rs72709458 — TERT

Uterine fibroids (leiomyomas) are benign smooth-muscle tumors of the uterus that affect up to 70% of women by age 50. While they are common, their underlying biology is clonal — each fibroid arises from a single cell that escapes normal growth control. A genome-wide association study of more than 400,000 women in the UK Biobank pinpointed rs72709458 in the TERT gene as one of the strongest genetic risk factors for leiomyoma, with a genome-wide significant odds ratio of 1.12 (p = 6.9 × 10⁻¹⁶). This is not the same biological story as TERT longevity variants — this variant acts through a different mechanism focused on the uterine smooth-muscle cell's capacity to maintain genome integrity¹¹ uterine smooth-muscle cell's capacity to maintain genome integrity
Telomere maintenance failure allows chromosomal instability, which can initiate clonal tumor growth.

TERT encodes the catalytic subunit of telomerase, the enzyme that rebuilds telomere caps on chromosome ends after cell division. Without adequate telomerase activity, telomeres shorten with each cell division until they trigger a DNA damage response — usually stopping the cell from dividing further, but sometimes allowing chromosomal instability and aberrant clonal expansion instead.

The rs72709458 variant sits in an intron of TERT at chromosome 5, position 1,283,640 (GRCh38). It does not change the protein sequence directly; rather, it is a regulatory tag variant in strong linkage disequilibrium with nearby functional elements that influence TERT expression levels or splicing in uterine tissue. Importantly, the three LD-independent TERT associations with leiomyoma risk (rs72709458, rs2736100, rs2853676) each contribute independently, and their combined signal points to the same biological axis: telomere maintenance capacity in the uterine myometrium²² telomere maintenance capacity in the uterine myometrium
The myometrium is estrogen-responsive, undergoes repeated cycles of growth and regression, and depends on intact genome surveillance to prevent clonal outgrowth. The TERT, TERC, and OBFC1 gene cluster together represent the telomere maintenance axis in the leiomyoma GWAS, grouping with TP53 and ATM as a "genome stability" gene cluster distinct from the "genitourinary development" gene cluster (WT1, ESR1/SYNE1, CDC42/WNT4).

Notably, rs72709458 and rs2853676 at TERT did not independently associate with blood leukocyte telomere length in this study — unlike rs2736100, which was significantly associated with shorter telomere length in tumor tissue. This suggests rs72709458 may act through a tissue-specific or context-specific mechanism rather than globally shortening telomeres. The combined effect of all three TERT SNPs plus TERC and OBFC1 variants showed a negative trend toward shorter telomeres (p = 0.055), consistent with a cumulative model.

Välimäki et al. (2018, eLife)³³ Välimäki et al. (2018, eLife)
Genetic predisposition to uterine leiomyoma is determined by loci for genitourinary development and genome stability conducted the largest uterine leiomyoma GWAS to date using the UK Biobank, identifying 22 genome-wide significant loci. The rs72709458 T allele at the TERT locus showed OR = 1.12, p = 6.9 × 10⁻¹⁶ — a highly reproducible, statistically unambiguous association. The effect allele frequency of approximately 0.21 means that a substantial fraction of women carry at least one T allele.

A subsequent Russian case-control study⁴⁴ A subsequent Russian case-control study
GWAS-Significant Loci and Uterine Fibroids Risk: Analysis of Associations, Gene-Gene and Gene-Environmental Interactions genotyped 737 hospitalized women with uterine fibroids and 451 controls for seven GWAS-validated SNPs including rs72709458. The study identified synergistic gene-gene interactions among these loci and a gene-environment interaction between the TERT variant and prior abortion history — reinforcing the view that rs72709458 acts within a broader biological context of uterine tissue stress and cell division history.

Vitamin D merits specific mention as a modifiable factor in fibroid biology. A comprehensive mechanistic review⁵⁵ A comprehensive mechanistic review
The Role of Vitamin D in Uterine Fibroid Biology, Baird & Wise 2015 documents that vitamin D (1,25-dihydroxyvitamin D3) exerts direct anti-fibroid effects: it induces G1 cell cycle arrest in leiomyoma cells, downregulates anti-apoptotic proteins (Bcl-2, Bcl-xL), reduces extracellular matrix remodeling enzymes (MMP-2/9), and suppresses estrogen and progesterone receptor expression. Three large observational studies found inverse associations between serum vitamin D levels and fibroid prevalence, with adjusted ORs ranging from 0.68 to 2.5 depending on the study. African American women — who have 2–3× higher fibroid incidence and carry the rs72709458 T allele at a frequency of ~14.5% — are also 10× more likely to be vitamin D deficient. Whether optimizing vitamin D status specifically attenuates fibroid risk in genetically predisposed women has not been formally tested in a randomized trial, but the mechanistic and epidemiological rationale is substantial.

The rs72709458 T allele also has prior associations to endometriosis, lung adenocarcinoma, and glioma — illustrating the broad neoplasia-predisposing context of TERT variation. This pleiotropy is consistent with the telomere maintenance model: cells that divide frequently in hormone-responsive or inflammatory contexts (uterine myometrium, lung epithelium, neural tissue) are particularly dependent on adequate TERT function.

For women who carry the T risk allele at rs72709458, the key message is that this genetic signal warrants increased awareness and proactive monitoring — not alarm. Uterine fibroids are common, usually benign, and often manageable. The OR of 1.12 per allele confers a modest individual risk increment; the variant matters most when combined with other risk factors (family history of fibroids, Black ethnicity, obesity, early menarche, low vitamin D).

The most evidence-supported modifiable interventions targeting fibroid biology include: - Optimizing vitamin D status: The mechanistic evidence is strong and the intervention is low-risk. Maintaining 25(OH)D levels ≥ 40 ng/mL is a reasonable target. - Early symptom reporting: Many fibroids are asymptomatic; those that become symptomatic cause heavy menstrual bleeding, pelvic pressure, or fertility impairment. Earlier diagnosis allows more conservative management options (myomectomy, UAE, progesterone IUDs). - Pelvic ultrasound awareness: Women with a genetic or family history of fibroids can discuss with their clinician whether surveillance ultrasound is appropriate, particularly in the reproductive years.

rs2736100 (TERT, intron 2): The strongest of the three LD-independent TERT signals for leiomyoma, and the one most directly associated with shorter telomeres in tumor tissue. If you carry risk alleles at both rs72709458 and rs2736100, the combined effect on TERT-related genome stability may be greater than either alone. A compound action analysis across these two variants would capture the combined telomere maintenance burden.

rs2853676 (TERT): A third independent TERT signal for leiomyoma risk, also not individually associated with telomere length. Its biological relationship to rs72709458 is not yet fully characterized.

rs12696304 (TERC): The RNA component of telomerase, which acts with TERT to maintain telomeres. Combined risk alleles at TERT and TERC loci showed a negative trend toward shorter telomeres (p = 0.055), suggesting an additive model of telomere maintenance failure.