FOXO3 Variant Associates with Reduced Cardiovascular Disease Mortality in Humans

Researchers recently published evidence for variants in the FOXO3 gene to correlate with modestly reduced mortality due to cardiovascular disease. FOXO3 is one of the very few longevity-associated genes in which the statistical associations have been replicated in different human study populations. In the vast majority of cases there is no replication, which suggests that the genetic contribution to longevity is very complex, made up of thousands of individually tiny contributions that strongly interact with one another and environmental circumstances. This effects in one group of people do not appear in another, even within the same region and heritage:

FoxO3 is an evolutionarily conserved transcription factor in the insulin signaling pathway. It regulates expression of genes controlling a multitude of processes that could enhance health and lifespan. A previous study of American men of Japanese ancestry was the first to find an association of three single nucleotide polymorphisms (SNPs) of FOXO3 with human longevity. The association was replicated in 11 other independent studies of populations of diverse ancestry. The mechanisms by which the protective alleles reduce mortality to promote human longevity are also not known. Identifying the cause of death in longevity-allele carriers vs. noncarriers may provide clues as to why FOXO3 SNPs strongly protect against mortality.

We hypothesized that the longevity-associated FOXO3 genotype would be associated with a sizable risk reduction for mortality and with one or more major age-associated clinical causes of death, such as coronary heart disease (CHD), cancer, and stroke. To test this hypothesis we utilized an extensive, prospectively collected dataset from our long-lived cohort of American men of Japanese ancestry, well characterized for aging phenotypes, drawn from the Honolulu Heart Program prospective cohort study. We genotyped this study population to prospectively assess the following: (i) the effect size of the protective (longevity-associated) FOXO3 genotype on total (all-cause) mortality in 17 years of follow-up; and (ii) the effect of the protective FOXO3 genotype on cause-specific mortality. We then attempted a replication of major findings in a suitable cohort of elderly white and black Americans of both sexes in the Health Aging and Body Composition cohort study, which had 17 years of follow-up.

we demonstrated a large (10%) protective effect against all-cause mortality and 26% for CHD mortality over 17 years of follow-up. The protective effect was, moreover, observed in three genetically different populations. Our study contrasts with the vast majority of prior investigations of FOXO3 variants and longevity, which have been case-control studies that did not quantify risk over time, but rather simply tested for association with an outcome. The magnitude of the impact of an absence of the protective FOXO3 G allele was comparable to the increase in risk of death from smoking a pack of cigarettes a day for 25 years in Japanese men. In black males and females, it was equivalent to having a 20 mmHg higher systolic blood pressure, and in white men and women to a 20 mg dL-1 elevation in fasting blood glucose. The data suggest a possible mediator role for hypertension, which we found to be less prevalent in middle-aged women carrying the FOXO3 G allele.