rs1250248 — 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 1¹¹ 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 remodeling²² 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 subpopulation³³ 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 endometriosis⁴⁴ 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 UK⁵⁵ 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 controls⁶⁶ 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 controls⁷⁷ 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 study⁸⁸ 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 studies⁹⁹ 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.