The DOI matches its Crossref record; 43 of the 44 references it cites were found in a registry or an index.
Effect of Long-Term Exposure to Lower Low-Density Lipoprotein Cholesterol Beginning Early in Life on the Risk of Coronary Heart Disease
Open accessAbstract
Objectives The purpose of this study was to estimate the effect of long-term exposure to lower plasma low-density lipoprotein cholesterol (LDL-C) on the risk of coronary heart disease (CHD).Background LDL-C is causally related to the risk of CHD. However, the association between long-term exposure to lower LDL-C beginning early in life and the risk of CHD has not been reliably quantified.Methods We conducted a series of meta-analyses to estimate the effect of long-term exposure to lower LDL-C on the risk of CHD mediated by 9 polymorphisms in 6 different genes. We then combined these Mendelian randomization studies in a meta-analysis to obtain a more precise estimate of the effect of long-term exposure to lower LDL-C and compared it with the clinical benefit associated with the same magnitude of LDL-C reduction during treatment with a statin.Results All 9 polymorphisms were associated with a highly consistent reduction in the risk of CHD per unit lower LDL-C, with no evidence of heterogeneity of effect (I(2) = 0.0%). In a meta-analysis combining nonoverlapping data from 312,321 participants, naturally random allocation to long-term exposure to lower LDL-C was associated with a 54.5% (95% confidence interval: 48.8% to 59.5%) reduction in the risk of CHD for each mmol/l (38.7 mg/dl) lower LDL-C. This represents a 3-fold greater reduction in the risk of CHD per unit lower LDL-C than that observed during treatment with a statin started later in life (p = 8.43 × 10(-19)).Conclusions Prolonged exposure to lower LDL-C beginning early in life is associated with a substantially greater reduction in the risk of CHD than the current practice of lowering LDL-C beginning later in life.
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In the citing paper
“Second, genetic variants reflect the effect of lifelong changes in ApoB-containing lipoproteins on the risk of cardiovascular disease, which appear to be cumulative over time.5,34”
From Association of Triglyceride-Lowering LPL Variants and LDL-C–Lowering LDLR Variants With Risk of Coronary Heart Disease (2019) · cites this paper as [34]
Experimental — accuracy not yet measuredIn the citing paper
“Numerous epidemiological studies, Mendelian randomization studies, and RCTs have consistently demonstrated a log-linear relationship between the absolute changes in plasma LDL-C and the risk of ASCVD [34,45-50].”
From 2019 ESC/EAS guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk (2019) · cites this paper as [47]
In the citing paper
“Additionally, increasing evidence also suggests that the duration of exposure to low LDL-C levels may be as important as the magnitude of LDL-C lowering [11][12][13][14][15][16].”
In the citing paper
“A large meta-analysis by Ference et al. has demonstrated that prolonged exposure to lower LDL-C levels beginning at a young age is associated with a substantially greater reduction in the risk of CVD than the current practice of lowering LDL-C levels later in life [13].”
In the citing paper
“It was found that lifelong exposure to low LDL-C levels as a result of these gene polymorphisms was associated with three-fold greater reduction in the risk of CVD per unit lower LDL-C level than that observed during treatment with a statin started later in life.”
In the citing paper
“The long-term follow-up of large clinical trials of statins that were conducted in the 1990s, such as the West of Scotland Coronary Prevention Study (WOSCOPS) and the Heart Protection Study (HPS)628, 629) confirmed that early initiation of LDLC-lowering therapy regardless of the plasma LDL-C level was useful for the long-term prevention of cardiovascular events and all-cause mortality in high-risk”
From Japan Atherosclerosis Society (JAS) guidelines for prevention of atherosclerotic cardiovascular diseases 2017 (2018) · cites this paper as [628]
In the citing paper
“No increases in new-incidence cancer or non-CVD deaths were observed, which reconfirms the safety of long-term LDL-C-lowering therapy using statins.”
From Japan Atherosclerosis Society (JAS) guidelines for prevention of atherosclerotic cardiovascular diseases 2017 (2018) · cites this paper as [628]
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Citations
Cites
Quantifying heterogeneity in a meta‐analysis
Higgins, J. P. T., & Thompson, S. G. (2002) · Statistics in Medicine · doi:10.1002/sim.1186 · Cited by 36,763
Cholesterol Treatment Trialists' (CTT) Collaboration (2010) · The Lancet · doi:10.1016/s0140-6736(10)61350-5 · Cited by 6,550
Mendelian randomization: Using genes as instruments for making causal inferences in epidemiology
Lawlor, D. A., Harbord, R. M., Sterne, J. A. C., Timpson, N., & Davey Smith, G. (2008) · Statistics in Medicine · doi:10.1002/sim.3034 · Cited by 4,618
Biological, clinical and population relevance of 95 loci for blood lipids
Teslovich, T. M., Musunuru, K., Smith, A. V., Edmondson, A. C., Stylianou, I. M., Koseki, M., Pirruccello, J. P., Ripatti, S., Chasman, D. I., Willer, C. J., et al. (2010) · Nature · doi:10.1038/nature09270 · Cited by 3,487
Sequence Variations in PCSK9, Low LDL, and Protection against Coronary Heart Disease
Cohen, J. C., Boerwinkle, E., Mosley, T. H., & Hobbs, H. H. (2006) · New England Journal of Medicine · doi:10.1056/nejmoa054013 · Cited by 3,181
Major lipids, apolipoproteins, and risk of vascular disease
The Emerging Risk Factors Collaboration* (2009) · JAMA · doi:10.1001/jama.2009.1619 · Cited by 2,731
Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk
The International Consortium for Blood Pressure Genome-Wide Association Studies (2011) · Nature · doi:10.1038/nature10405 · Cited by 2,033
Large-scale association analysis identifies 13 new susceptibility loci for coronary artery disease
Cardiogenics, Schunkert, H., the CARDIoGRAM Consortium, König, I. R., Kathiresan, S., Reilly, M. P., Assimes, T. L., Holm, H., Preuss, M., Stewart, A. F. R., et al. (2011) · Nature Genetics · doi:10.1038/ng.784 · Cited by 1,866
Newly identified loci that influence lipid concentrations and risk of coronary artery disease
Willer, C. J., Sanna, S., Jackson, A. U., Scuteri, A., Bonnycastle, L. L., Clarke, R., Heath, S. C., Timpson, N. J., Najjar, S. S., Stringham, H. M., et al. (2008) · Nature Genetics · doi:10.1038/ng.76 · Cited by 1,585
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1 of the 44 references couldn’t be matched to a known paper.
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Mendelian randomization: genetic anchors for causal inference in epidemiological studies
Davey Smith, G., & Hemani, G. (2014) · Human Molecular Genetics · doi:10.1093/hmg/ddu328 · Cited by 4,677
Mach, F., Baigent, C., Catapano, A. L., Koskinas, K. C., Casula, M., Badimon, L., Chapman, M. J., De Backer, G. G., Delgado, V., Ference, B. A., et al. (2019) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2019.08.014 · Cited by 4,854
Self-citationReading Mendelian randomisation studies: a guide, glossary, and checklist for clinicians
Davies, N. M., Holmes, M. V., & Davey Smith, G. (2018) · BMJ · doi:10.1136/bmj.k601 · Cited by 4,404
Ference, B. A., Ginsberg, H. N., Graham, I., Ray, K. K., Packard, C. J., Bruckert, E., Hegele, R. A., Krauss, R. M., Raal, F. J., Schunkert, H., et al. (2017) · European Heart Journal · doi:10.1093/eurheartj/ehx144 · Cited by 3,962
Self-citationIntegration of summary data from GWAS and eQTL studies predicts complex trait gene targets
Zhu, Z., Zhang, F., Hu, H., Bakshi, A., Robinson, M. R., Powell, J. E., Montgomery, G. W., Goddard, M. E., Wray, N. R., Visscher, P. M., et al. (2016) · Nature Genetics · doi:10.1038/ng.3538 · Cited by 3,352
Metadata
- Authors
- Ference, B. A., Yoo, W., Alesh, I., Mahajan, N., Mirowska, K. K., Mewada, A., Kahn, J., Afonso, L., Williams, K. A., & Flack, J. M.
- Affiliations
- Wayne State University (US)
- University of Tennessee Health Science Center (US)
- Detroit Medical Center (US)
- Corresponding author
- Ference, Brian A.
- Venue
- Journal of the American College of Cardiology
- Publisher
- Elsevier BV
- Published
- 2012-12
- Volume
- 60
- Issue
- 25
- Pages
- 2631-2639
- ISSN
- 0735-1097 (ISSN-L)
- OpenAlex
- W72392028
- Cited by
- 898
- References
- 44
- Citations by year
- 2026: 69 · 2025: 61 · 2024: 65 · 2023: 80 · 2022: 64 · 2021: 69 · 2020: 81 · 2019: 74 · 2018: 55 · 2017: 48 · 2016: 82 · 2015: 67 · 2014: 41 · 2013: 37 · 2012: 2
- FWCI
- 47.88
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Journal of the American College of Cardiology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Novartis
- Medtronic
- NIH
- 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
- LDL cholesterol, coronary heart disease risk, genetic polymorphism, Mendelian randomization, statin therapy, LDL cholesterol lowering, cardiovascular risk reduction
- MeSH terms
- Coronary Artery Disease, Follow-Up Studies, Genetic Markers, Humans, Cholesterol, LDL, Polymorphism, Genetic, Risk Factors, Time Factors, Global Health, Incidence, Risk Assessment, Genetic Predisposition to Disease, Mendelian Randomization Analysis
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