rs2456181 — ZNF346

Uterine fibroids (leiomyomas) are benign tumors of the uterine smooth muscle that affect up to 70–80% of women by age 50, though only about 20–25% experience significant symptoms. They are the most common benign gynecological tumor globally and the leading indication for hysterectomy. While most fibroids are managed conservatively or with minimally invasive procedures, they cause heavy menstrual bleeding, pelvic pain, and — in some locations — fertility complications.

The rs2456181 variant sits in an intron of ZNF346 (zinc finger protein 346, also known as JAZ) on chromosome 5q35.2. It was identified as a genome-wide significant fibroid susceptibility locus in a landmark 2018 GWAS by Välimäki et al.¹¹ landmark 2018 GWAS by Välimäki et al.
15,453 uterine leiomyoma cases and 392,628 controls from UK Biobank and Finnish cohorts. The risk (G) allele carries an odds ratio of 1.07 (p=6.3×10⁻⁹), a modest individual effect that is consistent with the polygenic architecture of fibroid susceptibility.

ZNF346 encodes a nucleolar zinc finger protein that preferentially binds double-stranded RNA and RNA/DNA hybrids. It shuttles between nucleus and cytoplasm via a complex with exportin-5 (XPO5) and ILF3, and plays a role in regulating cell cycle entry and apoptosis. Despite giving the locus its name, ZNF346 itself may not be the primary causal gene at this position.

The functional story points instead to FGFR4 (fibroblast growth factor receptor 4)²² FGFR4 (fibroblast growth factor receptor 4)
A nearby gene encoding a cell-surface receptor that drives cell proliferation, differentiation, and survival, which lies approximately 200 kb from rs2456181 at the same 5q35.2 locus. Transcriptomic analyses of this GWAS signal show that the G risk allele acts as a cis-eQTL³³ cis-eQTL
A regulatory variant that alters expression of nearby genes in the same chromosomal region: it increases FGFR4 expression in blood, arteries, subcutaneous adipose tissue, and cultured fibroblasts, and increases UIMC1 (RAP80) expression in blood and ovary. Simultaneously, the G allele decreases expression of ZNF346-IT1, an intronic transcript within ZNF346.

FGFR4 upregulation is biologically plausible as a fibroid risk mechanism. FGFR4 signaling promotes smooth muscle cell proliferation and survival — the same cellular program that drives leiomyoma growth. Studies in uterine leiomyosarcoma cells (smooth muscle tumor cells) show that FGFR4 inhibits apoptosis via the MST1/LATS1/GABP pathway, and elevated FGFR4 correlates with increased tumor aggressiveness. For the benign smooth muscle cells of the myometrium, excess FGFR4-driven proliferative signaling could lower the threshold for nodule formation.

The G allele also creates binding sites for 45 transcription factors, altering regulation of JAK-STAT signaling and vascular endothelial growth factor (VEGF) production⁴⁴ altering regulation of JAK-STAT signaling and vascular endothelial growth factor (VEGF) production
Pathways relevant to fibroid vascularization and growth, which may explain the observed link between this locus and cardiovascular comorbidity in fibroid patients.

The primary association was established in Välimäki et al. eLife 2018⁵⁵ Välimäki et al. eLife 2018
PMID 30226466, which analyzed 15,453 cases and 392,628 controls, identifying 22 genome-wide significant loci. The rs2456181 G allele showed OR 1.07 (p=6.3×10⁻⁹) — a small per-allele effect that is characteristic of common variant architecture. The study found that fibroid predisposition genes clustered into two pathways: genome stability (TERT, TERC, TP53, ATM) and genitourinary development (WNT4, WT1, ESR1, GREB1, FOXO1, MED12). The chromosome 5q35.2 locus did not fit cleanly into either category, suggesting it represents a distinct biological contribution.

A 2024 replication study⁶⁶ 2024 replication study
PMID 39736018, n=737 fibroid cases and 451 controls examined rs2456181 alongside six other GWAS loci and found it appeared in multiple significant gene-gene interaction models, particularly in combination with rs547025 (SIRT3) and rs10929757 (GREB1). A 2025 pilot study on fibroid-hypertension comorbidity⁷⁷ 2025 pilot study on fibroid-hypertension comorbidity
PMID 41504118 confirmed rs2456181's central role in epistatic networks — it appeared in five of seven most significant interaction models, with the G allele influencing JAK-STAT signaling and VEGF production pathways relevant to both fibroids and vascular disease.

Notably, the G allele frequency is substantially higher in women of African ancestry (~86%) compared to Europeans (~40%), consistent with the well-documented higher fibroid burden in Black women. However, population differences in fibroid prevalence and severity are multifactorial; social, environmental, and hormonal factors also contribute substantially.

Because each copy of the G allele adds only a modest increase in absolute risk (OR ~1.07), rs2456181 is not a clinically diagnostic variant on its own. Its value is in the context of a polygenic risk picture and in motivating proactive surveillance. Women who carry one or two G alleles have a modestly elevated lifetime probability of developing symptomatic fibroids and should be aware of the hallmark symptoms — heavy menstrual bleeding, pelvic pressure or pain, frequent urination, and back or leg pain — which are often normalized or attributed to other causes. Transvaginal ultrasound is the first-line detection method and is appropriate whenever symptoms are present.

Early detection of fibroids while they are small preserves the widest range of treatment options, from watchful waiting and medical management to uterine-sparing procedures like myomectomy or uterine artery embolization, rather than hysterectomy.

rs10929757 (GREB1): The GREB1 locus — a growth response gene regulated by estrogen — showed the most pronounced synergistic interaction with rs2456181 in gene-gene interaction analyses of uterine fibroid risk and hypertension comorbidity. GREB1 mediates estrogen-driven cell proliferation, suggesting that the FGFR4-upregulating effect of the G allele and estrogen-driven signaling through GREB1 may converge on the same pro-proliferative outcome in uterine smooth muscle.

rs58415480 (ESR1): The estrogen receptor alpha locus is the strongest individual GWAS signal for fibroids (OR 1.18). Together, ESR1 variants and rs2456181 place women carrying risk alleles at both loci at compounded risk, since estrogen receptor signaling is a primary driver of fibroid growth and FGFR4 amplifies the downstream proliferative response.