FOXO3 longevity genotype attenuates the impact of hypertension on cerebral microinfarct risk

Objective: The G-allele of FOXO3 SNP rs2802292, which is associated with human resilience and longevity, has been shown to attenuate the impact of hypertension on the risk of intracerebral hemorrhage (ICH). We sought to determine whether the FOXO3 G-allele similarly attenuates the impact of hypertension on the risk of cerebral microinfarcts (CMI). Methods: From a prospective population-based cohort of American men of Japanese ancestry from the Kuakini Honolulu Heart Program (KHHP) and Kuakini Honolulu-Asia Aging Study (KHAAS) that had brain autopsy data, age-adjusted prevalence of any CMI on brain autopsy was assessed. Logistic regression models, adjusted for age at death, cardiovascular risk factors, FOXO3 and APOE-epsilon 4 genotypes, were utilized to determine the predictors of any CMI. Interaction of FOXO3 genotype and hypertension was analyzed. Results: Among 809 men with complete data, 511 (63.2%) participants had evidence of CMI. A full multivariable model demonstrated that BMI [odds ratio (OR) 1.07, 95% confidence interval (CI) 1.011.14, P = 0.015) was the only predictor of CMI, while hypertension was a borderline predictor (OR 1.44, 95% CI 1.002.08, P = 0.052). However, a significant interaction between FOXO3 G-allele carriage and hypertension was observed (P = 0.020). In the stratified analyses, among the participants without the longevity-associated FOXO3 G-allele, hypertension was a strong predictor of CMI (OR 2.25, 95% CI 1.343.77, P = 0.002), while among those with the longevity-associated FOXO3 G-allele, hypertension was not a predictor of CMI (OR 0.88, 95% CI 0.511.54, P = 0.66). Conclusion: The longevity-associated FOXO3 G-allele mitigates the impact of hypertension on the risk of CMI.