,

–

Coffer PJ, Burgering BM (

) Forkhead-box transcription factors and their role in the immune system. Nat. Rev. Immunol.

,

–

Consortium TIH (

) The International Ha

ap Project. Nature

,

–

Dudbridge F (

) Pedigree disequilibrium tests for multilocus haplo- types. Genet. Epidemiol.

,

–

Flachsbart F, Caliebe A, Kleindorp R, Blanche H, von Eller-Eberstein H, Nikolaus S, Schreiber S, Nebel A (

) Association of FOXO

A vari- ation with human longevity confirmed in German centenarians. Proc. Natl Acad. Sci. USA

,

–

Furukawa-Hibi Y, Yoshida-Araki K, Ohta T, Ikeda K, Motoyama N (

) FOXO forkhead transcription factors induce G(

)-M check- point in response to oxidative stress. J. Biol. Chem.

,

–

Furuyama T, Nakazawa T, Nakano I, Mori N (

) Identification of the differential distribution patterns of

NAs and consensus bind- ing sequences for mouse DAF-

homologues. Biochem. J.

,

–

Go¨gele M, Pattaro C, Fuchsberger C, Minelli C, Pramstaller PP, Wjst M (

) Heritability analysis of life span in a semi-isolated population followed across four centuries reveals the presence of pleiotropy between life span and reproduction. J. Gerontol. A Biol. Sci. Med. Sci.

,

–

Hampe J, Wollstein A, Lu T, Frevel HJ, Will M, Manaster C, Schreiber S (

) An integrated system for high throughput Ta

an based SNP genotyping. Bioinformatics

,

–

Hjelmborg J

, Iachine I, Skytthe A, Vaupel JW, M

ue M, Koskenvuo M, Kaprio J, Pedersen NL, Christensen K (

) Genetic influence on human lifespan and longevity. Hum. Genet.

,

–

Statistical analysis

Haplotype-tagging SNPs (htSNPs) of FOXO1, FOXO4, and FOXO6 were selected based on the HapMap genotypes of Utah residents with ancestry from northern and western Europe (CEU; http://www.hapmap.org/) and the pairwise tagging option implemented in the Haploview v3.32 program (Barrett et al., 2005) (http://www.broad.mit.edu/mpg/haploview/) (minor allele frequency: > 0.05, pairwise r2 ‡ 0.8, P : > 0.01, for htSNPs HWE see Table 1). The exact genomic regions for the selection of the htSNPs were as follows: for FOXO1 chromosome 13: 40 022 274–40 144 279; for FOXO4 X chromosome: 70 227 715–70 245 118 and for FOXO6 chromosome 1: 41 596 756–41 624 373 (all NCBI36). The Haploview program was also applied for the haplotype analysis of FOXO1. An additional haplotype analy- sis using a two-marker sliding window was performed for all three genes with the sliding window option implemented in the programme COCAPHASE, version 2.403 that is part of PHASE, version 2.1 (http://www.stat.washington.edu/stephens/; Dud- bridge, 2003). Single-point analysis was performed using PLINK v1.07 (Purcell et al., 2007). P < 0.05 was considered statistically significant. The a priori power calculation for rs2755209 in the German and Italian women sample was carried out with the PS Power and Sample Size Program (PS version 3.0.14; http:// medipe.psu.ac.th/episoft/pssamplesize), assuming an OR of 0.77 as observed in the Chinese study (Li et al., 2009) and the minor allele frequency (40%) characteristic of the CEU HapMap sample.

Acknowledgments

We thank all study participants for their cooperation and the laboratory personnel at the Institute of Clinical Molecular Biol- ogy and the Popgen biobank for excellent technical assistance.

Funding

This study was supported by the DFG Excellence Cluster mation at Interfaces’.

Author contributions

R.K., A.N., S.S. designed research; R.K. performed R.K., F.F., A.A.P, A.M. analyzed data; R.K, A.N. wrote paper.

Hosaka T, Biggs

rd WH, Tieu D, Boyer AD, Varki NM, Cavenee WK, Arden KC (

) Disruption of forkhead transcription factor (FOXO) family members in mice reveals their functional diversification. Proc. Natl Acad. Sci. USA

,

–

Kato M, Yuan H, Xu ZG, Lanting L, Li SL, Wang M, Hu MC, Reddy MA, Natarajan R (

) Role of the Akt⁄Fo

a pathway in TGF- beta

-mediated mesangial cell dysfunction: a novel mechanism related to diabetic kidney disease. J. Am. Soc. Nephrol.

,

–

Kenyon C (

) The plasticity of aging: insights from long-lived mutants. Cell

,

–

Kojima T, Kamei H, Aizu T, Arai Y, Takayama M, Nakazawa S, Ebiha- ra Y, Inagaki H, Masui Y, Gondo Y, Sakaki Y, Hirose N (

) Association analysis between longevity in the Japanese population and polymorphic variants of genes involved in insulin and insulin- like growth factor

signaling pathways. Exp. Gerontol.

,

–

Kuningas M, Magi R, Westendorp RG, Slagboom PE, Remm M, van Heemst D (

) Haplotypes in the human Foxo

a and Foxo

a genes; impact on disease and mortality at old age. Eur. J. Hum. Genet.

,

–

Li Y, Wang WJ, Cao H, Lu J, Wu C, Hu FY, Guo J, Zhao L, Yang F, Zhang YX, Li W, Zheng GY, Cui H, Chen X, Zhu Z, He H, Dong B, Mo X, Zeng Y, Tian XL (

) Genetic association of FOXO

A and FOXO

A with longevity trait in Han Chinese populations. Hum. Mol. Genet.

,

–

Marchini J, Howie B, Myers S, M

ean G, Donnelly P (

) A new multipoint method for genome-wide association studies by imputa- tion of genotypes. Nat. Genet.

,

–

S (

) No association between microsomal triglyceride transfer protein (MTP) haplotype and longevity in humans. Proc. Natl Acad. Sci. USA

,

–

Pawlikowska L, Hu D, Huntsman S, Sung A, Chu C, Chen J, Joyner AH, Schork NJ, Hsueh WC, Reiner AP, Psaty BM, Atzmon G, Barzilai N, Cummings SR, Browner WS, Kwok PY, Ziv E (

) Association of common genetic variation in the insulin⁄IGF

signaling pathway with human longevity. Aging Cell

,

–

Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MA, Bender D, Maller J, Sklar P, de Bakker PI, Daly MJ, Sham PC (

) PLINK: a tool set for whole-genome association and population-based linkage analyses. Am. J. Hum. Genet.

,

–

Soerensen M, Dato S, Christensen K, M

ue M, Stevnsner T, Bohr VA, Christiansen L (

) Replication of an association of variation in the FOXO

A gene with human longevity using both case–control and longitudinal data. Aging Cell

,

–