Longevity-Associated FOXO3 Genotype and its Impact on Coronary Artery Disease Mortality in Japanese, Whites, and Blacks: A Prospective Study of Three American Populations

Abstract

Background: We recently reported that protection against coronary artery disease (CAD) mortality is the major contributor to longer life associated with FOXO3 genotype. The present study examined this relation in more detail.

Methods: We performed a 15-year observational study of 3,584 older American men of Japanese ancestry from the Kuakini Honolulu Heart Program cohort and 1,595 White and 1,067 Black elderly individuals from the Health Aging and Body Composition study.

Results: Multivariate Cox regression models demonstrated that carriage of the longevity-associated G allele of FOXO3 single nucleotide polymorphisms rs2802292 was a protective factor against CAD mortality in all three populations. In Japanese and Whites, but not in Blacks, the protective effect of the G allele was little changed in models adjusted for other major risk factors. Population-attributable risk (PAR) models found that the nonprotective TT genotype contributed 15%, 9%, and 3% to CAD mortality risk in Japanese, White, and Black Americans, respectively, and was one of the top three contributing factors to CAD mortality. In Japanese, this effect size was comparable with hypertension (15%), but in Whites and Blacks PAR for hypertension was higher (29% and 26%, respectively). G-allele carriers had lower plasma TNF-α than noncarriers, suggesting inflammation as a potential mediating factor for CAD mortality risk.

Conclusion: FOXO3 genotype is an important risk factor for CAD mortality in older populations. More research is needed to identify potential mechanisms and targets for intervention.

Keywords: Coronary artery disease; Genetic; Inflammation; Longevity; Mortality.

Figure 1.

Coronary artery disease (CAD) mortality in carriers (—) versus noncarriers (- -) of the longevity-associated G allele of SNP rs2802292 in 3,584 Japanese, 1,595 Whites, and 1,056 Blacks over 15 years of follow-up. Cox regression survival curves were generated by Cox proportional hazards models with baseline option, standardized at the age of 73 years; (A) Honolulu Heart Program (HHP; Japanese): 467 CAD deaths among 2,364 total deaths (19.8%; p = .0003 for difference between carriers and noncarriers); (B) Health Aging and Body Composition (ABC; Whites) study: 218 CAD deaths of 927 total deaths (23.5%; p = .045 for difference); (C) Health ABC (Blacks): 139 CAD deaths of 687 total deaths (20.2%; p = .080 for difference). A meta-analysis of the combined data (n = 6,269) for CAD mortality among 3,584 Japanese, 1,596 Whites, and 1,067 Blacks using a dominant model yielded a HR of 0.72 (95% CI 0.62–0.83; p = .00001).