rs547025 — SIRT3

SIRT3 and Uterine Fibroids — A Mitochondrial Guardian in Uterine Tissue

Uterine fibroids (leiomyomas) affect an estimated 70–80% of women by age 50 and are among the leading indications for hysterectomy worldwide. The mechanisms underlying fibroid development involve a combination of estrogen sensitivity, dysregulated proliferation, and — increasingly recognised — oxidative stress and mitochondrial dysfunction¹¹ oxidative stress and mitochondrial dysfunction
Reactive oxygen species (ROS) promote smooth muscle cell proliferation and extracellular matrix deposition, both hallmarks of fibroid growth. SIRT3 sits at the centre of the mitochondrial antioxidant network, and variants that may alter its expression or activity could modestly shift the threshold for fibroid formation in susceptible women.

SIRT3 (Sirtuin 3) is the principal NAD⁺-dependent protein deacetylase²² NAD⁺-dependent protein deacetylase
SIRT3 removes acetyl groups from lysine residues on mitochondrial proteins, activating enzymes involved in energy metabolism and antioxidant defence inside mitochondria. Its major substrates include MnSOD2 (the primary mitochondrial superoxide scavenger), IDH2 (which regenerates the NADPH needed to recycle glutathione), and complexes of the electron transport chain. When SIRT3 activity is adequate, mitochondrial ROS remain controlled; when SIRT3 is reduced, ROS accumulate and can drive cell proliferation and fibrosis — two defining features of fibroid growth.

The Mechanism

rs547025 is located in intron 6 of SIRT3 on chromosome 11p15.5, within a gene region that contains a characterised enhancer variable-number tandem repeat (VNTR) in intron 5. While rs547025 itself sits approximately 128 bp into the intron adjacent to exon 3 in some transcripts (HGVS: c.280+128A>G on the coding strand), the broader SIRT3 locus contains regulatory elements capable of allele-specific variation in transcriptional efficiency. The intronic location and the protective signal of the C allele are consistent with a regulatory mechanism in which different alleles at or near rs547025 alter the binding affinity of transcription factors — potentially GATA2 or AP-1 family members that have been shown to act on the nearby SIRT3 intron-5 VNTR enhancer — thereby modulating SIRT3 expression levels³³ modulating SIRT3 expression levels
The intron-5 VNTR of SIRT3 has allele-specific enhancer activity demonstrated in transfection experiments; alleles lacking enhancer repeat units show reduced SIRT3 transcription.

The link to fibroid tissue is directly supported by protein-expression data: normal myometrial tissue expresses substantially higher SIRT3 protein than matched uterine fibroid tissue in the same women. When SIRT3 is activated pharmacologically in human leiomyoma (HuLM) cells, proliferation and collagen deposition are selectively suppressed, while normal uterine smooth muscle (UTSM) cells are unaffected — indicating that lower SIRT3 expression is a feature of, and may contribute to, the fibroid phenotype⁴⁴ lower SIRT3 expression is a feature of, and may contribute to, the fibroid phenotype
Conference abstract, Fertility & Sterility 2020: honokiol (a SIRT3 activator) inhibits HuLM leiomyoma cell growth selectively while UTSM cells resist treatment at all tested doses.

A parallel line of evidence comes from the myometrium during parturition: SIRT3 expression falls sharply in term laboring myometrium relative to non-laboring myometrium, and SIRT3 knockdown in primary myometrial cells amplifies NF-κB signalling, driving production of pro-inflammatory cytokines (IL-6, CXCL8), prostaglandins (via PTGS2), and matrix metalloproteinases. The same NF-κB and ROS-driven inflammatory programme is implicated in fibroid growth⁵⁵ is implicated in fibroid growth
Lim et al. 2016, Biology of Reproduction.

The Evidence

The primary evidence linking rs547025 specifically to fibroid risk comes from a case-control study of 737 Central Russian women with ultrasound-confirmed uterine fibroids and 451 controls⁶⁶ case-control study of 737 Central Russian women with ultrasound-confirmed uterine fibroids and 451 controls
Ponomareva, Kobzeva, Bushueva et al. Front Biosci (Schol Ed), 2024. PMID 39736018. Probe-based PCR was used to genotype seven GWAS-significant SNPs. The C allele of rs547025 was associated with a statistically significant reduction in fibroid risk in the overall cohort (OR = 0.61, 95% CI 0.43–0.87, p = 0.005), placing it among the strongest single-locus protective associations in the panel. Subgroup analyses revealed that protection was most pronounced in women with normal fruit and vegetable intake (OR = 0.39, 95% CI 0.21–0.75, p = 0.002), no prior spontaneous abortions (OR = 0.48, 95% CI 0.33–0.70, p = 0.0001), and no prior pelvic inflammatory disease (OR = 0.55, 95% CI 0.38–0.80, p = 0.002), pointing to gene-environment interactions in which co-existing oxidative burden may attenuate the protective effect.

The broader SIRT3 locus at 11p15.5 has independently appeared in uterine fibroid GWAS datasets, and rs73392700 — an intronic SIRT3 variant identified in a multi-ancestry GWAS — showed an OR of 0.77 (95% CI 0.74–0.79, p = 1.09 × 10⁻⁵⁰) in East Asian and Central/South Asian ancestry analyses, confirming that protective variation in the SIRT3 locus for fibroids is not restricted to one population.

The evidence at the specific rs547025 locus is based on a single case-control study from a Central Russian population and has not yet been independently replicated; the evidence level is therefore rated moderate. The biological rationale is plausible and supported by functional data from fibroid tissue expression studies, but replication in independent cohorts is needed before clinical utility can be established.

Practical Implications

Carrying two copies of the common T allele (TT) removes the modest protection associated with the C allele. This does not meaningfully change population-level fibroid risk on its own — the absolute difference conferred by a single variant of this effect size is small — but it may be relevant when considered alongside other fibroid risk factors: African ancestry, nulliparity, obesity, early menarche, vitamin D deficiency, and family history.

SIRT3's primary substrate pathway (NAD⁺ → SIRT3 → MnSOD2/IDH2 → glutathione regeneration) is nutritionally modifiable: SIRT3 requires NAD⁺ as a cofactor, and NAD⁺ declines with age and metabolic stress⁷⁷ NAD⁺ declines with age and metabolic stress
The SIRT3/NAD⁺ axis is a recognised mechanism for age-related mitochondrial dysfunction and a target of active supplementation research | Weir et al. 2013. Maintaining adequate NAD⁺ precursor intake (via dietary sources or supplementation) may partially compensate for reduced SIRT3 activity in TT carriers, though direct evidence specific to fibroid outcomes is not yet available.

Interactions

rs7986407 (FOXO1, 13q14.11): FOXO1 is a decidualization marker downstream of estrogen receptor signalling, and the rs7986407 locus reached genome-wide significance for fibroid risk (OR ≈ 1.09, p = 1.2 × 10⁻¹¹) in UK Biobank GWAS. Both rs547025 (SIRT3) and rs7986407 (FOXO1) were included in the Ponomareva 2024 panel. SIRT3 and FOXO1 operate on converging pathways: SIRT3 deacetylates and activates FOXO3a (a related FOXO family member), which in turn upregulates MnSOD2. FOXO1 similarly controls oxidative stress gene expression in uterine stroma. Women carrying both the SIRT3 T allele (reduced mitochondrial antioxidant protection) and a risk allele at rs7986407 (disrupted FOXO1-driven decidualization and redox control) may experience additive impairment of the dual mitochondrial-nuclear antioxidant axis in uterine tissue.

Compound action proposal for supervisor: women carrying TT at rs547025 (SIRT3) and who also carry a risk allele at rs7986407 (FOXO1, 13q14.11) may have additive impairment of mitochondrial and FOXO-driven antioxidant defence in uterine smooth muscle. The combined recommendation would be enhanced monitoring for fibroid development (annual pelvic ultrasound from age 30 in symptomatic women) and targeted optimisation of the NAD⁺/SIRT3 axis (NAD⁺ precursor supplementation at evidence-supported dosages). Evidence level: emerging (pathway convergence, single association study, no formal published gene-gene interaction analysis for this specific pair).