title: Association of FOXO3A variation with human longevity confirmed in German centenarians.
abstract: The human forkhead box O3A gene (FOXO3A) encodes an evolutionarily conserved key regulator of the insulin-IGF1 signaling pathway that is known to influence metabolism and lifespan in model organisms. A recent study described 3 SNPs in the FOXO3A gene that were statistically significantly associated with longevity in a discovery sample of long-lived men of Japanese ancestry [Willcox et al. (2008) Proc Natl Acad Sci USA 105:13987-13992]. However, this finding required replication in an independent population. Here, we have investigated 16 known FOXO3A SNPs in an extensive collection of 1,762 German centenarians/nonagenarians and younger controls and provide evidence that polymorphisms in this gene were indeed associated with the ability to attain exceptional old age. The FOXO3A association was considerably stronger in centenarians than in nonagenarians, highlighting the importance of centenarians for genetic longevity research. Our study extended the initial finding observed in Japanese men to women and indicates that both genders were likely to be equally affected by variation in FOXO3A. Replication in a French centenarian sample generated a trend that supported the previous results. Our findings confirmed the initial discovery in the Japanese sample and indicate FOXO3A as a susceptibility gene for prolonged survival in humans.
authors.affiliation: Institute of Clinical Molecular Biology, Institute of Medical Informatics and Statistics, and Popgen Biobank, Christian-Albrechts-University, 24105 Kiel, Germany.
authors.forename: Friederike
authors.initials: F
authors.lastname: Flachsbart
authors.forename: Amke
authors.initials: A
authors.lastname: Caliebe
authors.forename: Rabea
authors.initials: R
authors.lastname: Kleindorp
authors.forename: Hélène
authors.initials: H
authors.lastname: Blanché
authors.forename: Huberta
authors.initials: H
authors.lastname: von Eller-Eberstein
authors.forename: Susanna
authors.initials: S
authors.lastname: Nikolaus
authors.forename: Stefan
authors.initials: S
authors.lastname: Schreiber
authors.forename: Almut
authors.initials: A
authors.lastname: Nebel
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D016022:Case-Control Studies; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000235:genetics*; D014644:Genetic Variation; D006801:Humans; D008136:Longevity / Q000235:genetics*; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide
chemical_list: C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors