Comparing Effects of FOXO3 and Residing in Urban Areas on Longevity: A Gene-Environment Interaction Study

Forkhead box O3 (FOXO3) is a candidate longevity gene. Urban residents are also positively associated with longer life expectancy. We conducted a gene-environment interaction to assess the synergistic effect of FOXO3 and urban/rural environments on mortality. We included 3 085 older adults from the Chinese Longitudinal Healthy Longevity Survey. We used single-nucleotide polymorphisms (SNPs) rs2253310, rs2802292, and rs4946936 to identify the FOXO3 gene and classified residential locations as "urban" and "rural." Given the open cohort design, we used the Cox-proportional hazard regression models to assess the mortality risk. We found the minor allele homozygotes of FOXO3 to have a protective effect on mortality (HR [95% CI] for rs4946936 TT vs CC: 0.807 [0.653-0.996]; rs2802292 GG vs TT: 0.812 [0.67-0.985]; rs2253310 CC vs GG: 0.808 [0.667-0.978]). Participants living in urban areas had a lower risk of mortality (HR of the urban vs the rural: 0.854 [0.759-0.962]). The interaction between FOXO3 and urban and rural regions was statistically significant (pinteraction < .01). Higher air pollution (fine particulate matter: PM2.5) and lower residential greenness (Normalized Difference Vegetation Index [NDVI]) both contributed to higher mortality. After adjusting for NDVI and PM2.5, the protective effect size of FOXO3 SNPs was slightly attenuated while the protective effect size of living in an urban environment increased. The effect size of the beneficial effect of FOXO3 on mortality is roughly equivalent to that of living in urban areas. Our research findings indicate that the effect of places of residence and genetic predisposition of longevity are intertwined.