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Cited by 19Lipoproteins and Cardiovascular HealthGenetic Associations and EpidemiologyAtherosclerosis and Cardiovascular Diseases

PCSK9 loss of function is protective against extra-coronary atherosclerotic cardiovascular disease in a large multi-ethnic cohort

Open access
Small, Aeron M., Huffman, Jennifer E., Klarin, Derek, Lynch, Julie A., Assimes, Themistocles, DuVall, Scott, Sun, Yan V., Shere, Labiba +11 more·2020·PLOS ONE
DOI 10.1371/journal.pone.0239752PMC PMC7652310
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Abstract

Background: Therapeutic inhibition of PCSK9 protects against coronary artery disease (CAD) and ischemic stroke (IS). The impact on other diseases remains less well characterized. Methods: We created a genetic risk score (GRS) for PCSK9 using four single nucleotide polymorphisms (SNPs) at or near the PCSK9 locus known to impact lower LDL-Cholesterol (LDL-C): rs11583680, rs11591147, rs2479409, and rs11206510. We then used our GRS to calculate weighted odds ratios reflecting the impact of a genetically determined 10 mg/dL decrease in LDL-C on several pre-specified phenotypes including CAD, IS, peripheral artery disease (PAD), abdominal aortic aneurysm (AAA), type 2 diabetes, dementia, chronic obstructive pulmonary disease, and cancer. Finally, we used our weighted GRS to perform a phenome-wide association study. Results: Genetic and electronic health record data that passed quality control was available in 312,097 individuals, (227,490 White participants, 58,907 Black participants, and 25,700 Hispanic participants).PCSK9 mediated reduction in LDL-C was associated with a reduced risk of CAD and AAA in trans-ethnic meta-analysis (CAD OR 0.83 [95% CI 0.80–0.87], p = 6.0 x 10−21; AAA OR 0.76 [95% CI 0.68–0.86], p = 2.9 x 10−06). Significant protective effects were noted for PAD in White individuals (OR 0.83 [95% CI 0.71–0.97], p = 2.3 x 10−04) but not in other genetic ancestries. Genetically reduced PCSK9 function associated with a reduced risk of dementia in trans-ethnic meta-analysis (OR 0.86 [95% CI 0.78–0.93], p = 5.0 x 10−04). Conclusions: Genetically reduced PCSK9 function results in a reduction in risk of several important extra-coronary atherosclerotic phenotypes in addition to known effects on CAD and IS, including PAD and AAA. We also highlight a novel reduction in risk of dementia, supporting a well-recognized vascular component to cognitive impairment and an opportunity for therapeutic repositioning.

AI snapshot

Written from the paper’s full text.

TL;DR

A PCSK9 genetic risk score was used in 312,097 multi-ethnic VA Million Veteran Program participants to estimate the effects of genetically lower LDL-C on atherosclerotic and non-atherosclerotic phenotypes. Genetically reduced PCSK9 function was protective for CAD, AAA, PAD in White individuals, and dementia, with no evidence of increased type 2 diabetes risk.

Key findings

  • In trans-ethnic meta-analysis, a genetically determined 10 mg/dL decrease in LDL-C was associated with lower CAD risk (OR 0.83, 95% CI 0.80–0.87, p = 6.0 × 10−21) and lower AAA risk (OR 0.76, 95% CI 0.68–0.86, p = 2.9 × 10−6).
  • PAD was significantly protective in White individuals (OR 0.83, 95% CI 0.71–0.97, p = 2.3 × 10−4) but not in other genetic ancestries or trans-ethnic meta-analysis.
  • Genetically reduced PCSK9 function was associated with reduced dementia risk in trans-ethnic meta-analysis (OR 0.86, 95% CI 0.78–0.93, p = 5.0 × 10−4).
  • There was no evidence for increased T2D risk; after adding statin use as a covariate, only CAD and AAA maintained significant associations, with diminished effect estimates and significance.

Methods

  • Genetic and EHR data passing quality control were available for 312,097 individuals: 227,490 White, 58,907 Black, and 25,700 Hispanic participants.
  • A PCSK9 genetic risk score was built from four SNPs (rs11583680, rs11591147, rs2479409, rs11206510), weighted by each variant’s LDL-C effect within MVP; associations with pre-specified phenotypes were adjusted for age, sex, and 5 ancestry-specific principal components.
  • Weighted odds ratios were calculated for a genetically determined 10 mg/dL decrease in LDL-C; a phenome-wide association study was also performed among traits with >200 cases in all three ancestries (n = 507), with Bonferroni thresholds of 6.3 × 10−3 for pre-specified traits and 9 × 10−5 for PheWAS.

Limitations

  • The paper states the MVP cohort is predominantly male, with reduced power to examine differences in females; pleiotropy may affect results due to high phenotypic correlations among atherosclerotic vascular diseases; and the GRS was established in White populations, so results in Black and Hispanic populations should be interpreted with care because SNP minor allele frequencies vary by ancestry.
  • The paper also notes that T2D was defined using ICD codes only, allowing possible case-control misclassification, and that the study had less power to detect T2D differences than larger published meta-analyses.
  • The text makes evident that these are genetic association analyses, not randomized interventions; the authors state that additional observational and intervention studies are warranted to establish causality.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1371/journal.pone.0239752

Cites

18 of 18 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

4 of 8 cited sources checked · 3 supported · 0 flagged · accuracy not yet measured

  • Study design and conductcitation

    The study had less power to detect a difference in type 2 diabetes risk compared to other larger published meta-analyses.

    “Further, our study had less power to detect a difference in T2D risk when compared to other larger published meta-analyses [4].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [4] A.F. Schmidt, 2017, PCSK9 genetic variants and risk of type 2 diabetes: a mendelian randomisation study, The Lancet Diabetes & Endocrinology source
  • Findingown data

    Genetically reduced PCSK9 function is associated with reduced risk of dementia in trans-ethnic meta-analysis (OR 0.86, 95% CI 0.78-0.93, p = 5.0 x 10−04).

    “Genetically reduced PCSK9 function associated with a reduced risk of dementia in trans-ethnic meta-analysis (OR 0.86 [95% CI 0.78–0.93], p = 5.0 x 10−04).”
    • Also stated in: § Results · plain
      “Of our non-atherosclerotic endpoints, genetically determined reduced PCSK9 function was associated with a reduced risk of dementia in trans-ethnic meta-analysis.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Diagnosis and procedure codes in the VA electronic health record accurately identify the pre-specified atherosclerotic and non-atherosclerotic phenotypes.
  • Findingown data

    PCSK9-mediated reduction in LDL-C is associated with reduced risk of abdominal aortic aneurysm (AAA) in trans-ethnic meta-analysis (OR 0.76, 95% CI 0.68-0.86, p = 2.9 x 10−06).

    “PCSK9 mediated reduction in LDL-C was associated with a reduced risk of CAD and AAA in trans-ethnic meta-analysis (CAD OR 0.83 [95% CI 0.80–0.87], p = 6.0 x 10−21; AAA OR 0.76 [95% CI 0.68–0.86], p = 2.9 x 10−06).”
    • Also stated in: § Results · plain
      “PCSK9 mediated reductions in LDL-C were associated with an approximately 20% reduced risk of both CAD and AAA in trans-ethnic meta-analysis.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Diagnosis and procedure codes in the VA electronic health record accurately identify the pre-specified atherosclerotic and non-atherosclerotic phenotypes.
  • Findingown data

    A nominal, but not experiment-wide, significant association was seen between PCSK9-mediated LDL-C reduction and ischemic stroke in White individuals and in meta-analysis.

    “A nominal, but not experiment-wide, significant association was seen between PCSK9 mediated LDL-C reduction and IS in White individuals and in meta-analysis.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Diagnosis and procedure codes in the VA electronic health record accurately identify the pre-specified atherosclerotic and non-atherosclerotic phenotypes.
  • Findingown data

    There is no evidence for increased risk of type 2 diabetes associated with genetically diminished PCSK9 function.

    “In contrast to previous reports, there was no evidence for increased risk of T2D associated with genetically diminished PCSK9 function.”
    • Also stated in: § Discussion · plain
      “We did not replicate the increased risk of diabetes seen in other studies examining pleiotropy of PCSK9 LoF.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Diagnosis and procedure codes in the VA electronic health record accurately identify the pre-specified atherosclerotic and non-atherosclerotic phenotypes.
  • Classified as probably not a substantial claim. 13
  • May combine two claims. 10

  • Classified as probably not a substantial claim.

    Premisecitation

    Four SNPs at or near the PCSK9 locus (rs11583680, rs11591147, rs2479409, and rs11206510) have been previously demonstrated in a genetic risk score to strongly associate with lower LDL-C in individuals of European genetic ancestry.

    “We created a genetic risk score (GRS) for PCSK9 function using four single nucleotide polymorphisms (SNPs) at or near the PCSK9 locus that have been previously demonstrated in a genetic risk score to strongly associate with lower LDL-C in individuals of European genetic ancestry [4]: rs11583680, rs11591147, rs2479409, and rs11206510.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [4] A.F. Schmidt, 2017, PCSK9 genetic variants and risk of type 2 diabetes: a mendelian randomisation study, The Lancet Diabetes & Endocrinology source

  • Classified as probably not a substantial claim.

    Premisecitation

    Both vascular and non-vascular dementias, including Alzheimer disease, have a recognized vascular component underlying their pathophysiology.

    “Both vascular dementia and non-vascular dementias, including Alzheimer Disease, have a recognized vascular component underlying their pathophysiology [14].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [14] Z. Arvanitakis, 2016, Relation of cerebral vessel disease to Alzheimer's disease dementia and cognitive function in elderly people: a cross-sectional study, The Lancet Neurology source

      The Discussion (page not provided) says that vascular disease is related to dementia, including the clinical syndrome of Alzheimer’s disease dementia. But it says the mechanisms remain elusive, so it does not establish a vascular component underlying the pathophysiology of both dementia categories as the claim implies. (LLM, conf=0.84)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductcitation

    Phenotyping for PheWAS was performed using the phecode method.

    “Phenotyping for PheWAS was performed using the phecode method, described elsewhere [7].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [7] J.C. Denny, 2010, PheWAS: demonstrating the feasibility of a phenome-wide scan to discover gene-disease associations, Bioinformatics source

  • May combine two claims.

    Findingown data

    For every standard deviation change in the PCSK9 genetic risk score, LDL-C decreased by 2.65 mg/dL in White individuals, 1.45 mg/dL in Black individuals, and 2.34 mg/dL in Hispanic individuals.

    “For every standard deviation change in GRS, we observed a reduction in LDL-C of 2.65 mg/dL, 1.45 mg/dL, and 2.34 mg/dL in White, Black, and Hispanic individuals, respectively (Fig 1).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    PCSK9-mediated reduction in LDL-C is not significantly associated with PAD in Black or Hispanic individuals or in trans-ethnic meta-analysis.

    “Significant protective effects were noted for PAD in White individuals (OR 0.83 [95% CI 0.71–0.97], p = 2.3 x 10−04) but not in other genetic ancestries.”
    • Also stated in: § Results · plain
      “Significant protective effects were noted for PAD in White individuals, but not in other genetic ancestries or in trans-ethnic meta-analysis.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Diagnosis and procedure codes in the VA electronic health record accurately identify the pre-specified atherosclerotic and non-atherosclerotic phenotypes.

  • May combine two claims.

    Findingown data

    Of the three phenotypes meeting the pre-specified Bonferroni correction in primary analysis (CAD, AAA, and dementia), only CAD and AAA maintained a significant association with the PCSK9 genetic risk score after adjusting for statin use, though effect estimates and significance were diminished.

    “Of the three phenotypes meeting our pre-specified Bonferroni correction in primary analysis (CAD, AAA, and dementia), only CAD and AAA maintained a significant association with our GRS after adjusting for statin use, though both the effect estimates and significance were diminished (S4 Table in S1 File).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Diagnosis and procedure codes in the VA electronic health record accurately identify the pre-specified atherosclerotic and non-atherosclerotic phenotypes.

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    All analyses were performed controlling for age, sex, and 5 ancestry-specific principal components.

    “All analyses were performed controlling for age, sex, and 5 ancestry-specific principal components.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    All PheWAS analyses were adjusted for age, sex, and 5 ancestry-specific principal components.

    “All PheWAS analyses were adjusted for age, sex, and 5 ancestry-specific principal components.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Genetically reduced PCSK9 function results in a reduction in risk of dementia, supporting a vascular component to cognitive impairment and an opportunity for therapeutic repositioning.

    “We also highlight a novel reduction in risk of dementia, supporting a well-recognized vascular component to cognitive impairment and an opportunity for therapeutic repositioning.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Diagnosis and procedure codes in the VA electronic health record accurately identify the pre-specified atherosclerotic and non-atherosclerotic phenotypes.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    The study was approved by the Department of Veteran's Affairs Central Institutional Review Board.

    “This study was approved by the Department of Veteran’s Affairs Central Institutional Review Board.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Statin use was added as a covariate for sensitivity analysis for all atherosclerotic phenotypes and for select other phenotypes meeting the significance threshold in the primary analysis.

    “Statin use was added as a covariate for sensitivity analysis for all atherosclerotic phenotypes and for select other phenotypes meeting our significance threshold in the primary analysis.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Study design and conductown data

    For PheWAS, the analysis was limited to traits with greater than 200 cases in all three genetic ancestries (n = 507) and used a Bonferroni-corrected p-value of 9.x10-5 (p = 0.05/n = 507) as the significance threshold.

    “For PheWAS, we limited our analysis to traits which had greater than 200 cases in all three genetic ancestries (n = 507) and used a Bonferroni corrected p-value of 9.x10-5 (p = 0.05/n = 507) as a significance threshold.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductnone given

    The MVP cohort is predominantly male, with reduced power to examine for differences in females.

    “Limitations of our work include that the MVP cohort is predominantly male, with reduced power to examine for differences in females.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    Genetically reduced PCSK9 function results in a reduction in risk of several important extra-coronary atherosclerotic phenotypes in addition to known effects on CAD and ischemic stroke, including PAD and AAA.

    “Genetically reduced PCSK9 function results in a reduction in risk of several important extra-coronary atherosclerotic phenotypes in addition to known effects on CAD and IS, including PAD and AAA.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Diagnosis and procedure codes in the VA electronic health record accurately identify the pre-specified atherosclerotic and non-atherosclerotic phenotypes.

  • May combine two claims.

    Interpretationown data

    The PCSK9 genetic risk score demonstrated a reduction in risk of several important extra-coronary atherosclerotic phenotypes in addition to known effects on CAD, including PAD, AAA, and ischemic stroke.

    “In summary, we generated a GRS predicting PCSK9 function and demonstrated a reduction in risk of several important extra-coronary atherosclerotic phenotypes in addition to known effects on CAD, including PAD, AAA, and ischemic stroke.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Diagnosis and procedure codes in the VA electronic health record accurately identify the pre-specified atherosclerotic and non-atherosclerotic phenotypes.

  • May combine two claims.

    Interpretationown data

    The PCSK9 genetic risk score confirms and extends evidence that reduction in LDL-C reduces risk for CAD and ischemic stroke, as observed in previous genetic studies and clinical trials of PCSK9 inhibitors.

    “Our GRS confirm and extend evidence that reduction in LDL-C reduces risk for CAD and IS, observed in previous genetic studies and in clinical trials of PCSK9 inhibitors.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Diagnosis and procedure codes in the VA electronic health record accurately identify the pre-specified atherosclerotic and non-atherosclerotic phenotypes.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    The PCSK9 genetic risk score was established in a White population.

    “Finally, our GRS was established in White population.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Elevated LDL-C increases the risk of both vascular dementia and Alzheimer disease.

    “Elevated LDL-C increases the risk of both vascular dementia and Alzheimer disease, although treatment with statins has not been shown to consistently reduce the risk of dementia [16].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [16] B. McGuinness, 2016, Statins for Prevention of Dementia, Cochrane Database of Systematic Reviews source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The FOURIER trial subgroup analysis demonstrated no difference in risk for new onset diabetes in patients treated with Evolocumab.

    “These considerations aside, our study is consistent with results from FOURIER trial subgroup analysis, which demonstrated no difference in risk for new onset diabetes in patients treated with Evolocumab [17].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [17] M.S. Sabatine, 2017, Cardiovascular safety and efficacy of the PCSK9 inhibitor evolocumab in patients with and without diabetes and the effect of evolocumab on glycaemia and risk of new-onset diabetes: a prespecified analysis of the FOURIER randomised controlled trial, The Lancet Diabetes & Endocrinology source

  • Classified as probably not a substantial claim.

    Study design and conductown data

    The significance threshold for pre-specified phenotypes was a Bonferroni-corrected p-value of 6.3x10-3 (p = 0.05/n = 8).

    “We considered a Bonferroni corrected p-value of 6.3x10-3 (p = 0.05/n = 8) significant.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Treatment with statins has not been shown to consistently reduce the risk of dementia.

    “Elevated LDL-C increases the risk of both vascular dementia and Alzheimer disease, although treatment with statins has not been shown to consistently reduce the risk of dementia [16].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [16] B. McGuinness, 2016, Statins for Prevention of Dementia, Cochrane Database of Systematic Reviews source
21 of 21

  • The paper relies on this without support.

    Diagnosis and procedure codes in the VA electronic health record accurately identify the pre-specified atherosclerotic and non-atherosclerotic phenotypes.

    “Atherosclerotic phenotypes were developed from a combination of diagnosis and procedure codes present in the VA electronic health record (EHR) of MVP participants (S1 Table in S1 File).”
    “Pre-selected non-atherosclerotic phenotypes were developed from a combination of appropriate diagnostic billing codes (S2 Table in S1 File).”
1 of 1

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Authors
Small, A. M., Huffman, J. E., Klarin, D., Lynch, J. A., Assimes, T., DuVall, S., Sun, Y. V., Shere, L., Natarajan, P., Gaziano, M., Rader, D. J., Wilson, P. W. F., Tsao, P. S., Chang, K.-M., Cho, K., O’Donnell, C. J., Casas, J. P., Damrauer, S. M., & Program, O. B. O. T. V. M. V.
Affiliations
  • Yale University (US)
  • VA Boston Healthcare System (US)
  • Broad Institute (US)
  • Edith Nourse Rogers Memorial Veterans Hospital (US)
  • VA Palo Alto Health Care System (US)
  • United States Department of Veterans Affairs (US)
  • Emory University (US)
  • Harvard University (US)
  • University of Pennsylvania (US)
  • Atlanta VA Health Care System (US)
  • Philadelphia VA Medical Center (US)
  • Brigham and Women's Hospital (US)
Corresponding author
Damrauer, Scott M.
ORCID
Venue
PLOS ONE
Publisher
Public Library of Science (PLoS)
Published
2020-11-09
Volume
15
Issue
11
Pages
e0239752
ISSN
1932-6203 (ISSN-L)
DOI
10.1371/journal.pone.0239752
PMC
PMC7652310
OpenAlex
W3103347999
Cited by
19
References
18
Citations by year
2026: 3 · 2025: 2 · 2024: 4 · 2023: 5 · 2022: 2 · 2021: 3
FWCI
2.05
Type
journal article
Language
en
Open access
Licence
Locations
  • PLoS ONE (publishedVersion, public-domain)
  • PubMed (publishedVersion)
  • PubMed Central (submittedVersion, public-domain)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • U.S. Department of Veterans Affairs (I01 BX003340, IK2-CX001780, I01-01BX03340, I01 CX001025, I01-BX003362, MVP000, BX003362, CX001025)
  • Office of Research and Development (MVP#000, I01-CX001025)
Topics
  • Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
  • Life Sciences › Immunology and Microbiology › Immunology › Atherosclerosis and Cardiovascular Diseases
Keywords
PCSK9, LDL cholesterol, polygenic risk score, coronary artery disease, peripheral arterial disease, abdominal aortic aneurysm, ischemic stroke, dementia, type 2 diabetes, chronic obstructive pulmonary disease, cancer risk, atherosclerotic cardiovascular disease, phenome-wide association study, multi-ethnic cohort
MeSH terms
Proprotein Convertase 9, Loss of Function Mutation, Ischemic Stroke, Coronary Artery Disease, Diabetes Mellitus, Type 2, Female, Humans, Cholesterol, LDL, Male, Risk, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Genome-Wide Association Study, Cognitive Dysfunction

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