rs1529868 — GREB1 GREB1 rs1529868

GREB1 rs1529868 — A High-LD Proxy for the Estrogen-Cofactor Endometriosis Signal at 2p25.1

Endometriosis affects an estimated 10% of reproductive-age women and is 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 through elevated aromatase activity, and this autocrine loop sustains ectopic tissue proliferation and immune evasion. The GREB1 locus at chromosome 2p25.1 is among the most consistently replicated genetic risk regions in endometriosis, and rs1529868 sits within it.

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. The gene was originally characterised in estrogen-responsive breast cancer cell lines but is expressed in endometrial tissue and plays a key role in the hormonal regulation of endometrial biology.

rs1529868 is an intronic variant at chr2:11578465 (GRCh38), positioned at c.772+34 of the primary GREB1 transcript. The GRCh38 reference allele is C; the alternate allele T is the endometriosis risk-tagged allele. Critically, rs1529868 itself has not been identified as an independent GWAS hit for endometriosis — its relevance derives from being in high linkage disequilibrium (r²=0.853 in CEU European populations) with rs11674184, the lead GWAS SNP at this locus as identified in the Rahmioglu et al. 2023 Nature Genetics multi-ancestry meta-analysis²² Rahmioglu et al. 2023 Nature Genetics multi-ancestry meta-analysis
Rahmioglu et al. The genetic basis of endometriosis and comorbidity with other pain and inflammatory conditions. Nature Genetics, 2023. At r²=0.853, rs1529868 tags approximately 85% of the variance in rs11674184 genotype status in European populations — a very high correlation that means the T allele at rs1529868 almost always co-occurs with the T risk allele at rs11674184.

The Mechanism

GREB1 operates as a context-dependent steroid hormone cofactor. In normal endometrium during the secretory phase, GREB1 supports progesterone signaling and promotes decidualization targets including WNT4 and FOXO1A³³ In normal endometrium during the secretory phase, GREB1 supports progesterone signaling and promotes decidualization targets including WNT4 and FOXO1A
Chadchan et al. 2024. In endometriotic lesions, where the cellular environment is estrogen-dominant owing to locally elevated aromatase, GREB1 switches roles — functioning as an estrogen receptor cofactor that amplifies estrogen-driven gene expression and ectopic cell proliferation. Mouse models with GREB1 knockout show substantially reduced endometriotic lesion volume and mass, and human endometriotic cells with GREB1 knockdown show reduced proliferation in response to estrogen stimulation.

GREB1 mRNA and protein are significantly elevated in peritoneal endometriotic lesions compared with eutopic endometrium from unaffected women⁴⁴ 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. The rs1529868-T allele, by tagging the rs11674184-T endometriosis risk signal, is associated with this GREB1-mediated estrogen-dependent growth pathway. The precise molecular mechanism connecting intronic variation at this position to GREB1 expression or splicing has not been fully resolved; fine mapping of the GREB1 locus by Fung et al. 2015 (Human Reproduction)⁵⁵ Fung et al. 2015 (Human Reproduction)
Fung et al. Fine mapping of GREB1 in endometriosis, 2015 identified multiple intronic variants with independent association signals, suggesting a complex regulatory landscape containing several functional elements.

The Evidence

The GREB1 locus was first established for endometriosis in a multi-population meta-analysis of 4,604 cases and 9,393 controls⁶⁶ multi-population meta-analysis of 4,604 cases and 9,393 controls
Nyholt et al. Nature Genetics, 2012 using rs13394619 as the index SNP (OR=1.15, P=6.1×10⁻⁸). The landmark Rahmioglu et al. 2023 Nature Genetics GWAS⁷⁷ Rahmioglu et al. 2023 Nature Genetics GWAS
Rahmioglu et al. 2023 — the largest endometriosis genetic study to date, incorporating data from 23andMe and major international biobanks — identified rs11674184, the variant in high LD with rs1529868, as a statistically independent and more significant signal at the same GREB1 locus: OR=1.13 (95% CI 1.10–1.15, P=3×10⁻¹⁷) for all endometriosis, strengthening to OR=1.16 (P=6×10⁻⁹) specifically for Stage III/IV moderate-to-severe disease.

Because rs1529868 itself is not independently catalogued in the GWAS Catalog and has no direct ClinVar entry, its evidence rating is appropriately moderate — the underlying biology and locus-level evidence are strong (established in multiple large GWAS), but the specific genetic contribution of rs1529868 is inferred through its LD relationship with rs11674184 rather than through direct association testing. At r²=0.853, this inference is highly reliable in European populations; it may be less reliable in populations where LD structure differs.

The T allele frequency shows modest ancestry stratification: approximately 0.55 in European and East Asian populations, approximately 0.47 in African populations, and approximately 0.60 in South Asian populations. The somewhat higher African C allele frequency (~0.53) means that, in women of African ancestry, TT genotypes are less common (~22%) compared to European women (~30%).

Practical Implications

For women carrying the T allele at rs1529868, the clinical guidance mirrors that for rs11674184-T carriers, given the high LD. The key actionable implication is prompt recognition of endometriosis symptoms rather than normalizing them. Endometriosis diagnostic delay averages 7–9 years across many healthcare systems, driven by normalization of menstrual pain and the requirement for laparoscopic confirmation. Women carrying one or two T alleles have elevated probability of endometriosis — and specifically moderate-to-severe Stage III/IV disease — and carry the strongest genetic motivation to pursue early specialist evaluation rather than waiting for symptoms to escalate.

Interactions

rs11674184 (GREB1): The lead GWAS SNP for the endometriosis signal at this locus (OR=1.13, P=3×10⁻¹⁷ in Rahmioglu 2023), in high LD with rs1529868 (r²=0.853 CEU). Most women with TT at rs1529868 will also carry TT at rs11674184. The two variants largely capture the same biological signal and should not be treated as fully independent additive risk factors.

rs13394619 (GREB1): A second intronic GREB1 variant at 2p25.1 (r²=0.65 with rs11674184 in Europeans, and therefore in moderate but imperfect LD with rs1529868). The three GREB1 variants — rs1529868, rs11674184, and rs13394619 — represent overlapping but distinct aspects of the GREB1 regulatory landscape. For supervisor compound action proposal: women carrying the T risk allele at rs1529868 (TT or CT) AND the G risk allele at rs13394619 (GG or AG) carry two partially independent GREB1 risk signals. Combined recommendation: lower threshold for specialist gynecological referral, earlier baseline ovarian reserve testing (AMH + antral follicle count), and proactive fertility counseling. Evidence level: moderate.

rs12700667 (7p15.2, HOXA locus): The other major replicated endometriosis GWAS locus, operating through distinct long-range regulation of HOXA10/HOXA11 — independent of the GREB1 pathway. Both loci show additive effects on endometriosis risk and both show enriched effects at Stage III/IV. Women carrying T alleles at rs1529868 AND risk alleles at rs12700667 carry the two strongest common endometriosis genetic signals simultaneously.