title: The FoxO3 gene and cause-specific mortality.
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.
authors.affiliation: Department of Research, Kuakini Medical Center, Honolulu, HI, 96817, USA.|Department of Geriatric Medicine, John A. Burns School of Medicine, University of Hawaii, Honolulu, HI, 96817, USA.
authors.forename: Bradley J
authors.initials: BJ
authors.lastname: Willcox
authors.affiliation: California Pacific Medical Center Research Institute, San Francisco, CA, 94107, USA.
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Tranah
authors.affiliation: Department of Research, Kuakini Medical Center, Honolulu, HI, 96817, USA.
authors.forename: Randi
authors.initials: R
authors.lastname: Chen
authors.affiliation: Department of Research, Kuakini Medical Center, Honolulu, HI, 96817, USA.|Department of Geriatric Medicine, John A. Burns School of Medicine, University of Hawaii, Honolulu, HI, 96817, USA.|School of Medical Sciences and Bosch Institute, University of Sydney, Sydney, NSW, 2006, Australia.
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Morris
authors.affiliation: Department of Research, Kuakini Medical Center, Honolulu, HI, 96817, USA.|Department of Geriatric Medicine, John A. Burns School of Medicine, University of Hawaii, Honolulu, HI, 96817, USA.
authors.forename: Kamal H
authors.initials: KH
authors.lastname: Masaki
authors.affiliation: Department of Research, Kuakini Medical Center, Honolulu, HI, 96817, USA.
authors.forename: Qimei
authors.initials: Q
authors.lastname: He
authors.affiliation: Department of Research, Kuakini Medical Center, Honolulu, HI, 96817, USA.|Department of Geriatric Medicine, John A. Burns School of Medicine, University of Hawaii, Honolulu, HI, 96817, USA.|Department of Human Welfare, Okinawa International University, Ginowan, Okinawa, 901-2701, Japan.
authors.forename: D Craig
authors.initials: DC
authors.lastname: Willcox
authors.affiliation: Institute for Biogenesis Research, University of Hawaii, Honolulu, HI, 96813, USA.
authors.forename: Richard C
authors.initials: RC
authors.lastname: Allsopp
authors.affiliation: Institute for Biogenesis Research, University of Hawaii, Honolulu, HI, 96813, USA.
authors.forename: Stefan
authors.initials: S
authors.lastname: Moisyadi
authors.affiliation: Institute of Gerontology, University of Georgia, Athens, GA, 30602, USA.
authors.forename: Leonard W
authors.initials: LW
authors.lastname: Poon
authors.affiliation: Department of Research, Kuakini Medical Center, Honolulu, HI, 96817, USA.|Department of Geriatric Medicine, John A. Burns School of Medicine, University of Hawaii, Honolulu, HI, 96817, USA.
authors.forename: Beatriz
authors.initials: B
authors.lastname: Rodriguez
authors.affiliation: Department of Epidemiology, University of Pittsburgh, Pittsburgh, PA, 15261, USA.
authors.forename: Anne B
authors.initials: AB
authors.lastname: Newman
authors.affiliation: Laboratory of Neurogenetics, Intramural Research Program, National Institute on Aging, Bethesda, MD, 20892, USA.
authors.forename: Tamara B
authors.initials: TB
authors.lastname: Harris
authors.affiliation: California Pacific Medical Center Research Institute, San Francisco, CA, 94107, USA.
authors.forename: Steven R
authors.initials: SR
authors.lastname: Cummings
authors.affiliation: Division of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, NC, 27157, USA.
authors.forename: Yongmei
authors.initials: Y
authors.lastname: Liu
authors.affiliation: California Pacific Medical Center Research Institute, San Francisco, CA, 94107, USA.
authors.forename: Neeta
authors.initials: N
authors.lastname: Parimi
authors.affiliation: California Pacific Medical Center Research Institute, San Francisco, CA, 94107, USA.
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Evans
authors.affiliation: Institute for Biogenesis Research, University of Hawaii, Honolulu, HI, 96813, USA.
authors.forename: Phil
authors.initials: P
authors.lastname: Davy
authors.affiliation: Department of Cell & Molecular Biology, University of Hawaii, Honolulu, HI, 96813, USA.
authors.forename: Mariana
authors.initials: M
authors.lastname: Gerschenson
authors.affiliation: Department of Research, Kuakini Medical Center, Honolulu, HI, 96817, USA.
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Donlon
mesh_terms: D000367:Age Factors; D000368:Aged; D000483:Alleles; D002423:Cause of Death; D015331:Cohort Studies; D003324:Coronary Artery Disease / Q000097:blood / Q000235:genetics / Q000401:mortality; D005260:Female; D000071316:Forkhead Box Protein O3 / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D006579:Heterozygote; D006801:Humans; D008297:Male; D009026:Mortality; D015999:Multivariate Analysis; D012307:Risk Factors; D014409:Tumor Necrosis Factor-alpha / Q000097:blood; D044465:White People / Q000235:genetics
chemical_list: C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; D014409:Tumor Necrosis Factor-alpha
keywords: FOXO3; heart disease; longevity; mortality