title: 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.
authors.affiliation: Center for Population Health and Aging, Duke University, Durham, NC 27708, USA. alexander.kulminski@duke.edu
authors.forename: Alexander M
authors.initials: AM
authors.lastname: Kulminski
authors.forename: Irina
authors.initials: I
authors.lastname: Culminskaya
authors.forename: Svetlana V
authors.initials: SV
authors.lastname: Ukraintseva
authors.forename: Konstantin G
authors.initials: KG
authors.lastname: Arbeev
authors.forename: Liubov
authors.initials: L
authors.lastname: Arbeeva
authors.forename: Deqing
authors.initials: D
authors.lastname: Wu
authors.forename: Igor
authors.initials: I
authors.lastname: Akushevich
authors.forename: Kenneth C
authors.initials: KC
authors.lastname: Land
authors.forename: Anatoli I
authors.initials: AI
authors.lastname: Yashin
mesh_terms: D000328:Adult; D017668:Age of Onset; D000483:Alleles; D001057:Apolipoproteins E / Q000235:genetics* / Q000378:metabolism; D002318:Cardiovascular Diseases / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D015331:Cohort Studies; D005787:Gene Frequency; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D053208:Kaplan-Meier Estimate; D008055:Lipids / Q000097:blood / Q000235:genetics; D008136:Longevity; D009369:Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D011110:Polymorphism, Genetic; D020033:Protein Isoforms / Q000235:genetics* / Q000378:metabolism
chemical_list: D001057:Apolipoproteins E; D008055:Lipids; D020033:Protein Isoforms