Comparing Effect of FOXO3 Gene and Urban-Rural Environment on Longevity: a Cohort Study among Older Adults in China

Abstract

BACKGROUND AND AIM: Empirical evidence points to urban residents having better health than their rural counterparts in several countries. Since lifespan has complex environmental and genetic underpinnings, we aim to study the effects of FOXO3 and the urban-rural disparity on mortality. METHODS: We used the Chinese Longitudinal Healthy Longevity Survey (CLHLS). The study cohort conducted surveys from 2008 to 2014, roughly biennially. The geographical distribution encompassed 22 out of 34 provinces in China. We used tagging SNPs rs2253310, rs2802292, and rs4946936 to identify the FOXO3A gene. We used residence classifications: village, town, and city. We used the Cox-proportional hazard regression models to assess the main effects and interaction of FOXO SNPs and residence on mortality risk adjusted for covariates. We conducted analysis to assess the effects of fine particulate matter (PM2.5) concentrations (three-year annual average, 1km×1km grid) and residential greenness (Normalized Difference Vegetation Index (NDVI), 500-meter radius) around participant residences. RESULTS:Among the 3179 participants, the baseline mean age was 85.1 (SD: 11.3) years, 1688 (53%) were female, 32.1% lived in urban areas (city/town), and 67.9% lived in the rural areas (village). The distributions of the six SNPs of FOXO3A are even across populations of different demographic characteristics (except for age and gender), indicating mendelian randomization. We found FOXO3A to have a protective effect on mortality [HR (95% CI): rs2802292 GG vs TT/TG: 0.825 (0.688, 0.989); rs2253310 CC vs. GG/GC 0.825 (0.689,0.989); rs4946936 TT vs. CC: 0.805 (0.655, 0.989)]. We found participants living in rural areas to have a lower risk of mortality [HR of the urban vs. the rural: 0.825 (95% CI: 0.735, 0.926)]. CONCLUSIONS:Higher air pollution and lower residential greenness both contributed to higher mortality. The effect size of the beneficial effect of FOXO3 on mortality is roughly equivalent to that living in urban areas. KEYWORDS: Longevity, FOXO3A, gene-environment interaction, air pollution, PM2.5, greenness