rs2802292

goodMag 5.5

This is a intron variant variant in the FOXO3 gene.

Key Literature Trait Associations

Longevity

rs2802292 in FOXO3 is one of the most replicated longevity-associated variants across multiple ethnic groups including Japanese, German, Chinese, Italian, and American cohorts. The T allele increases FOXO3 transcription, enhancing cellular stress resistance, DNA repair, autophagy, and apoptosis of damaged cells. FOXO3 is a master regulator of the insulin/IGF-1 signalling pathway, and its activation mimics some effects of caloric restriction.

Bao JM et al. “Association between FOXO3A gene polymorphisms and human longevity: a meta-analysis.” Asian Journal of Andrology 16(3):446 (2014)

Allele T

OR 1.54

p 1.0e-10

N 10,965

Meta-analysisLarge GWAS

multi-ancestry

Willcox BJ et al. “FOXO3A genotype is strongly associated with human longevity.” Proceedings of the National Academy of Sciences of the United States of America 105(37):13987-13992 (2008)

Allele T

OR 1.26

p 1.0e-4

Candidate gene study

Sun L et al. “FOXO3 variants are beneficial for longevity in Southern Chinese living in the Red River Basin: A case-control study and meta-analysis.” Scientific Reports (2015)

Allele T

OR 1.21

p 2.6e-2

N 9,935

Meta-analysis

East Asian

Ji JS et al. “Comparing Effects of FOXO3 and Residing in Urban Areas on Longevity: A Gene-Environment Interaction Study.” The Journals of Gerontology. Series A, Biological Sciences and Medical Sciences (2022)

Allele T

OR —

p 3.5e-2

N 3,085

Preliminary work

East Asian

Grossi V et al. “The longevity SNP rs2802292 uncovered: HSF1 activates stress-dependent expression of FOXO3 through an intronic enhancer.” Nucleic Acids Research (2018)

Allele T

OR —

p —

Candidate gene study

multi-ancestry

Revelas M et al. “Review and meta-analysis of genetic polymorphisms associated with exceptional human longevity.” Mechanisms of Ageing and Development (2018)

Allele T

OR 1.45

p 1.0e-3

Meta-analysis

multi-ancestry

Coronary heart disease mortality

The FOXO3 rs2802292 G allele is associated with a 26% reduction in coronary heart disease (CHD) mortality in older men. In a prospective cohort of 3,584 Japanese-American men followed for 17 years (Honolulu Heart Program), plus a replication cohort of 2,651 white and Black elderly individuals (Health ABC), G allele carriers showed HR=0.74 (95% CI 0.64–0.86, p=0.00004) for CHD death and HR=0.90 (95% CI 0.84–0.95, p=0.001) for total mortality. No significant associations were detected for cancer or stroke mortality, suggesting the longevity benefit is partly mediated through cardiovascular pathways.

Willcox BJ et al. “The FoxO3 gene and cause-specific mortality.” Aging Cell (2016)

Allele G

OR —

p 4.0e-5

N 6,235

Preliminary work

multi-ancestry

Essential hypertension

The rs2802292 G allele is associated with lower blood pressure and reduced essential hypertension risk, primarily in women of Japanese ancestry. In a meta-analysis with Japanese replication cohorts, women homozygous for the G allele had ~6 mmHg lower systolic and ~3 mmHg lower diastolic blood pressure, with minor allele homozygote frequency of 9.5% in normotensive vs. 3.3% in hypertensive women (p=0.03–0.04). A separate 2024 study found that the G allele mitigates the cerebral microinfarct risk associated with hypertension. Effects were not significant in men, and diverged across populations (European ancestry showed an opposite trend).

Morris BJ et al. “Association Analysis of FOXO3 Longevity Variants With Blood Pressure and Essential Hypertension.” American Journal of Hypertension (2016)

Allele G

OR —

p 3.0e-2

N 843

Preliminary work

East Asian

Nakagawa K et al. “FOXO3 longevity genotype attenuates the impact of hypertension on cerebral microinfarct risk.” Journal of Hypertension (2024)

Allele G

OR —

p 2.0e-2

N 809

Preliminary work

East Asian

Type 2 diabetes mellitus

The rs2802292 G allele is associated with lower fasting blood glucose levels in elderly Chinese women, though not with type 2 diabetes (T2D) risk per se. In a case-control study of 843 elderly Chinese adults (426 T2D, 417 controls), G-allele carriers showed reductions of 0.75–1.15 mmol/L in fasting glucose compared to TT homozygotes in women (p=0.001–0.03), with no comparable effect in men. Separately, a Southern Chinese longevity study found GG homozygotes had improved HOMA-IR (p=0.014), suggesting the G allele may confer metabolic benefits through improved insulin sensitivity, consistent with FOXO3's role in the insulin/IGF-1 pathway.

Mao YQ et al. “Longevity-Associated Forkhead Box O3 (FOXO3) Single Nucleotide Polymorphisms are Associated with Type 2 Diabetes Mellitus in Chinese Elderly Women.” Medical Science Monitor : International Medical Journal of Experimental and Clinical Research (2019)

Allele G

OR —

β -1.093

p 3.0e-2

N 843

Preliminary work

East Asian

Sun L et al. “FOXO3 variants are beneficial for longevity in Southern Chinese living in the Red River Basin: A case-control study and meta-analysis.” Scientific Reports (2015)

Allele G

OR —

p 1.4e-2

N 1,336

Meta-analysis

East Asian

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GWAS Catalog Trait Associations (1)

Genome-wide significant associations (p < 5×10⁻⁸) from the NHGRI-EBI GWAS Catalog.

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ClinVar annotation

Benign★☆☆☆

1 submitter

View on ClinVar →

Gene information from NCBI Gene. Variant classifications from ClinVar.

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