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 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 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 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) | 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)
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) |
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.
Alla genotyper
Two copies of the protective G allele — reduced genetic susceptibility to endometriosis at this GREB1 locus
You carry two copies of the G allele at rs11674184, meaning you do not carry the T risk allele associated with elevated endometriosis susceptibility at this GREB1 locus. The GG genotype is relatively uncommon in women of European descent (approximately 14%) but is more frequent in women of African ancestry (approximately 58%), reflecting the strong population stratification of this variant. This result does not eliminate endometriosis risk — the condition is influenced by many genetic and environmental factors — but at this particular locus you carry the protective genotype. Standard symptom awareness remains important regardless of genotype.
Two copies of the T risk allele — highest genetic susceptibility at this GREB1 locus
You carry two copies of the T risk allele at rs11674184. Under the additive model confirmed for this locus, TT homozygotes carry approximately double the additional endometriosis risk of GT heterozygotes. With OR≈1.13 per T allele, TT homozygotes carry an estimated combined OR of approximately 1.28 relative to GG non-carriers. Approximately 40% of European women share the TT genotype (given T allele frequency ~0.62 in Europeans), making TT the most common genotype in European ancestry populations. The enriched effect for Stage III/IV endometriosis (OR=1.16, P=6×10⁻⁹) in the Rahmioglu 2023 analysis indicates this variant is particularly relevant to the disease course most associated with fertility impairment and chronic pain.
One copy of the T risk allele — modestly elevated endometriosis susceptibility
You carry one copy of the T risk allele at rs11674184. Under the additive model confirmed for this locus, heterozygous GT individuals have modestly elevated endometriosis probability compared to GG non-carriers, with an odds ratio of approximately 1.13 per T allele. GT is the most common genotype globally (approximately 47% of people), since the T allele frequency is ~0.63 worldwide. The effect is enriched for moderate-to-severe (Stage III/IV) endometriosis — OR=1.16 for confirmed advanced disease versus 1.13 for all endometriosis combined. One T allele confers roughly half the additional risk of two T alleles under the additive model.