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

The FoxO3 gene and cause-specific mortality.

Author information

1
Department of Research, Kuakini Medical Center, Honolulu, HI, 96817, USA.
2
Department of Geriatric Medicine, John A. Burns School of Medicine, University of Hawaii, Honolulu, HI, 96817, USA.
3
California Pacific Medical Center Research Institute, San Francisco, CA, 94107, USA.
4
School of Medical Sciences and Bosch Institute, University of Sydney, Sydney, NSW, 2006, Australia.
5
Department of Human Welfare, Okinawa International University, Ginowan, Okinawa, 901-2701, Japan.
6
Institute for Biogenesis Research, University of Hawaii, Honolulu, HI, 96813, USA.
7
Institute of Gerontology, University of Georgia, Athens, GA, 30602, USA.
8
Department of Epidemiology, University of Pittsburgh, Pittsburgh, PA, 15261, USA.
9
Laboratory of Neurogenetics, Intramural Research Program, National Institute on Aging, Bethesda, MD, 20892, USA.
10
Division of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, NC, 27157, USA.
11
Department of Cell & Molecular Biology, University of Hawaii, Honolulu, HI, 96813, USA.

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

PMID:
27071935
PMCID:
PMC4933667
DOI:
10.1111/acel.12452
[Indexed for MEDLINE]
Free PMC Article

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