Effect of Naturally Random Allocation to Lower Low-Density Lipoprotein Cholesterol on the Risk of Coronary Heart Disease Mediated by Polymorphisms in NPC1L1, HMGCR, or Both
Open accessAbstract
Background Considerable uncertainty exists as to whether lowering low-density lipoprotein cholesterol (LDL-C) by inhibiting the Niemann-Pick C1-Like 1 (NPC1L1) receptor with ezetimibe, either alone or in combination with a 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) inhibitor (statin), will reduce the risk of coronary heart disease (CHD).Objectives This study evaluated the effect of naturally random allocation to lower LDL-C mediated by polymorphisms in the NPC1L1 gene (target of ezetimibe), the HMGCR gene (target of statins), or both (target of combination therapy) on the risk of CHD.Methods We constructed NPC1L1 and HMGCR genetic LDL-C scores to naturally randomize participants into 4 groups: reference, lower LDL-C mediated by NPC1L1 polymorphisms, lower LDL-C mediated by HMGCR polymorphisms, or lower LDL-C mediated by polymorphisms in both NPC1L1 and HMGCR. We compared the risk of CHD (fatal or nonfatal myocardial infarction) among each group using a 2 × 2 factorial mendelian randomization study design.Results A total of 108,376 persons (10,464 CHD events) from 14 studies were included. There were no significant differences in baseline characteristics among the 4 groups, thus confirming that allocation was random. Compared to the reference group, the NPC1L1 group had 2.4 mg/dl lower LDL-C and 4.8% lower risk of CHD (odds ratio [OR]: 0.952, 95% confidence interval [CI]: 0.920 to 0.985); whereas the HMGCR group had 2.9 mg/dl lower LDL-C and a similar 5.3% lower risk of CHD (OR: 0.947, 95% CI: 0.909 to 0.986). The group with lower LDL-C mediated by both NPC1L1 and HMGCR polymorphisms had 5.8 mg/dl additively lower LDL-C and a 10.8% log-linearly additive lower risk of CHD (OR: 0.892, 95% CI: 0.854 to 0.932).Conclusions The effect of lower LDL-C on the risk of CHD mediated by polymorphisms in NPC1L1, HMGCR, or both is approximately the same per unit lower LDL-C and log-linearly proportional to the absolute exposure to lower LDL-C.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Genetic association and Mendelian randomization studies demonstrate similarly lower rates of cardiovascular outcomes per unit lower LDL-C in patients with loss-of-function variants in NPC1L1 and HMG-CoA reductase.
“These results are also supported by genetic association and Mendelian randomization studies demonstrating similarly lower rates of cardiovascular outcomes per unit lower LDL-C in patients with loss-of-function variants in the Niemann-Pick C1-Like1 protein (the target of ezetimibe) and in HMG-CoA reductase (the target of statins).62,63”
From Association Between Lowering LDL-C and Cardiovascular Risk Reduction Among Different Therapeutic Interventions: A Systematic Review and Meta-analysis (2016) · cites this paper as [62]
The Results (External Validation Analyses; page not available) report similar reductions in coronary heart disease risk per 10 mg/dl lower LDL-C mediated by NPC1L1 and HMGCR polymorphisms. But the Methods describe genetic scores based on selected polymorphisms, not loss-of-function variants in both genes. The Discussion mentions rare NPC1L1 loss-of-function mutations as a separate validation finding; it does not establish the claimed comparison for loss-of-function variants in both genes. (LLM, conf=0.88)
Experimental — accuracy not yet measuredHuman genetic analyses of variants associated with low LDL-C, increased LDL receptors, and decreased coronary heart disease support the concept.
“This concept is further supported by human genetic analyses of variants that have been associated with low LDL-C, increased LDL receptors, and decreased coronary heart disease.58,62,63,65”
From Association Between Lowering LDL-C and Cardiovascular Risk Reduction Among Different Therapeutic Interventions: A Systematic Review and Meta-analysis (2016) · cites this paper as [62]
The Results (External Validation Analyses; page not provided) associate LDL-C-lowering polymorphisms with lower coronary heart disease risk and describe the hepatic LDL-C receptor as a common final pathway. The paper discusses receptor up-regulation by ezetimibe and statins, but does not establish that the studied variants themselves are associated with increased LDL receptors. (LLM, conf=0.84)
Experimental — accuracy not yet measuredTriglyceride-lowering lipoprotein lipase variants and LDL-C-lowering LDL receptor variants have the same effect on atherosclerotic cardiovascular disease risk per unit change in ApoB, suggesting all ApoB-containing lipoproteins have the same effect on coronary heart disease risk.
“A recent Mendelian randomization study demonstrated that TG-lowering lipoprotein lipase (LPL) variants and LDL-C-lowering LDL receptor variants had the same effect on the risk of ASCVD per unit change of ApoB, suggesting that all ApoB-containing lipoproteins have the same effect on the risk of CHD [53].”
From 2019 ESC/EAS guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk (2019) · cites this paper as [53]
The clinical benefit of lowering LDL-C is determined by the reduction in circulating LDL particles as estimated by ApoB, usually mirrored by a reduction in cholesterol carried by those particles.
“The clinical benefit of lowering LDL-C is determined by the reduction in circulating LDL particles as estimated by ApoB, which is usually mirrored by a reduction of cholesterol carried by those particles [2,53].”
From 2019 ESC/EAS guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk (2019) · cites this paper as [53]
Clinical benefit of therapies that lower LDL-C by dramatically modifying particle composition may not be proportional to observed absolute LDL-C reduction, but is expected to be proportional to absolute change in LDL particle concentration as measured by ApoB reduction.
“In contrast, the clinical benefit of therapies that lower LDL-C by a mechanism that may dramatically modify their composition may not be proportional to the observed absolute reduction in LDL-C, but instead would be expected to be proportional to the absolute change in LDL particle concentration as measured by a reduction in ApoB [2,53].”
From 2019 ESC/EAS guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk (2019) · cites this paper as [53]
CETP variants associate with risk of CHD; APOA1 variants do not associate with risk of CHD.
“CETP 23 variants associate with of CHD; APOA1 117 variants do not associate with risk of CHD”
From Integrating genomics with biomarkers and therapeutic targets to invigorate cardiovascular drug development (2021) · cites this paper as [117]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
The citation lists haven’t been fetched yet
References 22 · Cited by 407
- Authors
- Ference, B. A., Majeed, F., Penumetcha, R., Flack, J. M., & Brook, R. D.
- Affiliations
- Wayne State University (US)
- University of Michigan (US)
- Corresponding author
- Ference, Brian A.
- Venue
- Journal of the American College of Cardiology
- Publisher
- Elsevier BV
- Published
- 2015-04
- Volume
- 65
- Issue
- 15
- Pages
- 1552-1561
- ISSN
- 0735-1097 (ISSN-L)
- PMC
- PMC6101243
- OpenAlex
- W65262745
- Cited by
- 407
- References
- 22
- Citations by year
- 2026: 18 · 2025: 34 · 2024: 44 · 2023: 37 · 2022: 16 · 2021: 46 · 2020: 28 · 2019: 40 · 2018: 32 · 2017: 33 · 2016: 48 · 2015: 31
- FWCI
- 48.33
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of the American College of Cardiology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Human Genome Research Institute (U01HG005157)
- Topics
- Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Keywords
- coronary artery disease, LDL cholesterol lowering, ezetimibe, statins, NPC1L1, HMGCR, genetic polymorphism, myocardial infarction, combination therapy, lipid-lowering therapy
- MeSH terms
- Coronary Disease, Female, Humans, Hydroxymethylglutaryl CoA Reductases, Cholesterol, LDL, Male, Membrane Proteins, Middle Aged, Polymorphism, Genetic, Risk Assessment, Genetic Predisposition to Disease, Membrane Transport Proteins, Mendelian Randomization Analysis
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
