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Age, gender, and cancer but not neurodegenerative and cardiovascular diseases strongly modulate systemic effect of the Apolipoprotein E4 allele on lifespan.

dc.contributor.author Arbeev, Konstantin
dc.contributor.author Arbeeva, L
dc.contributor.author Christensen, Kaare
dc.contributor.author Culminskaya, IV
dc.contributor.author Kulminski, Alexander
dc.contributor.author Province, MA
dc.contributor.author Schupf, N
dc.contributor.author Stallard, Eric
dc.contributor.author Ukraintseva, Svetlana
dc.contributor.author Yashin, Anatoli I
dc.coverage.spatial United States
dc.date.accessioned 2017-06-02T18:06:49Z
dc.date.available 2017-06-02T18:06:49Z
dc.date.issued 2014-01
dc.identifier https://www.ncbi.nlm.nih.gov/pubmed/24497847
dc.identifier PGENETICS-D-13-02381
dc.identifier.uri http://hdl.handle.net/10161/14759
dc.description.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.
dc.language eng
dc.relation.ispartof PLoS Genet
dc.relation.isversionof 10.1371/journal.pgen.1004141
dc.subject Age Factors
dc.subject Aged
dc.subject Aged, 80 and over
dc.subject Alleles
dc.subject Apolipoprotein E4
dc.subject Cardiovascular Diseases
dc.subject Female
dc.subject Genotype
dc.subject Heterozygote
dc.subject Humans
dc.subject Longevity
dc.subject Male
dc.subject Neoplasms
dc.subject Neurodegenerative Diseases
dc.subject Polymorphism, Genetic
dc.subject Risk Factors
dc.subject Sex Characteristics
dc.title Age, gender, and cancer but not neurodegenerative and cardiovascular diseases strongly modulate systemic effect of the Apolipoprotein E4 allele on lifespan.
dc.type Journal article
pubs.author-url https://www.ncbi.nlm.nih.gov/pubmed/24497847
pubs.begin-page e1004141
pubs.issue 1
pubs.organisational-group Center for Population Health & Aging
pubs.organisational-group Duke
pubs.organisational-group Duke Cancer Institute
pubs.organisational-group Duke Population Research Center
pubs.organisational-group Duke Population Research Institute
pubs.organisational-group Institutes and Centers
pubs.organisational-group Institutes and Provost's Academic Units
pubs.organisational-group Sanford School of Public Policy
pubs.organisational-group School of Medicine
pubs.organisational-group Social Science Research Institute
pubs.organisational-group Staff
pubs.organisational-group University Institutes and Centers
pubs.publication-status Published online
pubs.volume 10
dc.identifier.eissn 1553-7404


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