rs7986407 — FOXO1

Intronic variant in FOXO1, a pro-apoptotic transcription factor whose suppression by the AKT/progestin pathway promotes uterine fibroid cell survival; the G allele is associated with elevated uterine leiomyoma risk in multiple GWAS, while the A allele associates with later age at natural menopause.

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FOXO1 rs7986407 — The Apoptosis Switch in Uterine Fibroid Cells

Uterine fibroids (leiomyomata) affect up to 70% of women by age 50 and are the leading indication for hysterectomy worldwide. Their growth depends on a fundamental imbalance: fibroid smooth muscle cells proliferate but resist dying. FOXO1 — forkhead box protein O111 forkhead box protein O1
a transcription factor that drives expression of pro-apoptotic genes including BIM, PUMA, and Fas ligand — is a central regulator of that life-or-death balance. An intronic variant in FOXO1, rs7986407, has emerged from multiple genome-wide association studies as a locus influencing both uterine leiomyoma risk and the timing of natural menopause, two phenotypes that converge on estrogen exposure duration and uterine smooth muscle cell biology.

The Mechanism

Under normal conditions, FOXO1 translocates to the nucleus and transcribes genes that initiate programmed cell death — a key brake on abnormal cell accumulation. In leiomyoma cells, however, progestins (which drive fibroid growth) rapidly activate the PI3K/AKT signaling cascade22 PI3K/AKT signaling cascade
a pro-survival kinase pathway that is constitutively elevated in many tumors. Activated AKT phosphorylates FOXO1 at Ser256, causing it to be sequestered in the cytoplasm where it cannot reach its target genes. The result: pro-death signals are silenced and fibroid cells survive and accumulate. This mechanism was directly demonstrated by Hoekstra et al. (2009), who showed that blocking AKT or forcing nuclear FOXO1 entry with Psammaplysene A restored apoptosis in leiomyoma cells33 blocking AKT or forcing nuclear FOXO1 entry with Psammaplysene A restored apoptosis in leiomyoma cells
Hoekstra AV et al. J Clin Endocrinol Metab 2009.

The rs7986407 variant is intronic and does not alter the FOXO1 protein sequence. Its functional effect likely operates through regulatory mechanisms — altered splicing efficiency, changes in intronic enhancer activity, or linkage disequilibrium with regulatory variants in the FOXO1 locus — that may modulate FOXO1 expression levels or transcript stability in uterine smooth muscle cells. The precise molecular consequence of the G allele in this tissue remains an open research question.

FOXO1 also plays a broader role in reproductive physiology: in ovarian granulosa cells, FOXO1 and its close family member FOXO3 regulate follicular development and granulosa cell apoptosis. Selective deletion of both in mice caused complete infertility44 caused complete infertility
Liu Z et al. Mol Endocrinol 2015, demonstrating that FOXO-family transcription factors are essential throughout the reproductive axis, not only in the uterus.

The Evidence

The locus around rs7986407 has been identified in multiple large-scale GWAS efforts. The GWAS Catalog reports two fibroid associations at this variant: one with OR 1.07 (95% CI 1.04–1.10; p = 7 × 10⁻⁸; risk allele G) from studies in European-ancestry women, and a second association in a larger meta-analysis (p = 2 × 10⁻¹³; beta 0.064) where the A allele direction diverges — reflecting the complexities of phenotypic stratification across studies. A third entry in the GWAS Catalog records an association with uterine leiomyoma specifically (OR 0.93 per A allele; p = 2 × 10⁻¹⁸), consistent with a protective role of the A allele on fibroid risk.

The same A allele is associated with later age at natural menopause55 later age at natural menopause
later menopause means longer total estrogen exposure across the reproductive lifespan at genome-wide significance (p = 4 × 10⁻¹⁹), suggesting that the A allele promotes prolonged functional ovarian activity. The relationship between these two A-allele phenotypes (later menopause and reduced fibroid risk, or context-dependent fibroid association) likely reflects the complex role of estrogen timing in uterine tissue biology.

A case-control study of 737 UF patients and 451 controls66 case-control study of 737 UF patients and 451 controls
Ponomareva et al. 2024 found rs7986407 appearing in multiple gene-gene interaction models alongside rs547025 (SIRT3), rs2456181 (ZNF346), rs7907606 (STN1/SLK), and rs72709458 (TERT) — suggesting that the fibroid risk associated with this locus may be amplified or modified by co-occurring variants in related pathways. The SIRT3 connection is biologically plausible: sirtuin-family deacetylases directly regulate FOXO1 nuclear localization and activity, as shown by the SIRT1–FOXO1 axis in granulosa cells77 SIRT1–FOXO1 axis in granulosa cells
miR-181a promotes SIRT1 downregulation, FOXO1 acetylation, and granulosa cell apoptosis via this axis.

Practical Actions

For women carrying two G alleles at rs7986407, the evidence may suggest a modest but biologically grounded susceptibility to uterine fibroid development, potentially acting through reduced FOXO1-mediated apoptotic surveillance in uterine smooth muscle cells. The fibroid phenotype in GG women may be modulated by factors that influence AKT pathway activity — including progestin exposure from hormonal contraception and body composition, as adipose tissue is a source of both estrogens and progestins.

Early pelvic ultrasound surveillance is the most actionable monitoring step for GG carriers. If fibroids are identified, awareness of the AKT/FOXO1 pathway biology may be relevant to treatment considerations, particularly given ongoing research into AKT-targeted fibroid therapies.

Interactions

The gene-gene interaction data from Ponomareva et al. 2024 and 2025 suggests that rs7986407 FOXO1 interacts with rs547025 SIRT3 in the context of uterine fibroid risk. SIRT3 (sirtuin 3) is a mitochondrial deacetylase with known roles in oxidative stress resistance and cellular longevity signaling. In the 2024 study, rs547025 SIRT3 showed the strongest individual protective effect against fibroids (C allele OR 0.61), while rs7986407 FOXO1 appeared repeatedly across interaction models. The biological rationale is compelling: SIRT3-family deacetylases regulate FOXO-family transcription factor activity through deacetylation, and FOXO1 acetylation status determines whether it can enter the nucleus to trigger apoptosis. A dual variant carrier — with both reduced SIRT3 protective capacity and a FOXO1 allele associated with fibroid risk — may face a convergent impairment of apoptotic regulation in uterine smooth muscle cells. Proposed compound action: SIRT3 rs547025 + FOXO1 rs7986407 — women carrying GG at rs7986407 (FOXO1, elevated fibroid risk) combined with TT at rs547025 (SIRT3, reduced protective effect) may have a compounded impairment of the SIRT3-FOXO1 apoptotic axis in uterine smooth muscle; recommended action would be earlier pelvic surveillance and monitoring of fibroid-related symptoms (heavy menstrual bleeding, pelvic pressure), plus consideration of lifestyle and dietary factors shown to support mitochondrial SIRT3 activity such as time-restricted eating and resistance exercise.

Genotype Interpretations

What each possible genotype means for this variant.

AA Lower-Risk Genotype Normal

Common genotype — may be associated with reduced fibroid susceptibility

In the GWAS Catalog, the A allele of rs7986407 is associated with a modest protective direction for uterine leiomyoma (OR 0.93 per A allele, p = 2 × 10⁻¹⁸ from one large study, GCST009158). The same allele also associates with later age at natural menopause (p = 4 × 10⁻¹⁹), though the mechanistic link between these two phenotypes is not fully established.

The A/A genotype is not risk-free for fibroid development — fibroids arise from a complex interplay of genetic, hormonal, and environmental factors, and this single SNP explains only a small portion of population variance. However, based on available GWAS evidence, this genotype does not confer the elevated susceptibility signal associated with the G allele.

AG Intermediate Risk Intermediate

One copy of the risk allele — modestly elevated fibroid susceptibility possible

Under an additive model, the heterozygous AG genotype may carry approximately half the fibroid susceptibility signal associated with GG homozygosity. The original GWAS-catalog entry for the G-risk association reports OR 1.07 (95% CI 1.04–1.10, p = 7 × 10⁻⁸) per allele from a large European-ancestry cohort, suggesting that each G allele provides a roughly 7% relative increase in odds, placing AG carriers modestly above baseline.

The effect is likely mediated through FOXO1's role in uterine smooth muscle cell apoptosis, with the AKT/progestin pathway trapping FOXO1 in the cytoplasm and preventing pro-apoptotic signaling in fibroid cells. Whether the rs7986407 G allele specifically reduces FOXO1 nuclear availability or expression in uterine tissue has not been directly measured.

GG Higher-Risk Genotype High Risk

Two copies of the risk allele — elevated uterine fibroid susceptibility suggested by GWAS data

Under an additive GWAS model, GG homozygotes at rs7986407 carry approximately twice the allelic fibroid risk associated with one G allele. The GWAS Catalog records genome-wide significant associations at this variant with uterine fibroids (p = 7 × 10⁻⁸, OR ~1.07 per G allele) and uterine leiomyoma (p = 2 × 10⁻¹³ to 2 × 10⁻¹⁸ across studies). The molecular rationale involves FOXO1's function as an apoptotic gatekeeper in uterine smooth muscle cells.

Under normal conditions, FOXO1 translocates to the nucleus and activates BIM, PUMA, and Fas ligand — genes that initiate programmed cell death in abnormal cells. Progestins (which drive fibroid growth) activate AKT, which phosphorylates FOXO1 at Ser256 and traps it in the cytoplasm. Restoring nuclear FOXO1 (via AKT inhibition or Psammaplysene A treatment) induced apoptosis in leiomyoma cells in vitro [Hoekstra et al. 2009, PMID 19240153]. The rs7986407 G allele may subtly impair FOXO1 activity in this tissue, lowering the apoptotic threshold and permitting greater fibroid cell accumulation over time.

The gene-gene interaction data from Ponomareva et al. 2024 (PMID 39736018) identified rs7986407 as one of five SNPs appearing in multiple fibroid risk interaction models, with SIRT3 rs547025 showing the strongest individual protective effect (C allele OR 0.61). Sirtuin-family deacetylases regulate FOXO1 through deacetylation-dependent nuclear localization, making the SIRT3-FOXO1 interaction biologically plausible. GG carriers who also lack the protective SIRT3 rs547025 C allele may face a compounded reduction in uterine cell apoptotic capacity.

The A-allele association with later natural menopause (p = 4 × 10⁻¹⁹) suggests that FOXO1 activity in the ovary also influences reproductive lifespan; GG carriers at rs7986407 may have a somewhat shorter window of natural estrogen protection, adding complexity to the overall reproductive phenotype.