Abstract 661: Foxo3 Genotype Increases Lifespan By A Major Effect On Cardiovascular Mortality

Abstract

The strongest, most consistently replicated genetic influences on human lifespan worldwide involve specific alleles of the ApoE and Foxo3 genes. For FOXO3 , the G allele of SNP rs2802292 exhibits the most robust association. The aim of the present study was to determine FOXO3 genotype-related cause-specific mortality over 9 years in 3,584 elderly American men of Japanese ancestry from the Kuakini Hawaii Lifespan Study, an extensively characterized, long-studied, robust cohort drawn from the Honolulu Heart Program, which recruited subjects in 1965–1968. A Cox proportional hazards model computed relative risk of mortality for coronary heart disease (CHD), cancer, stroke, other circulatory diseases, and remaining causes. We created multivariate models that included other major risk factors for all-cause and cause-specific mortality. We determined contribution of FOXO3 genotype and other risk factors to mortality by estimating population attributable risk over 9 years follow-up for cause-specific mortality, and total mortality over 21 years. The survival curve, age standardized at 78 years (mean subject age at baseline), for carriers and non-carriers of the longevity-associated G allele showed that G allele carriers had longer survival ( P =0.016) during follow-up over 9 years (1,272 total deaths), and 21 years ( P =0.004; 3,211 total deaths). Over the 9 years, the 1,683 carriers of the G allele exhibited risk reductions of 16% (RR 0.84, 95% CI 0.74–0.95; P =0.008) for all-cause mortality, 41% (RR 0.59, 95% CI 0.43–0.80; P <0.001) for CHD mortality (202 deaths) and 21% (RR 0.79, 95% CI 0.67–0.94; P =0.009) for 535 deaths from causes besides CHD, cancer or stroke, independent of other major risk factors. Population attributable risk for the TT non-protective genotype was 24% for 9-year CHD mortality, 24% for hypertension, 21% for diabetes, 18% for inflammation and 12% for hypercholesterolemia. In conclusion, the G allele of the FOXO3 SNP rs2802292 has a major effect on mortality, principally through reduction in CHD risk, independent of known major risk factors. The findings support research on FOXO3 as a target for therapeutic intervention in healthy aging.