LongevityMap Gene

Gene details

HGNC symbol: FOXO3
Aliases: FOXO2; AF6q21; FKHRL1; FOXO3A; FKHRL1P2
Common name: forkhead box O3
Description: This gene belongs to the forkhead family of transcription factors which are characterized by a distinct forkhead domain. This gene likely functions as a trigger for apoptosis through expression of genes necessary for cell death. Translocation of this gene with the MLL gene is associated with secondary acute leukemia. Alternatively spliced transcript variants encoding the same protein have been observed. [provided by RefSeq, Jul 2008]
Cytogenetic Location: 6q21
UCSC Genome Browser: View 6q21 on the UCSC genome browser
OMIM: 602681
Ensembl: ENSG00000118689
UniProt/Swiss-Prot: FOXO3_HUMAN
Entrez Gene: 2309
UniGene: 220950
1000 Genomes: 1000 Genomes

Homologs in model organisms

Caenorhabditis elegans: daf-16
Danio rerio: foxo3a
Danio rerio: foxo3b
Drosophila melanogaster: foxo
Mus musculus: Foxo3
Rattus norvegicus: Foxo3
Saccharomyces cerevisiae: HCM1

In other databases

GenAge model organism genes

A homolog of this gene for Caenorhabditis elegans is present as daf-16
A homolog of this gene for Drosophila melanogaster is present as foxo
A homolog of this gene for Saccharomyces cerevisiae is present as HCM1

GenAge human genes

This gene is present as FOXO3

GenDR gene manipulations

A homolog of this gene for Drosophila melanogaster is present as foxo
A homolog of this gene for Mus musculus is present as Foxo3
A homolog of this gene for Caenorhabditis elegans is present as daf-16

CellAge

This gene is present as FOXO3

Studies (13)

Significant/Non-significant: 8/5

Study 1

Longevity Association: Significant
Population: Italian (Southern)
Study Design: FOXO3A polymorphisms (rs2802292, rs2764264, and rs13217795) were analyzed for longevity associations in 281 long-lived men (age range 90-108 years) and 195 controls (age range 18-48 years) from the Southern Italian Centenarian Study.
Conclusions: rs2802288, a proxy of rs2802292, showed the best allelic association--minor allele frequency (MAF) = 0.49; p = 0.003; odds ratio (OR) = 1.51; 95% confidence interval (CI), 1.15-1.98).
Indentifier

Study 2

Longevity Association: Significant
Population: German
Study Design: 16 known FOXO3A SNPs were examined in 1,762 German centenarians/nonagenarians and younger controls
Conclusions: Polymorphisms in FOXO3A were associated with longevity. The FOXO3A association was considerably stronger in centenarians than in nonagenarians, highlighting the importance of centenarians for genetic longevity research. Replication in 535 French centenarians (mean age: 103.8 years) and 553 younger controls (aged 18–70 years) generated a trend that supported the results, although it was not statistically significant.
Indentifier

Study 3

Longevity Association: Significant
Population: Chinese (Han)
Study Design: Six tagging SNPs from FOXO1A and FOXO3A were selected and genotyped in 1817 centenarians and younger individuals
Conclusions: All 3 SNPs of FOXO3A were associated with longevity in both genders (P = 0.005-0.001)
Indentifier

Study 4

Longevity Association: Significant
Population: American of Japanese origin
Study Design: Nested-case control study of 5 candidate longevity genes in 8006 Japanese American men from the Honolulu Heart Program and 3741 men part of the Honolulu Asia Aging Study
Conclusions: Genetic variation in the FOXO3A gene was associated with longevity
Indentifier

Study 5

Longevity Association: Non-significant
Population: American of Japanese origin
Study Design: 85 multiethnic (Caucasian, Filipino, Japanese, Chinese, and mixed ethnicity; aged 10- 78 y) sequences were chosen to determine allele frequency. Then 282 Americans of Japanese ancestry were examined for the allele frequency. Furthermore, 675 Hawaii Lifespan Study case (>95 y, average 97.9 y)-control(< 81 y, average 78.5 y) study participants were examined for the allele frequency.
Conclusions: All 38 of the previously reported coding SNPs in FOXO3 are either invalid or too rare to be useful for phenotype–genotype association and other genetic mapping studies. These are likely not involved in longevity. A novel identified SNP (rs138174682) is prevalent in multiple ethnic groups but too rare for longevity analysis in Hawaii Lifespan Study.
Indentifier

Study 6

Longevity Association: Significant
Population: American (Caucasian)
Study Design: 291 SNPs in 30 genes in the insulin/IGF1 signaling pathway were evaluated in 293 long-lived cases and 603 average-lifespan controls (all female), then replicated the candidate genes in two independent cohorts: 279 cases (47% male vs 797 controls(52.6% male) and 383 cases (25.2% male) vs 363 controls (42.7 % male)
Conclusions: The association of FOXO3A rs1935949 and rs4946935 with longevity in the meta-analysis have statistical significance (adjusted P values were 0.0093 and 0.019 respectively) in female samples
Indentifier

Study 7

Longevity Association

Non-significant

Population

Study Design

Genome-wide association study comparing 664,472 autosomal SNPs in 763 long-lived individuals (mean age: 99.7 years) and 1085 controls (mean age: 60.2 years). Top SNPs from the GWAS were further investigated in an independent German sample comprised of 754 long-lived individuals (mean age: 96.9 years) and 860 controls (mean age: 67.3 years).

Conclusions

FOXO3A and EXO1 were not significantly associated with longevity

Indentifier

Reference

Study 8

Longevity Association: Non-significant
Population: Dutch
Study Design: Genome-wide association study in 403 unrelated nonagenarians from long-living families and 1670 younger controls. Strongest candidates were then investigated in a meta-analysis of 4149 nonagenarian cases and 7582 younger controls.
Conclusions: No association with survival into old age was observed for SNPs in FOXO3A
Indentifier

Study 9

Longevity Association

Population

Study Design

1,018 SNPs within a 10-kb window around 40 mTOR signalling genes were studied for differences in variation between 417 unrelated nonagenarian participants and 476 younger controls

Conclusions

As a whole, there was a significant association of genetic variation in the mTOR pathway and familial longevity, though no individual gene was significant after correcting for multiple hypothesis testing

Indentifier

Reference

Study 10

Longevity Association: Significant
Population: Chinese (Han)
Study Design: Three SNPs in FOXO1A and three in FOXO3A were analyzed in a sample of 760 centenarians (578 female and 182 male) and 1060 middle-age controls (378 female and 682 male)
Conclusions: All three SNPs in FOXO3A were positively associated with longevity in both genders, even at ages 92-110 (odds ratio [OR] = 1.61–1.73, p = .0002–0.005; dominant model)
Indentifier

Study 11

Longevity Association: Significant
Population: Danish
Study Design: 15 SNPs that covered FOXO3A common variation were examined in 1089 oldest old and 736 middle-aged for longevity association by longitudinal study design as well as case-control study design
Conclusions: 4 SNPs previously reported to be associated with longevity were verified in this study. 4 novel SNPs (rs12206094, rs13220810, rs7762395, and rs9486902 (corrected P-values 0.001–0.044)) and two haplotypes(corrected P-values: 0.01–0.03) associated with longevity were found in this study. FOXO3A was a candidate longevity gene for survival from younger ages to old age, yet not during old age.
Indentifier

Study 12

Longevity Association: Non-significant
Population: Danish
Study Design: 15 SNPs that covered FOXO3A common variation were examined in 1089 oldest old and 736 middle-aged for longevity association by longitudinal study design as well as case-control study design
Conclusions: 4 SNPs previously reported to be associated with longevity were verified in this study. 4 novel SNPs (rs12206094, rs13220810, rs7762395, and rs9486902 (corrected P-values 0.001–0.044)) and two haplotypes(corrected P-values: 0.01–0.03) associated with longevity were found in this study. FOXO3A was a candidate longevity gene for survival from younger ages to old age, yet not during old age.
Indentifier

Study 13

Longevity Association: Non-significant
Population: Italian (Southern)
Study Design: A two-stage case-control study was performed to identify the association between longevity and variation of in homeostasis regulation pathway genes. 317 SNPs in 104 genes were analyzed in 78 cases (≥90 years, median age 98 years, 42 females) and 71 controls (<90 years, median age 67 years, 32 females) in stage 1. Then, 31 candidate SNPs identified in stage 1 (π markers = 0.1) were analyzed in an independent sample composed by 288 cases (≥90 years, median age 92 years, 163 females) and 554 controls (<90 years, median age 67 years, 277 females).
Conclusions: After adjustment for multiple testing, no significant association was identified between various SNPs and longevity.
Indentifier