Age, gender, and cancer but not neurodegenerative and cardiovascular diseases strongly modulate systemic effect of the Apolipoprotein E4 allele on lifespan.
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.
Type
Journal articleSubject
Age FactorsAged
Aged, 80 and over
Alleles
Apolipoprotein E4
Cardiovascular Diseases
Female
Genotype
Heterozygote
Humans
Longevity
Male
Neoplasms
Neurodegenerative Diseases
Polymorphism, Genetic
Risk Factors
Sex Characteristics
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https://hdl.handle.net/10161/14759Published Version (Please cite this version)
10.1371/journal.pgen.1004141Publication Info
Kulminski, Alexander M; Arbeev, Konstantin G; Culminskaya, Irina; Arbeeva, Liubov;
Ukraintseva, Svetlana V; Stallard, Eric; ... Yashin, Anatoli I (2014). Age, gender, and cancer but not neurodegenerative and cardiovascular diseases strongly
modulate systemic effect of the Apolipoprotein E4 allele on lifespan. PLoS Genet, 10(1). pp. e1004141. 10.1371/journal.pgen.1004141. Retrieved from https://hdl.handle.net/10161/14759.This is constructed from limited available data and may be imprecise. To cite this
article, please review & use the official citation provided by the journal.
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Show full item recordScholars@Duke
Konstantin Arbeev
Associate Research Professor in the Social Science Research Institute
Konstantin G. Arbeev received the M.S. degree in Applied Mathematics from Moscow State
University (branch in Ulyanovsk, Russia) in 1995 and the Ph.D. degree in Mathematics
and Physics (specialization in Theoretical Foundations of Mathematical Modeling, Numerical
Methods and Programming) from Ulyanovsk State University (Russia) in 1999. He was
a post-doctoral fellow in Max Planck Institute for Demographic Research in Rostock
(Germany) before moving to Duke University in 2004 to work as a Resea
Svetlana Ukraintseva
Research Professor in the Social Science Research Institute
Dr. Ukraintseva studies causes of human aging and related decline in resilience, to
identify genetic and other factors responsible for the increase in mortality risk
with age eventually limiting longevity. She explores complex relationships, including
trade-offs, between physiological aging-changes and risks of major diseases (with
emphasis on Alzheimer’s and cancer), as well as survival, to find new genetic and
other targets for anti-aging interventions and disease prevention. S
Anatoli I. Yashin
Research Professor in the Social Science Research Institute
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