Trade-offs in the effects of the apolipoprotein E polymorphism on risks of diseases of the heart, cancer, and neurodegenerative disorders: insights on mechanisms from the Long Life Family Study.
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2015-04
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Abstract
The lack of evolutionary established mechanisms linking genes to age-related traits makes the problem of genetic susceptibility to health span inherently complex. One complicating factor is genetic trade-off. Here we focused on long-living participants of the Long Life Family Study (LLFS), their offspring, and spouses to: (1) Elucidate whether trade-offs in the effect of the apolipoprotein E e4 allele documented in the Framingham Heart Study (FHS) are a more general phenomenon, and (2) explore potential mechanisms generating age- and gender-specific trade-offs in the effect of the e4 allele on cancer, diseases of the heart, and neurodegenerative disorders assessed retrospectively in the LLFS populations. The e4 allele can diminish risks of cancer and diseases of the heart and confer risks of diseases of the heart in a sex-, age-, and LLFS-population-specific manner. A protective effect against cancer is seen in older long-living men and, potentially, their sons (>75 years, relative risk [RR]>75=0.48, p=0.086), which resembles our findings in the FHS. The protective effect against diseases of the heart is limited to long-living older men (RR>76=0.50, p=0.016), as well. A detrimental effect against diseases of the heart is characteristic for a normal LLFS population of male spouses and is specific for myocardial infarction (RR=3.07, p=2.1×10(-3)). These trade-offs are likely associated with two inherently different mechanisms, including disease-specific (detrimental; characteristic for a normal male population) and systemic, aging-related (protective; characteristic for older long-living men) mechanisms. The e4 allele confers risks of neurological disorders in men and women (RR=1.98, p=0.046). The results highlight the complex role of the e4 allele in genetic susceptibility to health span.
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Kulminski, Alexander M, Konstantin G Arbeev, Irina Culminskaya, Svetlana V Ukraintseva, Eric Stallard, Michael A Province and Anatoli I Yashin (2015). Trade-offs in the effects of the apolipoprotein E polymorphism on risks of diseases of the heart, cancer, and neurodegenerative disorders: insights on mechanisms from the Long Life Family Study. Rejuvenation Res, 18(2). pp. 128–135. 10.1089/rej.2014.1616 Retrieved from https://hdl.handle.net/10161/14864.
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Scholars@Duke
Alexander Kulminski
Konstantin Arbeev
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 Research Scientist and a Senior Research Scientist in the Department of Sociology and the Social Science Research Institute (SSRI). He is currently an Associate Research Professor in SSRI. Dr. Arbeev's major research interests are related to three interconnected fields of biodemography, biostatistics and genetic epidemiology as pertains to research on aging. The focus of his research is on discovering genetic and non-genetic factors that can affect the process of aging and determine longevity and healthy lifespan. He is interested in both methodological advances in this research area as well as their practical applications to analyses of large-scale longitudinal studies with phenotypic, genetic and, recently, genomic information. Dr. Arbeev authored and co-authored more than 150 peer-reviewed publications in these areas.
Irina Kulminskaya
Svetlana Ukraintseva
Dr. Ukraintseva studies the causes of human aging and the associated decline in whole-body resilience, with the goal of identifying genetic and other factors that drive this decline and contribute to the age-related increase in all-cause mortality risk, ultimately limiting longevity even in individuals without major diseases. She also investigates the “multi-hit” mechanism of Alzheimer’s disease and the complex, including trade‑off–like, relationships between Alzheimer’s disease and cancer. She actively explores the role of infectious diseases and compromised immunity in Alzheimer’s development, as well as the interplay between vaccines and genetic factors, to advance personalized vaccine repurposing for AD prevention. To address these questions, Dr. Ukraintseva and her team analyze large human datasets containing comprehensive information on millions of individuals. She is a PI and key investigator on several NIH-funded grants and has authored more than 150 peer‑reviewed publications, including in major journals such as JAMA, Nature group journals, Stroke, Alzheimer’s & Dementia, and others.
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Anatoli I. Yashin
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