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Association of Genetic Variants Related to CETP Inhibitors and Statins With Lipoprotein Levels and Cardiovascular Risk
Open accessAbstract
Importance: Some cholesteryl ester transfer protein (CETP) inhibitors lower low-density lipoprotein cholesterol (LDL-C) levels without reducing cardiovascular events, suggesting that the clinical benefit of lowering LDL-C may depend on how LDL-C is lowered. Objective: To estimate the association between changes in levels of LDL-C (and other lipoproteins) and the risk of cardiovascular events related to variants in the CETP gene, both alone and in combination with variants in the 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) gene. Design, Setting, and Participants: Mendelian randomization analyses evaluating the association between CETP and HMGCR scores, changes in lipid and lipoprotein levels, and the risk of cardiovascular events involving 102 837 participants from 14 cohort or case-control studies conducted in North America or the United Kingdom between 1948 and 2012. The associations with cardiovascular events were externally validated in 189 539 participants from 48 studies conducted between 2011 and 2015. Exposures: Differences in mean high-density lipoprotein cholesterol (HDL-C), LDL-C, and apolipoprotein B (apoB) levels in participants with CETP scores at or above vs below the median. Main Outcomes and Measures: Odds ratio (OR) for major cardiovascular events. Results: The primary analysis included 102 837 participants (mean age, 59.9 years; 58% women) who experienced 13 821 major cardiovascular events. The validation analyses included 189 539 participants (mean age, 58.5 years; 39% women) with 62 240 cases of coronary heart disease (CHD). Considered alone, the CETP score was associated with higher levels of HDL-C, lower LDL-C, concordantly lower apoB, and a corresponding lower risk of major vascular events (OR, 0.946 [95% CI, 0.921-0.972]) that was similar in magnitude to the association between the HMGCR score and risk of major cardiovascular events per unit change in levels of LDL-C (and apoB). When combined with the HMGCR score, the CETP score was associated with the same reduction in LDL-C levels but an attenuated reduction in apoB levels and a corresponding attenuated nonsignificant risk of major cardiovascular events (OR, 0.985 [95% CI, 0.955-1.015]). In external validation analyses, a genetic score consisting of variants with naturally occurring discordance between levels of LDL-C and apoB was associated with a similar risk of CHD per unit change in apoB level (OR, 0.782 [95% CI, 0.720-0.845] vs 0.793 [95% CI, 0.774-0.812]; P = .79 for difference), but a significantly attenuated risk of CHD per unit change in LDL-C level (OR, 0.916 [95% CI, 0.890-0.943] vs 0.831 [95% CI, 0.816-0.847]; P < .001) compared with a genetic score associated with concordant changes in levels of LDL-C and apoB. Conclusions and Relevance: Combined exposure to variants in the genes that encode the targets of CETP inhibitors and statins was associated with discordant reductions in LDL-C and apoB levels and a corresponding risk of cardiovascular events that was proportional to the attenuated reduction in apoB but significantly less than expected per unit change in LDL-C. The clinical benefit of lowering LDL-C levels may therefore depend on the corresponding reduction in apoB-containing lipoprotein particles.
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“Furthermore, Mendelian randomization studies demonstrated that the reduction in cardiovascular risk associated with genetic variation in clearance and processing of apoB-containing lipoproteins, including LDL particles as well as TG-rich VLDL particles and their remnants, was correlated with the change of concentration of these particles as measured by apoB rather than the cholesterol mass carried”
From Quantifying atherogenic lipoproteins for lipid-lowering strategies: Consensus-based recommendations from EAS and EFLM (2020) · cites this paper as [79]
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“Furthermore, the results of this study are consistent with a recent mendelian randomization study that demonstrated that the causal effect of LDL particles on the risk of cardiovascular disease appears to be determined by the concentration of circulating LDL particles as measured by ApoB rather than by the mass of cholesterol carried by those particles as measured by LDL-C.23”
From Association of Triglyceride-Lowering LPL Variants and LDL-C–Lowering LDLR Variants With Risk of Coronary Heart Disease (2019) · cites this paper as [23]
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“Fibrates are associated with a slightly increased risk of pancreatitis [321].”
From 2019 ESC/EAS guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk (2019) · cites this paper as [321]
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Metadata
- Authors
- Ference, B. A., Kastelein, J. J. P., Ginsberg, H. N., Chapman, M. J., Nicholls, S. J., Ray, K. K., Packard, C. J., Laufs, U., Brook, R. D., Oliver-Williams, C., Butterworth, A. S., Danesh, J., Smith, G. D., Catapano, A. L., & Sabatine, M. S.
- Affiliations
- Wayne State University (US)
- Amsterdam UMC Location University of Amsterdam (NL)
- Columbia University Irving Medical Center (US)
- Inserm (FR)
- South Australian Health and Medical Research Institute (AU)
- Imperial College London (GB)
- University of Glasgow (GB)
- Leipzig University (DE)
- University of Michigan (US)
- MRC/BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom
- University of Cambridge (GB)
- University of Bristol (GB)
- University of Milan (IT)
- Brigham and Women's Hospital (US)
- Corresponding author
- Ference, Brian A.
- ORCID
- Venue
- JAMA
- Publisher
- American Medical Association (AMA)
- Published
- 2017-09-12
- Volume
- 318
- Issue
- 10
- Pages
- 947
- ISSN
- 0002-9955 (ISSN-L)
- 0098-7484
- PMC
- PMC5710502
- OpenAlex
- W2749237115
- Cited by
- 304
- References
- 34
- Citations by year
- 2026: 13 · 2025: 23 · 2024: 23 · 2023: 34 · 2022: 28 · 2021: 41 · 2020: 43 · 2019: 46 · 2018: 37 · 2017: 15
- FWCI
- 39.51
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- JAMA (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Pure Amsterdam UMC (publishedVersion, other-oa)
- Apollo (University of Cambridge) (submittedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- ENLIGHTEN (Jurnal Bimbingan dan Konseling Islam) (submittedVersion)
- Bristol Research (University of Bristol) (submittedVersion, other-oa)
- Apollo
- Funders
- Amgen
- Eli Lilly and Company
- Pfizer
- AstraZeneca
- GlaxoSmithKline
- Sanofi
- Biogen
- NHS Blood and Transplant
- Regeneron Pharmaceuticals
- Wellcome Trust
- National Institute for Health and Care Research (NF-SI-0512-10165, MC_UU_12013/1)
- British Heart Foundation (CH/12/2/29428, RG/13/13/30194, RG/16/4/32218, RG/08/014/24067)
- Bupa Foundation
- European Commission (279143, 279233)
- University of Bristol (MC_UU_12013/1)
- Cambridge University Hospitals (3819-1516-29, BRC 2012-2017, 3819-1617-25, 146281)
- Evelyn Trust
- Medical Research Council (MC_UU_12013, MR/L003120/1, MR/M012816/1, MCUU12013/1, MR/P013880/1)
- Homerton College, University of Cambridge
- National Heart, Lung, and Blood Institute
- Fogarty International Center
- 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
- cholesteryl ester transfer protein, statins, CETP inhibitors, LDL cholesterol, HDL cholesterol, apolipoprotein B, lipoprotein levels, cardiovascular risk, coronary artery disease, major adverse cardiovascular events, lipid-lowering therapy, Mendelian randomization
- MeSH terms
- Anticholesteremic Agents, Apolipoproteins B, Cardiovascular Diseases, Female, Humans, Hydroxymethylglutaryl CoA Reductases, Hypercholesterolemia, Cholesterol, HDL, Cholesterol, LDL, Male, Middle Aged, Risk Factors, Genetic Variation, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Cholesterol Ester Transfer Proteins, Mendelian Randomization Analysis
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