title: 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.
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.
authors.affiliation: 1 Duke University , Center for Population Health and Aging, Durham, North Carolina.
authors.forename: Alexander M
authors.initials: AM
authors.lastname: Kulminski
authors.forename: Konstantin G
authors.initials: KG
authors.lastname: Arbeev
authors.forename: Irina
authors.initials: I
authors.lastname: Culminskaya
authors.forename: Svetlana V
authors.initials: SV
authors.lastname: Ukraintseva
authors.forename: Eric
authors.initials: E
authors.lastname: Stallard
authors.forename: Michael A
authors.initials: MA
authors.lastname: Province
authors.forename: Anatoli I
authors.initials: AI
authors.lastname: Yashin
mesh_terms: D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000235:genetics*; D053327:Apolipoprotein E4 / Q000235:genetics*; D003718:Denmark / Q000453:epidemiology; D005260:Female; D020022:Genetic Predisposition to Disease; D006331:Heart Diseases / Q000175:diagnosis / Q000453:epidemiology / Q000235:genetics*; D040941:Heredity; D006801:Humans; D053208:Kaplan-Meier Estimate; D008017:Life Expectancy; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000175:diagnosis / Q000453:epidemiology / Q000235:genetics*; D019636:Neurodegenerative Diseases / Q000175:diagnosis / Q000453:epidemiology / Q000235:genetics*; D016017:Odds Ratio; D010375:Pedigree; D011110:Polymorphism, Genetic; D016016:Proportional Hazards Models; D065840:Protective Factors; D018570:Risk Assessment; D012307:Risk Factors; D012737:Sex Factors; D014481:United States / Q000453:epidemiology
chemical_list: D053327:Apolipoprotein E4