Selection on Alleles Affecting Human Longevity and Late-Life Disease: The Example of Apolipoprotein E

Institute for Ageing and Health, Newcastle University, Newcastle Upon Tyne, Tyne, United Kingdom.
PLoS ONE (Impact Factor: 3.23). 04/2010; 5(4):e10022. DOI: 10.1371/journal.pone.0010022
Source: PubMed


It is often claimed that genes affecting health in old age, such as cardiovascular and Alzheimer diseases, are beyond the reach of natural selection. We show in a simulation study based on known genetic (apolipoprotein E) and non-genetic risk factors (gender, diet, smoking, alcohol, exercise) that, because there is a statistical distribution of ages at which these genes exert their influence on morbidity and mortality, the effects of selection are in fact non-negligible. A gradual increase with each generation of the epsilon2 and epsilon3 alleles of the gene at the expense of the epsilon4 allele was predicted from the model. The epsilon2 allele frequency was found to increase slightly more rapidly than that for epsilon3, although there was no statistically significant difference between the two. Our result may explain the recent evolutionary history of the epsilon 2, 3 and 4 alleles of the apolipoprotein E gene and has wider relevance for genes affecting human longevity.

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    • "With regards to this, a recent study showed that the levels of Aβ oligomers in AD patients were lowest in those carrying the ε2-allele (Hashimoto et al., 2012). The ε2-allele also seems to play a protective role against CVD (Bennet et al., 2007; Gerdes et al., 2000; Kolovou et al., 2002), though the evidence is probably weaker than for negative effect of the ε4-allele (Drenos and Kirkwood, 2010). In addition, previous large population-based longitudinal studies, i.e., the Rotterdam study (Slooter et al., 2001) and the Danish 1905 birth cohort (Lindahl-Jacobsen et al., 2013) reported no favorable effect of ε2-allele on mortality in the elderly, despite protecting against cognitive decline in the oldest old (≥93 years) (Lindahl-Jacobsen et al., 2013). "
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    ABSTRACT: The ApoE gene is associated with the risk of Alzheimer or cardiovascular disease but its influence on exceptional longevity (EL) is uncertain. Our primary purpose was to determine, using a case-control design, if the ApoE gene is associated with EL. We compared ApoE allele/genotype frequencies among the following cohorts: cases (centenarians, most with 1 + major disease condition; n = 163, 100-111y) and healthy controls (n = 1039, 20-85y) from Spain; disease-free cases (centenarians; n = 79, 100-104y) and healthy controls (n = 597, age 27-81y) from Italy; and cases (centenarians and semi-supercentenarians, most with 1 + major disease condition; n = 729, 100-116) and healthy controls (n = 498, 23-59y) from Japan. Our main findings were two-fold. First, the ε4-allele was negatively associated with EL in the three cohorts, with the following odds ratio (OR) values (adjusted by sex) been found: 0.55 (95% confidence interval (CI): 0.33, 0.94), P = 0.030 (Spain); 0.41 (95%CI: 0.18, 0.99), P = 0.05 (Italy); and 0.35 (95%CI: 0.26, 0.57), P < 0.001 (Japan). Second, although no association was found in the Spanish cohort (OR = 1.42 (95%CI: 0.89, 2.26), P = 0.145), the ε2-allele was positively associated with EL in the Italian (OR = 2.14 (95%CI: 1.18, 3.45), P = 0.01) and Japanese subjects (OR = 1.81 (95%CI: 1.25, 2.63), P = 0.002). Notwithstanding the limitations of case-control designs, our data suggest that the ApoE might be a candidate to influence EL. The ε4-allele appears to decrease the likelihood of reaching EL among individuals of different ethnic/geographic origins. An additional, novel finding of our study was that the ε2-allele might favor EL, at least in the Italian and Japanese cohorts.
    Full-text · Article · May 2014 · Experimental gerontology
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    • "Such deleterious effects are expected to be selected against (see e.g. Pavard and Metcalf 2007; Drenos and Kirkwood 2010), especially to the extent that they occur before reproduction and alloparental care-giving have largely ceased, they can be dissociated genetically via recombination, or they can be alleviated by selection and response at interacting loci. Antagonistically pleiotropic effects should thus often be evolutionarily transient. "
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    ABSTRACT: In this review, I describe how evolutionary genomics is uniquely suited to spearhead advances in understanding human disease risk, owing to the privileged position of genes as fundamental causes of phenotypic variation, and the ability of population genetic and phylogenetic methods to robustly infer processes of natural selection, drift, and mutation from genetic variation at the levels of family, population, species, and clade. I first provide an overview of models for the origins and maintenance of genetically based disease risk in humans. I then discuss how analyses of genetic disease risk can be dovetailed with studies of positive and balancing selection, to evaluate the degree to which the ‘genes that make us human’ also represent the genes that mediate risk of polygenic disease. Finally, I present four basic principles for the nascent field of human evolutionary medical genomics, each of which represents a process that is nonintuitive from a proximate perspective. Joint consideration of these principles compels novel forms of interdisciplinary analyses, most notably studies that (i) analyze tradeoffs at the level of molecular genetics, and (ii) identify genetic variants that are derived in the human lineage or in specific populations, and then compare individuals with derived versus ancestral alleles.
    Full-text · Article · Feb 2011 · Evolutionary Applications
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    • "It might well be the case that a certain risk factor for a late life disease can be relevant to reproductive age and fitness. Then, evolution can be relevant to late-life diseases (Di Rienzo & Hudson 2005; Drenos & Kirkwood 2010). The problem, however, is that such reproductive-age-related factors might well be relevant to fitness but: (i) not relevant to post-reproductive age diseases at all, (ii) predispose to them, (iii) be protective of them, or (iv) predispose to some diseases but be protective of the others. "
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    ABSTRACT: Progress in unraveling the genetic origins of healthy aging is tempered, in part, by a lack of replication of effects, which is often considered a signature of false-positive findings. We convincingly demonstrate that the lack of genetic effects on an aging-related trait can be because of trade-offs in the gene action. We focus on the well-studied apolipoprotein E (APOE) e2/3/4 polymorphism and on lifespan and ages at onset of cardiovascular diseases (CVD) and cancer, using data on 3924 participants of the Framingham Heart Study Offspring cohort. Kaplan-Meier estimates show that the e4 allele carriers live shorter lives than the non-e4 allele carriers (log rank = 0.016). The adverse effect was attributed to the poor survival of the e4 homozygotes, whereas the effect of the common e3/4 genotype was insignificant. The e3/4 genotype, however, was antagonistically associated with onsets of those diseases predisposing to an earlier onset of CVD and a later onset of cancer compared to the non-e4 allele genotypes. This trade-off explains the lack of a significant effect of the e3/4 genotype on survival; adjustment for it in the Cox regression model makes the detrimental effect of the e4 allele highly significant (P = 0.002). This trade-off is likely caused by the lipid-metabolism-related (for CVD) and nonrelated (for cancer) mechanisms. An evolutionary rationale suggests that genetic trade-offs should not be an exception in studies of aging-related traits. Deeper insights into biological mechanisms mediating gene action are critical for understanding the genetic regulation of a healthy lifespan and for personalizing medical care.
    Full-text · Article · Feb 2011 · Aging cell
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