FOXO3 Longevity Genotype Mitigates Risk Posed by Hypertension on Incident Coronary Artery Disease in Middle-Aged Men: Kuakini Honolulu Heart Program

Abstract

Background: This study tested whether the carriage of the longevity-associated G-allele of FOXO3 SNP rs2802292 (TG/GG) protects against incident coronary artery disease (CAD) in men with hypertension.

Methods: Subjects were American men residing on Oahu having Japanese (n = 5415) or Okinawan (n = 897) ancestry and free of CAD at baseline (1965-1968) when aged 45-68 years.

Results: During the follow-up, there were 1 629 incident CAD cases. Adjusting for age and cardiovascular disease risk factors, the main effect Cox model showed that in men of Japanese ancestry, hypertension was a strong predictor of CAD (hazard ratio [HR] 1.61; 95% confidence interval [CI] 1.44-1.80), p < .0001), but TG/GG genotype was not associated with CAD (HR 0.92; 95% CI = 0.82-1.02; p = .11). A full Cox model showed the interaction of TG/GG with hypertension was significant (β = -0.23, p = .038). Stratified by hypertension status, TG/GG genotype TG/GG had a protective effect against CAD in each group (HR 0.83; 95% CI 0.71-0.96; p = .021 in men of Japanese heritage, and HR 0.66; 95% CI 0.43-1.01; p = .054 in men of Okinawan heritage). No association with CAD was seen in normotensive men having either Japanese (HR 1.04; 95% CI 0.89-1.22; p = .61) or Okinawan (HR 0.95; 95% CI 0.66-1.38; p = .79) heritage.

Conclusions: The present prospective study found that longevity-associated FOXO3 genotype did not independently affect the risk of CAD in all men. Rather, it was associated with protection against incident CAD in men with hypertension. Hypertensive middle-aged men with FOXO3TT genotype may merit particular attention in CAD prevention programs.

Keywords: FOXO3; Coronary artery disease; Genetics; Hypertension; Longevity.

Graphical Abstract

Figure 1.

Kaplan–Meier survival curves for cohort participants free of incident coronary artery disease (CAD) by hypertension status, by FOXO3 genotypes, and by different combinations of hypertension status and FOXO3 genotypes for Japanese-ancestry cohort. The p-values of log rank tests are, for part A (HTN vs NT), p = 5.8 × 10^–27, for part B (FOXO3 TT vs TG/GG genotype), p = .14, and for part C (HTN × FOXO3 genotype) comparing genotype FOXO3 TG/GG vs TT, p = .75 in NT, and p = .013 in HTN; comparing HTN vs NT, p = 9.6 × 10^–9 for FOXO3 genotype TG/GG, and p = 5.7 × 10^–21 for FOXO3 genotype TT. HTN, hypertensive; NT, normotensive.