Protective role of the apolipoprotein E2 allele in age-related disease traits and survival: evidence from the Long Life Family Study

Abstract

The apolipoprotein E (apoE) is a classic example of a gene exhibiting pleiotropism. We examine potential pleiotropic associations of the apoE2 allele in three biodemographic cohorts of long-living individuals, offspring, and spouses from the Long Life Family Study, and intermediate mechanisms, which can link this allele with age-related phenotypes. We focused on age-related macular degeneration, bronchitis, asthma, pneumonia, stroke, creatinine, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol, diseases of heart (HD), cancer, and survival. Our analysis detected favorable associations of the ε2 allele with lower LDL-C levels, lower risks of HD, and better survival. The ε2 allele was associated with LDL-C in each gender and biodemographic cohort, including long-living individuals, offspring, and spouses, resulting in highly significant association in the entire sample (beta=-7.1, p=6.6×10-44). This allele was significantly associated with HD in long-living individuals and offspring (relative risk [RR]=0.60, p=3.1×10-6) but this association was not mediated by LDL-C. The protective effect on survival was specific for long-living women but it was not explained by LDL-C and HD in the adjusted model (RR=0.70, p=2.1×10-2). These results show that ε2 allele may favorably influence LDL-C, HD, and survival through three mechanisms. Two of them (HD- and survival-related) are pronounced in the long-living parents and their offspring; the survival-related mechanism is also sensitive to gender. The LDL-C-related mechanism appears to be independent of these factors. Insights into mechanisms linking ε2 allele with age-related phenotypes given biodemographic structure of the population studied may benefit translation of genetic discoveries to health care and personalized medicine.

Exome-wide association studies in general and long-lived populations identify genetic variants related to human age

“…Similar with prior longevity studies (Kulminski et al, 2016;Schachter et al, 1994;Sebastiani et al, 2019), our Case-Control association analyses showed association with increased and decreased frequencies of APOEe2 and APOEe4 haplotypes, respectively, in LLI as compared to controls. As with many prior GWAS studies (Partridge et al, 2018), our analysis revealed APOE as the only locus that was age-associated and replicated in our studies.…”

Strong impact of natural-selection–free heterogeneity in genetics of age-related phenotypes

“…The current study supports this concept by highlighting strong impact of antagonistic heterogeneity, which is counter-intuitive in medical genetics but natural within the evolutionary framework. The antagonistic heterogeneity is also supported by the analyses of alleles from well-known apolipoprotein B and E genes [ 16 , 17 ].…”

“…Accordingly, different, even antagonistic, effects of the same allele on the same phenotype in different population groups are biologically plausible [ 14 , 15 ]. Another challenge in the evolutionary framework is that genetic variants predisposing to a phenotype may not necessarily predispose to another, even causally related, phenotype [ 16 , 17 ] or such genetic variants can predispose to seemingly unrelated phenotypes [ 18 - 20 ].…”

A serum protein signature of APOE genotypes in centenarians

“…The e 3 allele is the “neutral allele” in many ethnicities, while e 2 is the least common allele that emerged as a longevity variant when Schachter et al noted an increased frequency of e 2 in French centenarians (Schachter et al, ). Since then, several studies have provided evidence that e 2 has a beneficial neuroprotective effect (Kim et al, ), decreases neuroinflammation (Dorey, Chang, Liu, Yang, & Zhang, ), and promotes longevity (Sebastiani, Bae, et al, ; Sebastiani, Gurinovich, et al, ; Sebastiani et al, ) and healthy aging (Kulminski et al, ; Wu & Zhao, ). Therefore, we hypothesize that targets of this allele may lead to the discovery of treatments that help maintain good cognitive function and escape cognitive impairment with aging.…”