European Journal of Human Genetics (2007) 15, 294–301. doi:10.1038/sj.ejhg.5201766; published online 24 January 2007

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

Maris Kuningas1,2, Reedik Mägi3, Rudi G J Westendorp1, P Eline Slagboom4, Maido Remm3 and Diana van Heemst1

  1. 1Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, The Netherlands
  2. 2Department of Biotechnology, Institute of Molecular and Cell Biology, University of Tartu, Tartu, Estonia
  3. 3Department of Bioinformatics, Institute of Molecular and Cell Biology, Tartu University, Tartu, Estonia
  4. 4Section of Molecular Epidemiology, Department of Medical Statistics, Leiden University Medical Center, Leiden, The Netherlands

Correspondence: Maris Kuningas, Leiden University Medical Center (LUMC), Department of Gerontology and Geriatrics, C2-R, PO box 9600, 2300 RC Leiden, The Netherlands. Tel: +31 71 526 6640; Fax: +31 71 524 8159; E-mail:

Received 25 July 2006; Revised 20 November 2006; Accepted 21 November 2006; Published online 24 January 2007.



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.


Foxo1a, Foxo3a, mortality, lifespan, age-related disease, haplotype