Cargando…

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

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 coho...

Descripción completa

Detalles Bibliográficos
Autores principales: Kulminski, Alexander M., Arbeev, Konstantin G., Culminskaya, Irina, Arbeeva, Liubov, Ukraintseva, Svetlana V., Stallard, Eric, Christensen, Kaare, Schupf, Nicole, Province, Michael A., Yashin, Anatoli I.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3907310/
https://www.ncbi.nlm.nih.gov/pubmed/24497847
http://dx.doi.org/10.1371/journal.pgen.1004141
_version_ 1782301584565207040
author Kulminski, Alexander M.
Arbeev, Konstantin G.
Culminskaya, Irina
Arbeeva, Liubov
Ukraintseva, Svetlana V.
Stallard, Eric
Christensen, Kaare
Schupf, Nicole
Province, Michael A.
Yashin, Anatoli I.
author_facet Kulminski, Alexander M.
Arbeev, Konstantin G.
Culminskaya, Irina
Arbeeva, Liubov
Ukraintseva, Svetlana V.
Stallard, Eric
Christensen, Kaare
Schupf, Nicole
Province, Michael A.
Yashin, Anatoli I.
author_sort Kulminski, Alexander M.
collection PubMed
description 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.
format Online
Article
Text
id pubmed-3907310
institution National Center for Biotechnology Information
language English
publishDate 2014
publisher Public Library of Science
record_format MEDLINE/PubMed
spelling pubmed-39073102014-02-04 Age, Gender, and Cancer but Not Neurodegenerative and Cardiovascular Diseases Strongly Modulate Systemic Effect of the Apolipoprotein E4 Allele on Lifespan Kulminski, Alexander M. Arbeev, Konstantin G. Culminskaya, Irina Arbeeva, Liubov Ukraintseva, Svetlana V. Stallard, Eric Christensen, Kaare Schupf, Nicole Province, Michael A. Yashin, Anatoli I. PLoS Genet Research Article 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. Public Library of Science 2014-01-30 /pmc/articles/PMC3907310/ /pubmed/24497847 http://dx.doi.org/10.1371/journal.pgen.1004141 Text en © 2014 Kulminski et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Kulminski, Alexander M.
Arbeev, Konstantin G.
Culminskaya, Irina
Arbeeva, Liubov
Ukraintseva, Svetlana V.
Stallard, Eric
Christensen, Kaare
Schupf, Nicole
Province, Michael A.
Yashin, Anatoli I.
Age, Gender, and Cancer but Not Neurodegenerative and Cardiovascular Diseases Strongly Modulate Systemic Effect of the Apolipoprotein E4 Allele on Lifespan
title Age, Gender, and Cancer but Not Neurodegenerative and Cardiovascular Diseases Strongly Modulate Systemic Effect of the Apolipoprotein E4 Allele on Lifespan
title_full Age, Gender, and Cancer but Not Neurodegenerative and Cardiovascular Diseases Strongly Modulate Systemic Effect of the Apolipoprotein E4 Allele on Lifespan
title_fullStr Age, Gender, and Cancer but Not Neurodegenerative and Cardiovascular Diseases Strongly Modulate Systemic Effect of the Apolipoprotein E4 Allele on Lifespan
title_full_unstemmed Age, Gender, and Cancer but Not Neurodegenerative and Cardiovascular Diseases Strongly Modulate Systemic Effect of the Apolipoprotein E4 Allele on Lifespan
title_short Age, Gender, and Cancer but Not Neurodegenerative and Cardiovascular Diseases Strongly Modulate Systemic Effect of the Apolipoprotein E4 Allele on Lifespan
title_sort age, gender, and cancer but not neurodegenerative and cardiovascular diseases strongly modulate systemic effect of the apolipoprotein e4 allele on lifespan
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3907310/
https://www.ncbi.nlm.nih.gov/pubmed/24497847
http://dx.doi.org/10.1371/journal.pgen.1004141
work_keys_str_mv AT kulminskialexanderm agegenderandcancerbutnotneurodegenerativeandcardiovasculardiseasesstronglymodulatesystemiceffectoftheapolipoproteine4alleleonlifespan
AT arbeevkonstanting agegenderandcancerbutnotneurodegenerativeandcardiovasculardiseasesstronglymodulatesystemiceffectoftheapolipoproteine4alleleonlifespan
AT culminskayairina agegenderandcancerbutnotneurodegenerativeandcardiovasculardiseasesstronglymodulatesystemiceffectoftheapolipoproteine4alleleonlifespan
AT arbeevaliubov agegenderandcancerbutnotneurodegenerativeandcardiovasculardiseasesstronglymodulatesystemiceffectoftheapolipoproteine4alleleonlifespan
AT ukraintsevasvetlanav agegenderandcancerbutnotneurodegenerativeandcardiovasculardiseasesstronglymodulatesystemiceffectoftheapolipoproteine4alleleonlifespan
AT stallarderic agegenderandcancerbutnotneurodegenerativeandcardiovasculardiseasesstronglymodulatesystemiceffectoftheapolipoproteine4alleleonlifespan
AT christensenkaare agegenderandcancerbutnotneurodegenerativeandcardiovasculardiseasesstronglymodulatesystemiceffectoftheapolipoproteine4alleleonlifespan
AT schupfnicole agegenderandcancerbutnotneurodegenerativeandcardiovasculardiseasesstronglymodulatesystemiceffectoftheapolipoproteine4alleleonlifespan
AT provincemichaela agegenderandcancerbutnotneurodegenerativeandcardiovasculardiseasesstronglymodulatesystemiceffectoftheapolipoproteine4alleleonlifespan
AT yashinanatolii agegenderandcancerbutnotneurodegenerativeandcardiovasculardiseasesstronglymodulatesystemiceffectoftheapolipoproteine4alleleonlifespan