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

Abstract

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.

Fig 1. Graphical representation of the polymorphisms and LD structure across FOXO3 in the subjects of this study.

The FOXO3 locus consists of four exons (thin dark-shaded boxes represent UTRs, and thick dark-shaded boxes represent coding exons). The thin lines represent introns. The relative locations of seven variants are listed. Two linkage disequilibrium (LD) blocks are defined. The measures of LD (D’) among paired of variants are shown graphically by color (r²). A white box represents very low LD, and a dark box represents very high LD. The constitutions and frequencies of three common haplotypes in block 1 are listed.

Fig 2. Comparisons of alleles and haplotypes in FOXO3 and tertiles of hyperglycemia related parameters in each cohort.

MAF: minor allele frequency; T1,T2 and T3 represents the lowest, middle and highest tertile, respectively. p-values were obtained from logistic regression analysis adjusted for age and gender. Only in LLI, was a significant contribution of FOXO3 found. Both frequencies of rs2802288*A and rs2802292*G were reduced when A) fasting plasma glucose and B) HbA_1c increased. C) The frequency of Haplotype 2 “AGGC” in block 1 decreased when fasting plasma glucose increased. D) The frequency of rs2802292*G decreased when HOMA-IR increased.

Fig 3. Schematic of the potential hypothesis for an inconsistence in genetic and environmental determinants across human lifespan.

SNPs having more severe effects on glucose homeostasis are likely to have resulted in earlier mortality, removing them/their effects from the long-lived cohort, and that this allows them to easier detect other variants having more modest effects.