Authors: Kulminski AM; Culminskaya I; Ukraintseva SV; Arbeev KG; Arbeeva L; Wu D; Akushevich I; Land KC; Yashin AI
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.
Keywords: Adult; Age of Onset; Alleles; Apolipoproteins E/*genetics/metabolism; Cardiovascular Diseases/*genetics/mortality/pathology; Cohort Studies; Gene Frequency; Genetic Association Studies; *Genetic Predisposition to Disease; Genotype; Humans; Kaplan-Meier Estimate; Lipids/blood/genetics; *Longevity; Neoplasms/*genetics/mortality/pathology; Polymorphism, Genetic; Protein Isoforms/*genetics/metabolism|
Journal: Aging cell Volume: 10 Issue: 3 Pages: 533-41 Date: Feb. 22, 2011 PMID: 21332925 |
Kulminski AM, Culminskaya I, Ukraintseva SV, Arbeev KG, Arbeeva L, Wu D, Akushevich I, Land KC, Yashin AI (2011) Trade-off in the effects of the apolipoprotein E polymorphism on the ages at onset of CVD and cancer influences human lifespan. Aging cell 10: 533-41.
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