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. 2016 Aug;15(4):617-24.
doi: 10.1111/acel.12452. Epub 2016 Apr 13.

The FoxO3 gene and cause-specific mortality

Bradley J Willcox  1   2 , Gregory J Tranah  3 , Randi Chen  1 , Brian J Morris  1   2   4 , Kamal H Masaki  1   2 , Qimei He  1 , D Craig Willcox  1   2   5 , Richard C Allsopp  6 , Stefan Moisyadi  6 , Leonard W Poon  7 , Beatriz Rodriguez  1   2 , Anne B Newman  8 , Tamara B Harris  9 , Steven R Cummings  3 , Yongmei Liu  10 , Neeta Parimi  3 , Daniel S Evans  3 , Phil Davy  6 , Mariana Gerschenson  11 , Timothy A Donlon  1
Affiliations

The FoxO3 gene and cause-specific mortality

Bradley J Willcox et al. Aging Cell. 2016 Aug.

Abstract

The G allele of the FOXO3 single nucleotide polymorphism (SNP) rs2802292 exhibits a consistently replicated genetic association with longevity in multiple populations worldwide. The aims of this study were to quantify the mortality risk for the longevity-associated genotype and to discover the particular cause(s) of death associated with this allele in older Americans of diverse ancestry. It involved a 17-year prospective cohort study of 3584 older American men of Japanese ancestry from the Honolulu Heart Program cohort, followed by a 17-year prospective replication study of 1595 white and 1056 black elderly individuals from the Health Aging and Body Composition cohort. The relation between FOXO3 genotype and cause-specific mortality was ascertained for major causes of death including coronary heart disease (CHD), cancer, and stroke. Age-adjusted and multivariable Cox proportional hazards models were used to compute hazard ratios (HRs) for all-cause and cause-specific mortality. We found G allele carriers had a combined (Japanese, white, and black populations) risk reduction of 10% for total (all-cause) mortality (HR = 0.90; 95% CI, 0.84-0.95; P = 0.001). This effect size was consistent across populations and mostly contributed by 26% lower risk for CHD death (HR = 0.74; 95% CI, 0.64-0.86; P = 0.00004). No other causes of death made a significant contribution to the survival advantage for G allele carriers. In conclusion, at older age, there is a large risk reduction in mortality for G allele carriers, mostly due to lower CHD mortality. The findings support further research on FOXO3 and FoxO3 protein as potential targets for therapeutic intervention in aging-related diseases, particularly cardiovascular disease.

Keywords: FOXO3; heart disease; longevity; mortality.

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Figures

Figure 1
Figure 1
Meta‐analysis of all‐cause mortality for G allele carriers. Hazard ratios (HRs) for mortality over prospective follow‐up periods of 17 years for the cohorts of Americans of black (Health ABC) and white (Health ABC) individuals and 17 years for Americans of Japanese (Honolulu Heart Program (HHP)) ancestry, utilizing a dominant model. Tests for heterogeneity for all populations combined were P = 0.96, demonstrating that the populations are appropriate for a combined meta‐analysis. During the 17‐year prospective follow‐up, G allele carriers (FOXO3 SNP rs2802292) had HR that ranged from 0.87 (blacks) to 0.91 (whites) and a combined risk reduction of 10% for total mortality (HR = 0.90; 95% CI, 0.84–0.95; P = 0.001).
Figure 2
Figure 2
Meta‐analysis of CHD mortality. Hazard ratios (HRs) for CHD mortality over prospective follow‐up periods of 17 years for the cohorts of Americans of black (Health ABC; n = 140 CHD deaths), white (Health ABC; n = 224 CHD deaths) and 17 years for Americans of Japanese (Honolulu Heart Program (HHP; n = 524 CHD deaths)) ancestry, utilizing a dominant model. Tests for heterogeneity for all populations combined yielded P = 0.75, demonstrating that the populations could be used for a combined analysis, utilizing a dominant model. CHD mortality risk for G allele carriers ranged from 0.61 (blacks) to 0.76 (whites) with a combined (Japanese, white and black populations) risk reduction of 26% for total mortality (HR = 0.74; 95% CI, 0.64–0.86; P = 0.00004). Tests of model proportionality were met.
Figure 3
Figure 3
FOXO3 G allele carrier status (as % of cohort) by attained age. Percentage of carriers of the longevity‐associated FOXO3 G allele of SNP rs2802292 increased with age in the pooled population (P < 0.0001; logistic regression; adjusted for race).
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