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


CONCLUSIONS
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.
Department of Research, Kuakini Medical Center, Honolulu, Hawaii.|Department of Geriatric Medicine, John A. Burns School of Medicine, University of Hawaii, Honolulu.
Bradley J
BJ
Willcox
Department of Research, Kuakini Medical Center, Honolulu, Hawaii.|Department of Geriatric Medicine, John A. Burns School of Medicine, University of Hawaii, Honolulu.|School of Medical Sciences and Bosch Institute, University of Sydney, New South Wales, Australia.
Brian J
BJ
Morris
California Pacific Medical Center Research Institute, San Francisco.
Gregory J
GJ
Tranah
Department of Research, Kuakini Medical Center, Honolulu, Hawaii.
Randi
R
Chen
Department of Research, Kuakini Medical Center, Honolulu, Hawaii.|Department of Geriatric Medicine, John A. Burns School of Medicine, University of Hawaii, Honolulu.
Kamal H
KH
Masaki
Department of Research, Kuakini Medical Center, Honolulu, Hawaii.
Qimei
Q
He
Department of Research, Kuakini Medical Center, Honolulu, Hawaii.|Department of Geriatric Medicine, John A. Burns School of Medicine, University of Hawaii, Honolulu.|Department of Human Welfare, Okinawa International University, Ginowan, Japan.
D Craig
DC
Willcox
Institute for Biogenesis Research, University of Hawaii, Honolulu.
Richard C
RC
Allsopp
Institute for Biogenesis Research, University of Hawaii, Honolulu.
Stefan
S
Moisyadi
Department of Cell and Molecular Biology, John A. Burns School of Medicine, University of Hawaii, Honolulu.
Mariana
M
Gerschenson
Institute for Biogenesis Research, University of Hawaii, Honolulu.
Philip M C
PMC
Davy
Institute of Gerontology, University of Georgia, Athens.
Leonard W
LW
Poon
Department of Research, Kuakini Medical Center, Honolulu, Hawaii.|Department of Geriatric Medicine, John A. Burns School of Medicine, University of Hawaii, Honolulu.
Beatriz
B
Rodriguez
Department of Epidemiology, University of Pittsburgh, Pennsylvania.
Anne B
AB
Newman
Laboratory of Neurogenetics, Intramural Research Program, National Institute on Aging, Bethesda, Maryland.
Tamara B
TB
Harris
California Pacific Medical Center Research Institute, San Francisco.
Steven R
SR
Cummings
Division of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, North Carolina.
Yongmei
Y
Liu
California Pacific Medical Center Research Institute, San Francisco.
Neeta
N
Parimi
California Pacific Medical Center Research Institute, San Francisco.
Daniel S
DS
Evans
Department of Research, Kuakini Medical Center, Honolulu, Hawaii.|Department of Cell and Molecular Biology, John A. Burns School of Medicine, University of Hawaii, Honolulu.|Department of Pathology, John A. Burns School of Medicine, University of Hawaii, Honolulu, Hawaii.
Timothy A
TA
Donlon
D000368:Aged; D000369:Aged, 80 and over; D006801:Humans; D008297:Male; D008875:Middle Aged; D001213:Asian; D001741:Black or African American; D003324:Coronary Artery Disease / Q000208:ethnology / Q000235:genetics / Q000401:mortality; D000071316:Forkhead Box Protein O3 / Q000235:genetics; D005838:Genotype; D007564:Japan / Q000208:ethnology; D008136:Longevity; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D012307:Risk Factors; D014481:United States; D000095223:White
D000071316:Forkhead Box Protein O3; C499517:FOXO3 protein, human
Coronary artery disease; Genetic; Inflammation; Longevity; Mortality
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