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.

Fig. 1.

Fine mapping of the FOXO3A region on chromosome 6 (German centenarian sample). The physical position (in kb) of all 16 genotyped SNPs with their allele-based P values (−log₁₀ P_CCA, German centenarian sample) and a schematic representation of the gene structure NM_201559 are shown. Coordinates refer to National Center for Biotechnology Information genome assembly build 36. Plotted association results (PAR) of SNPs that have previously been typed in the Dutch sample are indicated by a pentagon; PAR of SNPs that are in perfect LD with SNPs typed in the Japanese sample (according to CEU HapMap data) are indicated by a gray curb; PAR with no available HapMap data are presented as a black circle. The LD plot of the locus is based on the measure r² and was generated with Haploview by using CEU HapMap data. The markers typed in the German sample are indicated by a gray box; markers typed in Germans that are in perfect LD with the significant SNPs typed in the Japanese (according to CEU HapMap data) are indicated by a white circle; markers typed in the German and Dutch samples are indicated by a double gray box; markers typed in the German and Dutch samples that are in perfect LD with the significant SNPs typed in the Japanese (according to CEU HapMap data) are indicated by a white circle and a double gray box; markers only genotyped in the Japanese sample with no corresponding P_CCA values in the German sample are indicated by a black circle; perfect LD between the SNPs typed in the Japanese and the German samples (according to CEU HapMap data) is indicated by a white circle in the lower LD plot.