title: 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=0.025) and a 1.14-fold higher all-cause mortality risk (P=0.021). This increase in mortality was attributable to death from diabetes, for which a 2.43-fold increase was observed (P=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=0.007) and haplotype 4 'AAAT' (P=0.014) carriers. In addition, the haplotype 2 'GAGC' carriers had a 1.13-fold increased risk for all-cause mortality (P=0.036) and 1.19-fold increased risk for cardiovascular mortality (P=0.052). In conclusion, this study shows that genetic variation in evolutionarily conserved Foxo1a and Foxo3a genes influences lifespan in our study population.
authors.affiliation: Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, The Netherlands. m.kuningas@lumc.nl
authors.forename: Maris
authors.initials: M
authors.lastname: Kuningas
authors.forename: Reedik
authors.initials: R
authors.lastname: Mägi
authors.forename: Rudi G J
authors.initials: RG
authors.lastname: Westendorp
authors.forename: P Eline
authors.initials: PE
authors.lastname: Slagboom
authors.forename: Maido
authors.initials: M
authors.lastname: Remm
authors.forename: Diana
authors.initials: D
authors.lastname: van Heemst
mesh_terms: D000328:Adult; D000369:Aged, 80 and over; D005260:Female; D000071161:Forkhead Box Protein O1; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000235:genetics*; D006239:Haplotypes / Q000235:genetics*; D006801:Humans; D008297:Male; D009017:Morbidity; D009026:Mortality
chemical_list: C085126:FOXO1 protein, human; C499517:FOXO3 protein, human; D000071161:Forkhead Box Protein O1; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors