Age-Based Differences in the Genetic Determinants of Glycemic Control: A Case of FOXO3 Variations

BACKGROUND: Glucose homeostasis is a trait of healthy ageing and is crucial to the elderly, but less consideration has been given to the age composition in most studies involving genetics and hyperglycemia. METHODS: Seven variants in FOXO3 were genotyped in three cohorts (n = 2037; LLI, MI_S and MI_N; mean age: 92.5 ± 3.6, 45.9 ± 8.2 and 46.8 ± 10.3, respectively) to compare the contribution of FOXO3 to fasting hyperglycemia (FH) between long-lived individuals (LLI, aged over 90 years) and middle-aged subjects (aged from 35-65 years). RESULTS: A different genetic predisposition of FOXO3 alleles to FH was observed between LLI and both of two middle-aged cohorts. In the LLI cohort, the longevity beneficial alleles of three variants with the haplotype "AGGC" in block 1 were significantly protective to FH, fasting glucose, hemoglobin A1C and HOMA-IR. Notably, combining multifactor dimensionality reduction and logistic regression, we identified a significant 3-factor interaction model (rs2802288, rs2802292 and moderate physical activity) associated with lower FH risk. However, not all of the findings were replicated in the two middle-aged cohorts. CONCLUSION: Our data provides a novel insight into the inconsistent genetic determinants between middle-aged and LLI subjects. FOXO3 might act as a shared genetic predisposition to hyperglycemia and lifespan.