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

Journal Article

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

Duke Authors

Cited Authors

  • Kulminski, AM; Culminskaya, I; Ukraintseva, SV; Arbeev, KG; Arbeeva, L; Wu, D; Akushevich, I; Land, KC; Yashin, AI

Published Date

  • June 2011

Published In

Volume / Issue

  • 10 / 3

Start / End Page

  • 533 - 541

PubMed ID

  • 21332925

Electronic International Standard Serial Number (EISSN)

  • 1474-9726

International Standard Serial Number (ISSN)

  • 1474-9718

Digital Object Identifier (DOI)

  • 10.1111/j.1474-9726.2011.00689.x

Language

  • eng