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Cited by 52Lipoproteins and Cardiovascular HealthGenetic Associations and EpidemiologyAlzheimer's disease research and treatments

Age, Gender, and Cancer but Not Neurodegenerative and Cardiovascular Diseases Strongly Modulate Systemic Effect of the Apolipoprotein E4 Allele on Lifespan

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Kulminski, Alexander M., Arbeev, Konstantin G., Culminskaya, Irina, Arbeeva, Liubov, Ukraintseva, Svetlana V., Stallard, Eric, Christensen, Kaare, Schupf, Nicole +2 more·2014·PLoS Genetics
DOI 10.1371/journal.pgen.1004141PMC PMC3907310
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Abstract

Enduring interest in the Apolipoprotein E (ApoE) polymorphism is ensured by its evolutionary-driven uniqueness in humans and its prominent role in geriatrics and gerontology. We use large samples of longitudinally followed populations from the Framingham Heart Study (FHS) original and offspring cohorts and the Long Life Family Study (LLFS) to investigate gender-specific effects of the ApoE4 allele on human survival in a wide range of ages from midlife to extreme old ages, and the sensitivity of these effects to cardiovascular disease (CVD), cancer, and neurodegenerative disorders (ND). The analyses show that women's lifespan is more sensitive to the e4 allele than men's in all these populations. A highly significant adverse effect of the e4 allele is limited to women with moderate lifespan of about 70 to 95 years in two FHS cohorts and the LLFS with relative risk of death RR = 1.48 (p = 3.6 × 10(-6)) in the FHS cohorts. Major human diseases including CVD, ND, and cancer, whose risks can be sensitive to the e4 allele, do not mediate the association of this allele with lifespan in large FHS samples. Non-skin cancer non-additively increases mortality of the FHS women with moderate lifespans increasing the risks of death of the e4 carriers with cancer two-fold compared to the non-e4 carriers, i.e., RR = 2.07 (p = 5.0 × 10(-7)). The results suggest a pivotal role of non-sex-specific cancer as a nonlinear modulator of survival in this sample that increases the risk of death of the ApoE4 carriers by 150% (p = 5.3 × 10(-8)) compared to the non-carriers. This risk explains the 4.2 year shorter life expectancy of the e4 carriers compared to the non-carriers in this sample. The analyses suggest the existence of age- and gender-sensitive systemic mechanisms linking the e4 allele to lifespan which can non-additively interfere with cancer-related mechanisms.

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  • The potential association between APOE genotype and cancer outcome has remained inconclusive.

    “The potential association between APOE genotype and cancer outcome has remained inconclusive10,11.”

    From Common germline variants of the human APOE gene modulate melanoma progression and survival (2020) · cites this paper as [10]

    The Results section reports a significant association between APOE4 and survival among women with cancer, while the corresponding result for men was only marginally significant. These sex-specific findings address cancer outcomes, but the paper does not characterize the overall evidence on APOE genotype and cancer outcomes as inconclusive. Page numbers are unavailable in our copy. (LLM, conf=0.78)

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Authors
Kulminski, A. M., Arbeev, K. G., Culminskaya, I., Arbeeva, L., Ukraintseva, S. V., Stallard, E., Christensen, K., Schupf, N., Province, M. A., & Yashin, A. I.
Affiliations
  • Duke University (US)
  • University of Southern Denmark (DK)
  • Columbia University Irving Medical Center (US)
  • Washington University in St. Louis (US)
Corresponding author
Kulminski, Alexander M.
ORCID
Venue
PLoS Genetics
Publisher
Public Library of Science (PLoS)
Published
2014-01-30
Volume
10
Issue
1
Pages
e1004141
ISSN
  • 1553-7390 (ISSN-L)
  • 1553-7404
DOI
10.1371/journal.pgen.1004141
PMC
PMC3907310
OpenAlex
W2042625373
Cited by
52
References
67
Citations by year
2026: 1 · 2024: 3 · 2022: 3 · 2021: 2 · 2020: 4 · 2019: 6 · 2018: 9 · 2017: 5 · 2016: 9 · 2015: 6 · 2014: 3
FWCI
7.61
Type
journal article
Language
en
Open access
Licence
Locations
  • PLoS Genetics (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Digital Commons@Becker (Washington University School of Medicine) (submittedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • DukeSpace (Duke University) (submittedVersion, cc-by-nc-nd)
  • DukeSpace (Duke University) (submittedVersion)
  • University of Southern Denmark Research Portal (University of Southern Denmark) (submittedVersion)
  • Columbia Academic Commons (Columbia University)
Funders
  • National Institute on Aging (U01AG023712, P50AG008702, U01AG023746, R01AG030612, P30AG034424, U01AG023749)
  • National Heart, Lung, and Blood Institute
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development (P2CHD065563, R24HD065563)
Topics
  • Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
Keywords
APOE ε4, APOE polymorphism, lifespan, gender differences, age effects, cancer mortality, cardiovascular disease, neurodegenerative diseases, mortality risk, life expectancy, sex differences in aging
MeSH terms
Age Factors, Aged, Aged, 80 and over, Alleles, Cardiovascular Diseases, Female, Genotype, Heterozygote, Humans, Longevity, Male, Neoplasms, Polymorphism, Genetic, Risk Factors, Sex Characteristics, Neurodegenerative Diseases, Apolipoprotein E4

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