rs11674184 — GREB1 GREB1 Estrogen-Responsive Endometriosis Variant

GREB1 at 2p25.1 — A Second Independent Endometriosis Signal in the Estrogen Cofactor Gene

Endometriosis affects an estimated 10% of reproductive-age women and remains one of the most under-diagnosed causes of chronic pelvic pain and infertility. The condition is estrogen-dependent: ectopic lesions generate their own local estrogen supply through elevated aromatase activity, and this autocrine estrogen loop drives lesion proliferation and immune evasion. GREB1 — Growth Regulation by Estrogen in Breast Cancer 1 — encodes a nuclear co-factor that physically binds steroid hormone receptors and amplifies their transcriptional output¹¹ GREB1 — Growth Regulation by Estrogen in Breast Cancer 1 — encodes a nuclear co-factor that physically binds steroid hormone receptors and amplifies their transcriptional output
Chadchan et al. Nature Communications, 2024.

rs11674184 is an intronic variant in GREB1 at chromosome 2p25.1 that was identified as a statistically independent endometriosis risk signal in the landmark 2023 Rahmioglu Nature Genetics multi-ancestry GWAS meta-analysis. Critically, it is not simply a proxy for the previously described rs13394619 GREB1 variant already in the GeneOps database: the two variants have r²=0.65 in European populations — moderate linkage disequilibrium, not the r²>0.8 threshold that would indicate redundancy. They tag different aspects of the GREB1 regulatory landscape.

The GRCh38 reference allele (T) is the risk allele here, with the less common G allele conferring protection. This is the reverse of the intuitive direction — the T allele at rs11674184 is common (~63% globally) and constitutes the risk-conferring genotype.

The Mechanism

GREB1 operates as a context-dependent steroid hormone cofactor. In normal endometrium during the secretory phase, GREB1 binds the progesterone receptor and promotes downstream decidualization targets including WNT4 and FOXO1A²² In normal endometrium during the secretory phase, GREB1 binds the progesterone receptor and promotes downstream decidualization targets including WNT4 and FOXO1A
Chadchan et al. 2024. In endometriotic lesions, where estrogen dominates, GREB1 switches roles to act as an estrogen receptor cofactor — amplifying estrogen-driven gene expression and ectopic cell proliferation. GREB1 mRNA and protein are significantly elevated in peritoneal endometriotic lesions compared with eutopic endometrium from unaffected women³³ GREB1 mRNA and protein are significantly elevated in peritoneal endometriotic lesions compared with eutopic endometrium from unaffected women
Pellegrini et al. Fertility and Sterility, 2012. Mouse knockout models with GREB1 deletion show substantially reduced ectopic lesion volume and mass.

The intronic rs11674184 variant lies within c.901+577 of the GREB1 transcript. Its modest CADD score (~7.7) and low evolutionary constraint (GERP −0.61) suggest limited direct functional impact on the protein, consistent with a regulatory tag SNP. Fine-mapping of the GREB1 locus by Fung et al. 2015 (Human Reproduction)⁴⁴ Fung et al. 2015 (Human Reproduction)
Fung et al. Fine mapping of GREB1 in endometriosis, 2015 identified multiple intronic variants at this locus with independent association signals, suggesting the region contains at least two distinct regulatory elements influencing GREB1 expression or splicing in endometrial tissue.

The Evidence

Rahmioglu et al. 2023 (Nature Genetics)⁵⁵ Rahmioglu et al. 2023 (Nature Genetics) conducted the largest endometriosis GWAS to date, incorporating data from 23andMe and major biobanks across European and East Asian populations. rs11674184 reached genome-wide significance for all endometriosis (risk allele T: OR=1.13, 95% CI 1.10–1.15, P=3×10⁻¹⁷) and showed a stronger association for confirmed Stage III/IV disease (OR=1.16, P=6×10⁻⁹), consistent with the pattern seen for the nearby rs13394619 where the GREB1 locus effect is enriched in moderate-to-severe disease.

A small Greek case-control study (166 cases, 168 controls) by Matalliotaki et al. 2019 (Molecular Medicine Reports)⁶⁶ Matalliotaki et al. 2019 (Molecular Medicine Reports)
Matalliotaki et al. 2019 found no association for rs11674184, which the authors acknowledged was "one of the most consistently associated SNPs with endometriosis in European ancestry populations." The non-significant result in this study is consistent with insufficient statistical power rather than a true null: the effect size (OR≈1.13) and a sample of 166 cases would require approximately 2,000+ cases to reach genome-wide significance. The Rahmioglu 2023 finding with many thousands of cases is authoritative on this point.

The T allele frequency shows marked ancestry stratification: approximately 0.62 in Europeans, 0.57 in East Asians, but only approximately 0.24 in African populations — meaning GG protective homozygotes are far more common in women of African ancestry (~58%) than in Europeans (~14%).

Practical Implications

Carrying T alleles at rs11674184 raises endometriosis susceptibility, with OR≈1.13 per allele across the full endometriosis phenotype and OR≈1.16 for Stage III/IV. As with all common GWAS variants, these are population-level probability shifts rather than deterministic predictions. The key actionable implication is recognizing and acting on symptoms promptly. Endometriosis diagnostic delay averages 7–9 years across many healthcare systems, driven by normalization of menstrual pain. Women carrying the TT genotype — with the highest common genetic load at this locus — have the strongest motivation to pursue early specialist evaluation rather than accepting pain as normal.

For TT carriers in whom fertility is a consideration, the particular enrichment of this variant's effect at Stage III/IV disease supports proactive ovarian reserve assessment: moderate-to-severe endometriosis, especially ovarian endometriomas, is the mechanism through which endometriosis most directly impairs fertility.

Interactions

rs13394619 (GREB1): The other replicated intronic GREB1 variant in the GeneOps database. The two variants have r²=0.65 in European populations — they share roughly 65% of their variance but are not redundant. Women carrying risk alleles at both rs11674184 (TT or GT) and rs13394619 (GG or AG) may represent a subgroup with elevated cumulative GREB1-pathway genetic load. No formal published study has tested the joint effect of both variants in the same sample; pending such analysis, the individual effects should be considered as partially overlapping but not identical signals.

For supervisor compound action proposal: women carrying the T risk allele at rs11674184 (TT or GT) AND the G risk allele at rs13394619 (GG or AG) carry both GREB1 locus signals simultaneously. The combined recommendation would be: lower threshold for specialist gynecological referral, earlier baseline ovarian reserve testing (AMH + antral follicle count), and proactive fertility counseling. Evidence level: moderate (both independently established at the GREB1 locus; combined effect inferred from consistent additive direction but LD of r²=0.65 means they partially overlap; formal joint analysis not yet published).

rs12700667 (7p15.2, HOXA locus): The other major replicated endometriosis GWAS locus, operating through regulation of HOXA10/HOXA11 — distinct biological pathway from GREB1. Both loci show independent additive effects on endometriosis risk in GWAS meta-analyses, both show stronger signals for Stage III/IV disease, and women carrying risk alleles at both may represent the highest-risk common-variant group identifiable today.