Trade-off in the effects of the apolipoprotein E polymorphism on the ages at onset of CVD and cancer influences human lifespan

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.

Figure 1

Kaplan-Meier survival age patterns for carriers of different APOE genotypes. (A) Survival patterns for carriers of the non-e4 (NoE4), e2/4, e3/4, and e4/4 genotypes. (B) Survival patterns for carriers of the non-e4 (NoE4) and any risk allele (E4) genotypes. Log rank (LR) measures equality of the survival distributions. Total/died denotes the total number of carriers and the number of deaths among them. LE=life expectancy; CI=confidence interval.

Figure 2

Kaplan-Meier age patterns of probability of staying free of a disease for carriers of different APOE genotypes. (A) Probability patterns for onsets of CVDs for carriers of the non-e4 (NoE4), e2/4, e3/4, and e4/4 genotypes. (B) Probability patterns for onsets of CVDs for carriers of the non-e4 (NoE4) and any risk allele (E4) genotypes. (C) and (D) The same as (A) and (B) but for cancer. Log rank (LR) measures equality of the probability distributions. Total/CVD (or cancer) denotes the total number of carriers and the number of CVD (or cancer) onsets among them. Healthy life expectancy (HLE) is defined as life without CVD (diseases of heart and stroke) or cancer (all sites but skin). CI=confidence interval.