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Variation in PCSK9 and HMGCR and Risk of Cardiovascular Disease and Diabetes
Open accessAbstract
BACKGROUND: Pharmacologic inhibitors of proprotein convertase subtilisin-kexin type 9 (PCSK9) are being evaluated in clinical trials for the treatment of cardiovascular disease. The effect of lowering low-density lipoprotein (LDL) cholesterol levels by inhibiting PCSK9 on the risk of cardiovascular events or diabetes is unknown. METHODS: We used genetic scores consisting of independently inherited variants in the genes encoding PCSK9 and 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR; the target of statins) as instruments to randomly assign 112,772 participants from 14 studies, with 14,120 cardiovascular events and 10,635 cases of diabetes, to groups according to the number of LDL cholesterol-lowering alleles that they had inherited. We compared the effects of lower LDL cholesterol levels that were mediated by variants in PCSK9, HMGCR, or both on the risk of cardiovascular events and the risk of diabetes. RESULTS: Variants in PCSK9 and HMGCR were associated with nearly identical protective effects on the risk of cardiovascular events per decrease of 10 mg per deciliter (0.26 mmol per liter) in the LDL cholesterol level: odds ratio for cardiovascular events, 0.81 (95% confidence interval [CI], 0.74 to 0.89) for PCSK9 and 0.81 (95% CI, 0.72 to 0.90) for HMGCR. Variants in these two genes were also associated with very similar effects on the risk of diabetes: odds ratio for each 10 mg per deciliter decrease in LDL cholesterol, 1.11 (95% CI, 1.04 to 1.19) for PCSK9 and 1.13 (95% CI, 1.06 to 1.20) for HMGCR. The increased risk of diabetes was limited to persons with impaired fasting glucose levels for both scores and was lower in magnitude than the protective effect against cardiovascular events. When present together, PCSK9 and HMGCR variants had additive effects on the risk of both cardiovascular events and diabetes. CONCLUSIONS: In this study, variants in PCSK9 had approximately the same effect as variants in HMGCR on the risk of cardiovascular events and diabetes per unit decrease in the LDL cholesterol level. The effects of these variants were independent and additive. (Funded by the Medical Research Council and the National Heart, Lung, and Blood Institute.).
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“As an extension of MR, drug target MR has emerged as efficient way to estimate therapeutic potential by using genetic variants in genes encoding drug targets (referred to as cis variants) to mimic the actions of drugs.”
From Genetic insights into causal effects of lipids and lipid-modifying targets on calcific aortic valve stenosis: a Mendelian randomized study (2025) · cites this paper as [13]
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“Likewise, these observations are supported by data from a recent mendelian randomization study in which variants in PCSK9 and variants in HMGCR were associated with nearly identical lower risks of cardiovascular events per unit reduction in LDL cholesterol.29”
From Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease (2017) · cites this paper as [29]
In the citing paper
“mendelian randomisation studies 8,[19][20][21] of genetic polymorphisms that mimic the effects of statins, ezetimibe, or PCSK9 inhibitors suggest that lifelong reductions in LDL cholesterol, irrespective of the mechanism, are associated with an increased risk of diabetes.”
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“Mendelian randomisation analyses 8,20,21 have shown that genetically determined loss of function of PCSK9 is associated with an increased risk of incident diabetes, but clinical trials of PCSK9 inhibitors have shown no such effect.9”
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“Therefore, the clinical benefit of therapies that lower LDL-C by reducing LDL particle mass will be proportional to the absolute reduction in LDLC, because-on average-the reduction in LDL-C and LDL particles will be concordant [34,50,54,55].”
From 2019 ESC/EAS guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk (2019) · cites this paper as [54]
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Metadata
- Authors
- Ference, B. A., Robinson, J. G., Brook, R. D., Catapano, A. L., Chapman, M. J., Neff, D. R., Voros, S., Giugliano, R. P., Davey Smith, G., Fazio, S., & Sabatine, M. S.
- Affiliations
- University of Iowa (US)
- ORCID
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 2016-12
- Volume
- 375
- Issue
- 22
- Pages
- 2144-2153
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- OpenAlex
- W2557654447
- Cited by
- 743
- References
- 39
- Citations by year
- 2026: 38 · 2025: 55 · 2024: 77 · 2023: 64 · 2022: 74 · 2021: 76 · 2020: 75 · 2019: 86 · 2018: 97 · 2017: 92 · 2016: 8
- FWCI
- 104.43
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- New England Journal of Medicine (publishedVersion)
- PubMed (publishedVersion)
- Explore Bristol Research (submittedVersion, other-oa)
- Archivio Istituzionale della Ricerca (Universita Degli Studi Di Milano) (submittedVersion, other-oa)
- Bristol Research (University of Bristol) (submittedVersion, other-oa)
- Funders
- National Heart, Lung, and Blood Institute
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipoproteins and Cardiovascular Health
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Paraoxonase enzyme and polymorphisms
- Keywords
- PCSK9, HMGCR, LDL cholesterol, cardiovascular disease, diabetes mellitus, genetic variants, PCSK9 inhibitors, statins, genetic score, impaired fasting glucose, additive genetic effects, cardiovascular risk prediction, LDL-C lowering therapy, HMG-CoA reductase inhibition, cardiovascular events, diabetes risk
- MeSH terms
- Proprotein Convertase 9, Cardiovascular Diseases, Diabetes Mellitus, Female, Humans, Hydroxymethylglutaryl CoA Reductases, Cholesterol, LDL, Male, Middle Aged, Random Allocation, Risk, Genetic Variation, Genetic Predisposition to Disease
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