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

Kulminski, Alexander M

Culminskaya, Irina

Ukraintseva, Svetlana V

Arbeev, Konstantin G

Arbeeva, Liubov

Wu, Deqing

Akushevich, Igor

Land, Kenneth C

Yashin, Anatoli I

England

2017-06-06T17:15:31Z

2017-06-06T17:15:31Z

2011-06

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.

https://www.ncbi.nlm.nih.gov/pubmed/21332925

1474-9726

https://hdl.handle.net/10161/14853

eng

Wiley

Aging Cell

10.1111/j.1474-9726.2011.00689.x

Adult

Age of Onset

Alleles

Apolipoproteins E

Cardiovascular Diseases

Cohort Studies

Gene Frequency

Genetic Association Studies

Genetic Predisposition to Disease

Genotype

Humans

Kaplan-Meier Estimate

Lipids

Longevity

Neoplasms

Polymorphism, Genetic

Protein Isoforms

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

Journal article

Arbeev, Konstantin G|0000-0002-4195-7832

Land, Kenneth C|0000-0002-9551-7314

https://www.ncbi.nlm.nih.gov/pubmed/21332925

533

541

3

Center for Population Health & Aging

Duke

Duke Cancer Institute

Duke Population Research Center

Duke Population Research Institute

Institutes and Centers

Institutes and Provost's Academic Units

Physics

Sanford School of Public Policy

School of Medicine

Social Science Research Institute

Sociology

Staff

Trinity College of Arts & Sciences

University Institutes and Centers

Published

10