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Sequence Variations in PCSK9, Low LDL, and Protection against Coronary Heart Disease
Open accessAbstract
BACKGROUND: A low plasma level of low-density lipoprotein (LDL) cholesterol is associated with reduced risk of coronary heart disease (CHD), but the effect of lifelong reductions in plasma LDL cholesterol is not known. We examined the effect of DNA-sequence variations that reduce plasma levels of LDL cholesterol on the incidence of coronary events in a large population. METHODS: We compared the incidence of CHD (myocardial infarction, fatal CHD, or coronary revascularization) over a 15-year interval in the Atherosclerosis Risk in Communities study according to the presence or absence of sequence variants in the proprotein convertase subtilisin/kexin type 9 serine protease gene (PCSK9) that are associated with reduced plasma levels of LDL cholesterol. RESULTS: Of the 3363 black subjects examined, 2.6 percent had nonsense mutations in PCSK9; these mutations were associated with a 28 percent reduction in mean LDL cholesterol and an 88 percent reduction in the risk of CHD (P=0.008 for the reduction; hazard ratio, 0.11; 95 percent confidence interval, 0.02 to 0.81; P=0.03). Of the 9524 white subjects examined, 3.2 percent had a sequence variation in PCSK9 that was associated with a 15 percent reduction in LDL cholesterol and a 47 percent reduction in the risk of CHD (hazard ratio, 0.50; 95 percent confidence interval, 0.32 to 0.79; P=0.003). CONCLUSIONS: These data indicate that moderate lifelong reduction in the plasma level of LDL cholesterol is associated with a substantial reduction in the incidence of coronary events, even in populations with a high prevalence of non-lipid-related cardiovascular risk factors.
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In the citing paper
“Proprotein convertase subtilisin-kexin type 9 (PCSK9) promotes degradation of LDL receptors, thereby diminishing the clearance of LDL from the circulation. 6”
From Alirocumab and Cardiovascular Outcomes after Acute Coronary Syndrome (2018) · cites this paper as [6]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“In 2005, a causative association was established between the presence of loss-of-function mutations in PCSK9 and lifelong reductions in LDL-C associated with lower CHD risk (3).”
From PCSK9 and the nervous system: a no-brainer? (2023) · cites this paper as [3]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Genetic studies have shown that carriage of PCSK9 loss-of-function alleles is associated with lower LDL cholesterol levels and a reduced risk of myocardial infarction.7,8”
From Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease (2017) · cites this paper as [7]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“These data suggest that drugs that ultimately reduce LDL-C level predominantly through upregulation of LDL receptor expression should, barring any off-target adverse effects, lead to clinical benefit in proportion to the degree of LDL-C reduction.64”
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 [64]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Some of the most important human metabolic disease genes have been identified using germline genetic methods such as GWAS and whole exome sequencing42-44.”
From Positive selection of somatically mutated clones identifies adaptive pathways in metabolic liver disease (2023) · cites this paper as [44]
Experimental — accuracy not yet measured
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In the citing paper
“Unlike gain-of-function PCSK9 variants (7), loss-of-function (LOF) variants enhance LDLR levels and promote LDLc clearance (4, 8).”
From Asialoglycoprotein receptor 1 is a novel PCSK9-independent ligand of liver LDLR cleaved by furin (2021) · cites this paper as [8]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“mutations conveying gain or loss of function of PCSK9 result in a higher or lower level of LDL cholesterol, respectively, which in turn is associated with a corresponding higher 7 or lower 6 risk of incident coronary heart disease.”
From Alirocumab and Cardiovascular Outcomes after Acute Coronary Syndrome (2018) · cites this paper as [6]
The cited source says what the claim attributes to it.
In the citing paper
“Whereas PCSK9 loss-of-function mutations carriers with lifelong reductions in LDL-C and coronary heart disease incidence, were not initially found at significantly reduced risk of stroke (3, 72), a much larger study of the UK Biobank database described the first genetic evidence of a protective effect of the R46L loss-of-function mutation on PCSK9 on ischemic stroke (73).”
From PCSK9 and the nervous system: a no-brainer? (2023) · cites this paper as [3]
In the citing paper
“and that lowering LDL-C reduces the risk of ASCVD proportionally to the absolute achieved reduction in LDL-C [2,51].”
From 2019 ESC/EAS guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk (2019) · cites this paper as [51]
In the citing paper
“The remarkable consistency among these studies, in addition to biological and experimental evidence, provides compelling evidence that LDL-C is causally associated with the risk of ASCVD”
From 2019 ESC/EAS guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk (2019) · cites this paper as [51]
In the citing paper
“Both studies had relatively short follow-up periods and the evidence from statin trials indicates that the clinical benefits of LDL-lowering may only emerge after about 1 year [51], so these trials may have underestimated the potential impact of longer-term treatment [120,290].”
From 2019 ESC/EAS guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk (2019) · cites this paper as [51]
In the citing paper
“These developments have enabled researchers to bridge the gap between the monogenic and polygenic realms, identifying common variant modifiers of monogenic phenotypes contributing to the variable expression of rare, large-effect alleles26,93, and low-frequency and rare variants that influence common multifactorial traits94,95.”
From A brief history of human disease genetics (2020) · cites this paper as [95]
In the citing paper
“At the same time, it has become increasingly evident now that not only the magnitude of LDL-C lowering is important but that the duration of exposure to elevated LDL-C levels is equally important [11,16,38].”
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
“The exceptionally low rates of CV events observed in patients carrying mutations in PCSK9 or other similar genes despite only modestly low LDL-C levels strongly support this notion [11].”
In the citing paper
“Hobbs and Cohen sequenced the gene (126, 127) and identified low-frequency common variants (0.5 to 1%), which allowed epidemiological research documenting a protective effect on myocardial infarction (128).”
From Genetic Mapping in Human Disease (2008) · cites this paper as [128]
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Metadata
- Authors
- Cohen, J. C., Boerwinkle, E., Mosley, T. H., & Hobbs, H. H.
- Affiliations
- The University of Texas Southwestern Medical Center (US)
- The University of Texas Health Science Center at Houston (US)
- Howard Hughes Medical Institute (US)
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 2006-03-23
- Volume
- 354
- Issue
- 12
- Pages
- 1264-1272
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- OpenAlex
- W2067539811
- Semantic Scholar
- 5cb1ad66116f87a0743739413b3b5f7f633657f8
- Cited by
- 3,181
- References
- 27
- Citations by year
- 2026: 130 · 2025: 121 · 2024: 150 · 2023: 182 · 2022: 169 · 2021: 175 · 2020: 193 · 2019: 180 · 2018: 210 · 2017: 229 · 2016: 235 · 2015: 244 · 2014: 171 · 2013: 145 · 2012: 126
- FWCI
- 104.04
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- New England Journal of Medicine (publishedVersion)
- PubMed (publishedVersion)
- Funders
- W. M. Keck Foundation
- Donald W. Reynolds Foundation
- National Institutes of Health (n01hc55021-47-0-1, n01hc55020-39-0-0, n01hc55016-37-0-0, n01hc055022-024, n01hc55019-35-0-1, n01hc55018-38-0-1, N01-HC55020, N01-HC-55021, HL20948, N01-HC-55019, N01-HC-55022, N01-HC55016, N01-HC55018, N01-HC-55015, n01hc55015-48-0-1)
- National Heart, Lung, and Blood Institute (N01-HC55022, N01-HC-55018, HL-20948, N01 HC 55020, N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, and N01-HC-55022, N01 HC 55019, N01-HC55016, P01HL020948, N01‐HC‐55015, N01-HC55021)
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipoproteins and Cardiovascular Health
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
- Keywords
- PCSK9, LDL cholesterol, coronary artery disease, myocardial infarction, coronary revascularization, nonsense mutation, genetic variants, LDL cholesterol lowering, cardiovascular risk, Atherosclerosis Risk in Communities Study, black and white populations
- MeSH terms
- Proprotein Convertase 9, Black or African American, Carotid Arteries, Coronary Disease, Female, Gene Frequency, Genotype, Humans, Hypolipoproteinemias, Cholesterol, LDL, Male, Middle Aged, Risk, Serine Endopeptidases, United States, Genetic Variation, Cohort Studies, Incidence, Proportional Hazards Models, Codon, Nonsense, Proprotein Convertases, Black People, White People
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