Abstract 19547: FOXO3 Genotype Strongly Impacts Coronary Heart Disease Mortality in Three Populations

The G allele of the FOXO3 SNP rs2802292 has a strong, consistently replicated protective association with longevity. We investigated the effect of FOXO3 genotype on coronary heart disease (CHD) mortality - a major cause of mortality worldwide. We genotyped DNA collected in 1991-93, at Exam 4 of the Honolulu Heart Program (HHP), from 3,584 American males of Japanese ancestry aged 71-93 years. Study participants were followed for up to 9 years for CHD mortality and for up to 11 years in a replication cohort - the Health Aging and Body Composition (Health ABC) study. Health ABC is a prospective observational study of 3,075 well functioning, community-dwelling, male and female, white and black Americans, aged 70-79 years at baseline. Cox proportional hazards models demonstrated that Americans of Japanese, white and black ethnicity who were G allele carriers had a combined risk reduction of 31% for CHD mortality (HR = 0.69; 95% CI, 0.58-0.82; P =0.00002). Reduction in risk of death from CHD was 38% in Japanese, 24% in whites and 29% in blacks. This finding remained virtually unchanged when included in a multivariable model of common CHD risk factors. We subsequently assessed the contribution of FOXO3 genotype, relative to other common risk factors, to CHD mortality in these populations by estimating population attributable risk (PAR). In the Americans of Japanese ancestry, PAR for the TT (non-protective) genotype was high, at 24%, equivalent to hypertension (24%), and greater than diabetes (21%), hypercholesterolemia (12%) and ever smoking (6%). PAR for FOXO3 genotype was lower at 9% and 3% in white and black Americans, respectively, principally due to lower prevalence of the TT (risk) genotype. We subsequently measured C-reactive protein (CRP) in a population subsample, and found lower blood CRP levels in G allele carriers ( P G allele of the FOXO3 SNP rs2802292 has a major protective effect on CHD mortality, possibly related to lower blood levels of inflammation. The findings support further research on potential mechanisms and point to FoxO3 as a potential target therapeutic target.