Trade-Off in the Effect of the APOE Gene on the Ages at Onset of Cardiocascular Disease and Cancer across Ages, Gender, and Human Generations

Abstract

Decades of studies of candidate genes show their complex role in aging-related traits. We focus on apolipoprotein E e2/3/4 polymorphism and ages at onset of cardiovascular diseases (CVD) and cancer in the parental and offspring generations of the Framingham Heart Study participants to gain insights on the role of age and gender across generations in genetic trade-offs. The analyses show that the apolipoprotein E e4 allele carriers live longer lives without cancer than the non-e4 allele carriers in each generation. The role of the e4 allele in onset of CVD is age-and generation-specific, constituting two modes of sexually dimorphic genetic trade-offs. In offspring, the e4 allele confers risk of CVD primarily in women and can protect against cancer primarily in men of the same age. In the parental generation, genetic trade-off is seen in different age groups, with a protective role of the e4 allele against cancer in older men and its detrimental role in CVD in younger women. The puzzling complexity of genetic mechanisms working in different genders, ages, and environments calls for more detail and systemic analyses beyond those adapted in current large-scale genetic association studies.

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

“…A protective effect of the e4 allele against cancer was also documented in two independent samples of genotyped participants of the original and offspring cohorts in the FHS. 18,34 The potentially protective effect in the LLFS is concordant with findings in the FHS, not merely in the effect direction, but also in two additional aspects, i.e., it is seen at the same old ages and primarily in men. The role of the e4 allele in cancer in other groups of the LLFS participants is uncertain largely due to insufficient numbers of cancer cases in these groups of survivors.…”

“…This protective effect appears to be limited to onsets of cancers at ages older than 75 years, which resembles a similar finding of protective effect of this allele in two independent populations of older males from the FHS original and Offspring APOE GENE AND TRADE-OFFS 129 cohorts. 34 The e4 allele may also be protective against cancer in sons of the long-living parents at older ages in the LLFS (Fig. S1B).…”

“…This effect is concordant with the protective effect of the e4 allele against cardiovascular diseases observed in a more homogeneous subsample of the FHS original cohort in terms of the effect direction and expression at the same old ages. 34 This result suggests that aging-related processes can shape the effect of the e4 allele not only on cancer but also on cardiovascular diseases. However, the age-specific protective effect of the e4 allele was seen in the LLFS men, whereas in the FHS it was seen in women.…”

“…24,[30][31][32][33][34][35][36] In this study, we used information on 4659 genotyped participants of the Long Life Family Study (LLFS) to address two questions. First, we investigated whether recently documented trade-offs in the effects of the apolipoprotein E (APOE) common polymorphism on major human diseases in the Framingham Heart Study (FHS) 18,34 are a more general phenomenon extendable to other populations. Second, we explore mechanisms that can generate age-and gender-specific trade-offs in the effect of the APOE e4 allele on major human diseases, including cancer, diseases of the heart, and neurodegenerative disorders.…”

“…That is, rather than attempting to evaluate unconditional population genetic risks, comprehensive analyses of the mechanisms that shape the conditional risks of genes on age-related traits in a given environment are required. 43 Guided by this paradigm, we extended our prior analyses of trade-offs in the effects of the APOE e4 allele on major human diseases in the FHS, 18,34 examining phenotypic mechanisms that can drive such trade-offs in a specific population of the LLFS families enriched for chances of exceptional longevity.…”