Abstract
Background: We have shown that the FOXO3 longevity genotype moderates the mortality risk in men with hypertension. This study aimed to test whether the FOXO3 longevity genotype moderates the risk of incident coronary heart disease (CHD) in men with hypertension. Methods: The study included 6,312 Japanese American men who were free of CHD at the baseline examination of the Kuakini Honolulu Heart Program (1965-1968, age 53.9±5.4, range 45-68 years), and had been genotyped for the FOXO3 SNP rs2802292 ( FOXO3-292 ). The minor G allele, i.e., TG or GG (TG / GG) genotype is associated with longevity vs. the common TT genotype, which is not . Hypertension was defined as systolic/diastolic BP ≥ 140/90 mmHg or taking antihypertensive medication. Incident CHD was diagnosed from hospital records and follow up examinations to 12/31/2000 (35 years of follow-up). The date of the first coronary event was defined as onset date of CHD, including myocardial infarction, coronary insufficiency, angina, coronary bypass, coronary angioplasty, silent myocardial ischemia, and CHD death. Cox proportional hazard models were used to assess the association of FOXO3-292 genotype and hypertension with incident CHD. Results: During follow-up, 1,629 men developed incident CHD. The age-adjusted incidence rate of CHD was 8.99, 8.31, and 8.62 per 1,000 person-years ( p =0.62) for FOXO3-292 genotypes TT, TG, and GG , respectively. The Cox model, adjusting for age and CVD risk factors, showed hazard ratio (95%CI) for CHD with FOXO3-292 genotypes TG / GG compared to genotype TT was 0.91 (0.82-1.00; p =0.058). The full Cox model, adjusting for age and CVD risk factors, showed a significant interaction effect of FOXO3-292 genotypes TG / GG with hypertension on incident CHD (β= -0.22, p =0.03). After stratifying for hypertension, FOXO3-292 genotypes TG / GG had no effect on incident CHD in those without hypertension HR=1.01 (0.88-1.17; p =0.84) but had a protective effect on incident CHD HR=0.82 (0.74-0.95; p = 0.0064) in those with hypertension. Conclusion: We found the longevity associated FOXO3 genotype may not independently affect the risk of CHD in all men but was associated with protection against incident CHD in men with hypertension.
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