Exploring the Relationship of rs2802292 with Diabetes and NAFLD in a Southern Italian Cohort—Nutrihep Study

<b>Background:</b> The minor G-allele of FOXO3 rs2802292 is associated with human longevity. The aim of this study was to test the protective effect of the variant against the association with type 2 Diabetes and NAFLD. <b>Methods:</b> rs2802292 was genotyped in a large population of middle-aged subjects (n = 650) from a small city in Southern Italy. All participants were interviewed to collect information about lifestyle and dietary habits; clinical characteristics were recorded, and blood samples were collected from all subjects. The association between rs2802292 and NAFLD or diabetes was tested using a logistic model and mediation analysis adjusted for covariates. <b>Results:</b> Overall, the results indicated a statistical association between diabetes and rs2802292, especially for the TT genotype (OR = 2.14, 1.01 to 4.53 95% C.I., <i>p</i> = 0.05) or in any case for those who possess the G-allele (OR = 0.45, 0.25 to 0.81 95% C.I., <i>p</i> = 0.008). Furthermore, we found a mediation effect of rs2802292 on diabetes (as mediator) and NAFLD. There is no direct relationship between rs2802292 and NAFLD, but the effect is direct (β = 0.10, -0.003 to 0.12 95% C.I., <i>p</i> = 0.04) on diabetes, but only in TT genotypes. <b>Conclusions:</b> The data on our cohort indicate that the longevity-associated FOXO3 variant may have protective effects against diabetes and NAFLD.