Haplotypes in the human Foxo1a and Foxo3a genes; impact on disease and mortality at old age

Abstract

Recently, the Daf-16 gene has been shown to regulate the lifespan of nematodes and flies. In mammals, the Daf-16 homologues are forkhead (FOXO) transcription factors, of which specific functions have been identified for Foxo1a and Foxo3a. Despite that, their influence on human age-related trajectories and lifespan is unknown. Here, we analysed the effect of genetic variance in Foxo1a and Foxo3a on metabolic profile, age-related diseases, fertility, fecundity and mortality. This study was carried out in the prospective population-based Leiden 85-plus Study, which includes 1245 participants, aged 85 years or more. The mean follow-up time was 4.4 years. Haplotype analyses of Foxo1a revealed that carriers of haplotype 3 'TCA' have higher HbA1c levels (P ¼ 0.025) and a 1.14-fold higher all-cause mortality risk (P ¼ 0.021). This increase in mortality was attributable to death from diabetes, for which a 2.43-fold increase was observed (P ¼ 0.025). The analyses with Foxo3a haplotypes revealed no differences in metabolic profile, fertility or fecundity. However, increased risks of stroke were observed for Foxo3a block-A haplotype 2 'GAGC' (P ¼ 0.007) and haplotype 4 'AAAT' (P ¼ 0.014) carriers. In addition, the haplotype 2 'GAGC' carriers had a 1.13-fold increased risk for all-cause mortality (P ¼ 0.036) and 1.19-fold increased risk for cardiovascular mortality (P ¼ 0.052). In conclusion, this study shows that genetic variation in evolutionarily conserved Foxo1a and Foxo3a genes influences lifespan in our study population.

Association of FOXO3A variation with human longevity confirmed in German centenarians

“…reported by us (Table 5) and Willcox et al are rather large, the available data do not allow us to ascertain whether there is an additive or a dominant effect. The influence of FOXO3A variation on longevity had also been examined in the Dutch Leiden 85-plus study using both single-point and haplotype analysis (15). None of the 11 tested SNPs yielded a significant result when 2 elderly cohorts (aged 85 and 88-92 years) were, in a cross-sectional manner, compared with a younger control sample (aged 27-36 years).…”

“…Kuningas et al (15) observed that carriers of a particular 4-SNP haplotype (GAGC from rs2802288, rs2883881, rs12200646, and rs13220810) had increased risks for all-cause and cardiovascular mortalities. The effects were very small, and the findings did not hold up to multiple testing (15). These 4 SNPs were also subjected to haplotype analysis in our sample collection.…”

“…It has recently been shown by computer simulation that samples of nonagenarians need to be 5 times larger than those of centenarians to achieve comparable power and that the performance of association studies is drastically reduced when nonagenarians are considered as cases (18). It can be expected that the power is even more decreased when octogenarians are used, as was done in the Dutch study (15), which may explain why Kuningas et al did not observe any association with FOXO3A in their cross-sectional comparisons. Our results highlight the relevance of centenarians for genetic longevity research, because they appear more valuable for such studies than octogenarians and nonagenarians.…”

FOXO3A genotype is strongly associated with human longevity

“…Two recent studies suggest that FOXO genes deserve further scrutiny. First, a longitudinal study of elderly Dutch men and women found that a FOXO1A haplotype predicted 4-year survival and that a FOXO3A haplotype predicted stroke risk (39). Second, the Framingham Study, in a genome-wide association analysis, found that a FOXO3A SNP was strongly associated with age at natural menopause in women (P ϭ 0.00003).…”

“…Prior studies have found links between FOXO genes and other aging phenotypes, including 4-year survival and stroke risk (39) as well as premature menopause (40).…”