Longevity-Associated FOXO3 Genotype and its Impact on Coronary Artery Disease Mortality in Japanese, Whites, and Blacks: A Prospective Study of Three American Populations.
Level 3 - non-randomized controlled study
Prospective cohort study across three cohorts
PubMed 27694344 · doi:10.1093/gerona/glw196
What was done
Authors conducted a 15-year prospective observational study evaluating the relationship between the longevity-associated FOXO3 single nucleotide polymorphism (rs2802292) and coronary artery disease (CAD) mortality. The study analyzed 3,584 older American men of Japanese ancestry from the Kuakini Honolulu Heart Program and 1,595 White and 1,067 Black elderly individuals from the Health, Aging and Body Composition study (total n = 6,246). Associations were evaluated using multivariate Cox regression models, population-attributable risk (PAR) models, and plasma TNF-α comparisons.
What was found
Carriage of the FOXO3 rs2802292 G allele was protective against CAD mortality across all three racial groups. This association remained stable after multivariable adjustment for major risk factors in Japanese and White individuals, but not in Black individuals. The nonprotective TT genotype contributed a PAR of 15% in Japanese, 9% in Whites, and 3% in Blacks, ranking among the top three risk contributors to CAD mortality. In Japanese participants, the TT genotype PAR equaled that of hypertension (15%), whereas hypertension had a higher PAR in Whites (29%) and Blacks (26%). G-allele carriers demonstrated lower plasma TNF-α levels compared to noncarriers.
Why it matters
This study demonstrates that the longevity-associated FOXO3 G allele confers cross-ethnic protection against CAD mortality and suggests lower systemic inflammation as a potential mediating mechanism.
Limits
The observational design precludes establishing causality. The protective effect attenuated after adjustment for other risk factors in Black participants, and the Japanese cohort included only men. The abstract does not report hazard ratios, confidence intervals, or exact p-values.
Cited by
- contradicts The FOXO3A TT genotype has been consistently associated with human longevity and plays a protective role against oxidative stress, apoptosis, DNA repair, immune cell regulation, and stem cell maintenance.