins
Mendelian randomization
metabolomics

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.jacc.2015.12.060

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MRC UoB UNITE Unit - Programme 1
Davey Smith, G. (Principal Investigator)
1/06/13 → 31/03/18
Project: Research
MRC UoB UNITE Unit - Programme 5
Lawlor, D. A. (Principal Investigator) & Lawlor, D. A. (Principal Investigator)
1/06/13 → 31/03/18
Project: Research
NIHR Senior Investigator
Lawlor, D. A. (Principal Investigator)
1/04/12 → 31/03/17
Project: Research

Cite this

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., ... Ala-Korpela, M. J. (2016). Metabolomic Profiling of Statin Use and Genetic Inhibition of HMG-CoA Reductase. Journal of the American College of Cardiology, 67(10), 1200-1210. https://doi.org/10.1016/j.jacc.2015.12.060

@article{d39c6ef2109b41e3bbee20b53cf48d8f,

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. 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.",

keywords = "cholesterol lowering, drug development, lipoproteins, Mendelian randomization, metabolomics",

author = "Peter W{\"u}rtz and Qin Wang and Pasi Soininen and Kangas, {Antti J.} and Ghazaleh Fatemifar and Tuulia Tynkkynen and Mika Tiainen and Markus Perola and Therese Tillin and Hughes, {Alun D.} and Pekka M{\"a}ntyselk{\"a} and Mika K{\"a}h{\"o}nen and Terho Lehtim{\"a}ki and Naveed Sattar and Hingorani, {Aroon D.} and Juan-Pablo Casas and Veikko Salomaa and Mika Kivim{\"a}ki and Marjo-Riitta J{\"a}rvelin and {Davey Smith}, George and Mauno Vanhala and Lawlor, {Debbie A.} and Raitakari, {Olli T.} and Nish Chaturvedi and Johannes Kettunen and Ala-Korpela, {Mika J}",

year = "2016",

month = mar,

day = "15",

doi = "10.1016/j.jacc.2015.12.060",

language = "English",

volume = "67",

pages = "1200--1210",

journal = "Journal of the American College of Cardiology",

issn = "0735-1097",

publisher = "Elsevier Inc.",

number = "10",

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Würtz, P, Wang, Q, Soininen, P, Kangas, AJ, Fatemifar, G, Tynkkynen, T, Tiainen, M, Perola, M, Tillin, T, Hughes, AD, Mäntyselkä, P, Kähönen, M, Lehtimäki, T, Sattar, N, Hingorani, AD, Casas, J-P, Salomaa, V, Kivimäki, M, Järvelin, M-R, Davey Smith, G, Vanhala, M, Lawlor, DA, Raitakari, OT, Chaturvedi, N, Kettunen, J & Ala-Korpela, MJ 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

TY - JOUR

T1 - Metabolomic Profiling of Statin Use and Genetic Inhibition of HMG-CoA Reductase

AU - Würtz, Peter

AU - Wang, Qin

AU - Soininen, Pasi

AU - Kangas, Antti J.

AU - Fatemifar, Ghazaleh

AU - Tynkkynen, Tuulia

AU - Tiainen, Mika

AU - Perola, Markus

AU - Tillin, Therese

AU - Hughes, Alun D.

AU - Mäntyselkä, Pekka

AU - Kähönen, Mika

AU - Lehtimäki, Terho

AU - Sattar, Naveed

AU - Hingorani, Aroon D.

AU - Casas, Juan-Pablo

AU - Salomaa, Veikko

AU - Kivimäki, Mika

AU - Järvelin, Marjo-Riitta

AU - Davey Smith, George

AU - Vanhala, Mauno

AU - Lawlor, Debbie A.

AU - Raitakari, Olli T.

AU - Chaturvedi, Nish

AU - Kettunen, Johannes

AU - Ala-Korpela, Mika J

PY - 2016/3/15

Y1 - 2016/3/15

N2 - 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.

AB - 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.

KW - cholesterol lowering

KW - drug development

KW - lipoproteins

KW - Mendelian randomization

KW - metabolomics

U2 - 10.1016/j.jacc.2015.12.060

DO - 10.1016/j.jacc.2015.12.060

M3 - Article (Academic Journal)

C2 - 26965542

SN - 0735-1097

VL - 67

SP - 1200

EP - 1210

JO - Journal of the American College of Cardiology

JF - Journal of the American College of Cardiology

IS - 10

ER -

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

Abstract

Keywords

UN SDGs

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Projects

MRC UoB UNITE Unit - Programme 1

MRC UoB UNITE Unit - Programme 5

NIHR Senior Investigator

Cite this