FN1

FN1 rs1250248 — Fibronectin, Extracellular Matrix, and Endometriosis Susceptibility

Endometriosis — in which tissue resembling the uterine lining grows and implants outside the
uterus — affects an estimated 10% of women of reproductive age and accounts for a major share
of chronic pelvic pain, dyspareunia, and infertility. Its causes are multifactorial, but genetic
factors account for roughly half of the susceptibility variance. FN1, encoding
fibronectin 1 | a large glycoprotein of the extracellular matrix (ECM) that provides scaffolding
for cell adhesion, migration, proliferation, and tissue remodeling,
is one of the first confirmed common genetic loci for this disease.

The rs1250248 variant sits in an intronic region of FN1 between exons 10 and 11. It does not
change the fibronectin protein sequence, but the position overlaps a predicted transcription
factor-binding site, raising the possibility that the A allele alters the regulation of FN1
expression in endometrial tissue.

The Mechanism

Fibronectin is a critical mediator of
extracellular matrix remodeling | ECM remodeling refers to the continuous process of synthesis
and degradation of matrix proteins that governs cell behavior; dysregulated ECM remodeling is
a hallmark of fibrosis and invasion in endometriotic lesions.
In peritoneal endometriotic lesions, fibronectin is overexpressed compared with eutopic
endometrium, and FN1-integrin signaling at the interface of mesothelial cells and ectopic
endometrial stromal cells may promote progesterone resistance and lesion persistence.

A 2025 single-cell and spatial transcriptomic study identified a specific
CXCR4⁺ fibroblast subpopulation | Fibroblasts are the main ECM-producing cells; the CXCR4⁺
subset identified here had high stemness and proliferative capacity, acting as a hub for FN1
signaling in immune and fibrotic responses
within ectopic lesions as a central mediator of FN1-driven immune remodeling and fibrosis.
This subpopulation coordinates both ECM deposition and immune suppression, creating an
environment that may sustain ectopic implant viability. The intronic rs1250248 A allele may
subtly shift FN1 expression in this context.

Additionally, plasma fibronectin concentrations are
significantly elevated in women with endometriosis | Fibronectin 292.6 ± 96.2 mg/L in
endometriosis vs 226.6 ± 91.9 mg/L in controls; high-molecular-mass fibronectin-fibrin
complexes absent in healthy women but present in endometriosis patients,
and novel fibronectin-fibrin complexes have been identified exclusively in affected women,
suggesting altered fibronectin molecular biology is a downstream consequence of the disease
process that rs1250248 may predispose toward.

The Evidence

The association between rs1250248 and endometriosis was first identified in a
genome-wide association study of 3,194 surgically confirmed cases and 7,060 controls from
Australia and the UK | Painter et al. Nature
Genetics, 2011. The rs1250248 locus in
FN1 reached P = 3.2 × 10⁻⁸ in the Stage III/IV-restricted analysis of the discovery
dataset, though it did not replicate independently in a US validation cohort, leaving
the signal sub-threshold at the time.

A subsequent
meta-analysis of eight GWAS datasets in 11,506 cases and 32,678 controls | Rahmioglu et al.
Human Reproduction Update, 2014
confirmed the FN1 locus signal with greater precision. Across all endometriosis cases
the A allele showed OR = 1.11 (P = 1.1 × 10⁻⁴), rising to OR = 1.26
(95% CI 1.16–1.38, P = 8.0 × 10⁻⁸) when restricted to Stage III/IV disease. The lead
SNP in that analysis was rs1250241 (r² = 0.95 with rs1250248), representing the same
genetic signal.

An
Italian study in 305 laparoscopically confirmed cases and 2,710 controls | Pagliardini et al.
J Med Genet, 2013
confirmed genome-wide significance specifically for severe disease (P = 3.89 × 10⁻⁹) and
identified an epistatic interaction with rs7521902 (WNT4): the combined effect of risk alleles
at both loci reached OR = 1.56 overall and OR = 2.15 specifically for ovarian endometriosis,
suggesting these two ECM-related pathways converge in promoting cyst formation.

A
Greek case-control study | Matalliotaki et al. Mol Med Rep, 2019
found the A allele conferred OR = 1.87 (95% CI 1.34–2.61, P = 0.002); the AA genotype was
present in 16.9% of patients versus 9.5% of controls (OR = 2.59). Notably, this cohort found
the strongest effect in early-stage (I/II) disease — suggesting rs1250248 may have distinct
stage-specific effects across populations.

Practical Implications

Carrying the A allele at rs1250248 raises the likelihood of endometriosis, with the clearest
signal for moderate-to-severe disease in European populations. The absolute risk conferred by
a single common intronic variant remains modest on an individual basis, but the biological
plausibility is strong: fibronectin overexpression in ectopic tissue and elevated plasma
fibronectin are both documented features of endometriosis, and FN1 signaling coordinates
the fibrosis and immune evasion that sustain lesion persistence.

Women carrying the A allele — particularly AA homozygotes — may benefit from heightened
vigilance around endometriosis symptoms, proactive specialist referral, and awareness of
the potential for fibronectin-related ECM involvement when discussing treatment options
with a clinician. N-acetylcysteine (NAC) has shown
benefit in multiple endometriosis studies | Porpora et al. 2013 (PMID 23737821): NAC-treated
patients showed reduced cyst size after 3 months vs increase in controls; reduces oxidative
stress and ECM-promoting pathways
and may work in part through reduction of the oxidative ECM signaling environment that
fibronectin overexpression supports.

Interactions

rs7521902 (WNT4 locus): An epistatic interaction between rs1250248 (FN1) and rs7521902
(WNT4) has been formally demonstrated in the Italian replication dataset. For women carrying
the A risk allele at both loci, the combined OR for ovarian endometriosis reaches 2.15
(P = 3.12 × 10⁻⁴). WNT4 regulates Müllerian duct development and suppresses androgen
production; its intersection with fibronectin-mediated ECM biology in the ovarian
microenvironment represents a plausible convergent pathway for endometrioma formation.

Supervisor compound action proposal: women carrying the A risk allele at rs1250248 (FN1)
AND the risk allele at rs7521902 (WNT4 locus) represent a subgroup with substantially
elevated ovarian endometriosis risk (OR ~2.15). Combined recommendation: early transvaginal
ultrasound surveillance targeting ovarian endometrioma formation, proactive AMH testing
to establish baseline ovarian reserve, and expedited fertility consultation if conception
is desired. Evidence level: moderate (single formal interaction study, biologically plausible).

rs12700667 (7p15.2 locus, near HOXA10/HOXA11): This locus, which influences HOXA10/11
regulation and endometrial receptivity, has been identified as another major endometriosis
susceptibility locus. Both the 7p15.2 and FN1 loci are among the most replicated GWAS
signals for endometriosis. Additive effects of risk alleles across multiple loci are
expected under a polygenic architecture, though formal interaction testing between rs12700667
and rs1250248 has not been published.