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Cited by 51Lipoproteins and Cardiovascular HealthGenetic Associations and EpidemiologyParaoxonase enzyme and polymorphisms

Low LDL cholesterol by PCSK9 variation reduces cardiovascular mortality

Open access
Benn, Marianne, Tybjærg-Hansen, Anne, Nordestgaard, Børge G.·2019·Journal of the American College of Cardiology
DOI 10.1016/j.jacc.2019.03.517
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Abstract

Background Reduced low-density lipoprotein (LDL) cholesterol due to inhibition of proprotein convertase subtilisin/kexin 9 (PCSK9) reduces cardiovascular events and may therefore also reduce cardiovascular and all-cause mortality. Objectives This study tested the hypothesis that genetically low LDL cholesterol due to PCSK9 variation is causally associated with low cardiovascular and all-cause mortality in the general population. Methods A total of 109,566 individuals from the Copenhagen General Population Study and the Copenhagen City Heart Study were genotyped for PCSK9 R46L (rs11591147), R237W (rs148195424), I474V (rs562556), and E670G (rs505151). During a median follow-up of 10 years (range 0 to 42 years) and 1,247,225 person-years, there were 3,828 cardiovascular deaths and 16,373 deaths from any cause. Results were validated using data on 431,043 individuals from the UK Biobank. Results An increasing number of weighted PCSK9 alleles were associated with stepwise lower LDL cholesterol of up to 0.61 mmol/l (24 mg/dl; 18.2%; p for trend <0.001) and with lower cardiovascular mortality (p = 0.001), but not with lower all-cause mortality (p = 0.11). In causal, genetic analyses, a 0.5-mmol/l (19.4-mg/dl) lower LDL cholesterol was associated with risk ratios for cardiovascular and all-cause mortality of 0.79 (95% confidence interval [CI]: 0.63 to 0.99; p = 0.04) and 1.02 (95% CI: 0.94 to 1.12; p = 0.63) in the Copenhagen studies, 0.79 (95% CI: 0.58 to 1.08; p = 0.14) and 0.98 (95% CI: 0.87 to 1.10; p = 0.75) in the UK Biobank, and of 0.79 (95% CI: 0.65 to 0.95; p = 0.01) and 1.01 (95% CI: 0.94 to 1.08; p = 0.85), respectively, in studies combined. Conclusions Genetically low LDL cholesterol due to PCSK9 variation was causally associated with low risk of cardiovascular mortality, but not with low all-cause mortality in the general population.

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  • Statin-adjusted LDL values were corrected for the overall random effect on LDL cholesterol for individuals in statin therapy (-33%).

    “A third potential limitation is that the statin-adjusted LDL values were corrected for the overall random effect on LDL cholesterol for individuals in statin therapy (-33% [38][39][40]).”

    From APOE and vascular disease: Sequencing and genotyping in general population cohorts (2023) · cites this paper as [40]

    The lipids and lipoproteins passage (page not specified) says LDL cholesterol values for people using cholesterol-lowering medication were multiplied by 1.43; more than 97% of those users took statins. It describes the adjustment as an estimated 30% reduction, not 33%, and does not describe it as an overall random effect. (LLM, conf=0.88)

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Cited by

Sorted by citations

Authors
Benn, M., Tybjærg-Hansen, A., & Nordestgaard, B. G.
Affiliations
University of Copenhagen (DK)
Corresponding author
Benn, Marianne
ORCID
Venue
Journal of the American College of Cardiology
Publisher
Elsevier BV
Published
2019-06
Volume
73
Issue
24
Pages
3102-3114
ISSN
0735-1097 (ISSN-L)
DOI
10.1016/j.jacc.2019.03.517
OpenAlex
W2950442821
Cited by
51
References
15
Citations by year
2026: 8 · 2025: 8 · 2024: 4 · 2023: 6 · 2022: 4 · 2021: 7 · 2020: 8 · 2019: 6
FWCI
6.02
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of the American College of Cardiology (publishedVersion)
  • PubMed (publishedVersion)
  • Research at the University of Copenhagen (University of Copenhagen) (submittedVersion)
Funders
  • Sundhed og Sygdom, Det Frie Forskningsråd
  • Danmarks Frie Forskningsfond
Topics
  • Health Sciences › Medicine › Surgery › 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, LDL cholesterol, cardiovascular mortality, all-cause mortality, genetic variants, PCSK9 inhibitors, causal inference, polygenic risk score, cardiovascular disease, hypercholesterolemia
MeSH terms
Proprotein Convertase 9, Cardiovascular Diseases, Cause of Death, Denmark, Female, Humans, Cholesterol, LDL, Male, Middle Aged, Mutation, Genetic Variation, Risk Assessment, Polymorphism, Single Nucleotide

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