rs13394619 — GREB1

GREB1 — An Estrogen-Responsive Gene at the Heart of Endometriosis Susceptibility

Endometriosis — tissue similar to the uterine lining growing outside the uterus — affects an estimated 10% of women of reproductive age and accounts for a substantial share of chronic pelvic pain and infertility. The condition is driven by estrogen¹¹ estrogen
estrogen is the primary hormonal fuel for endometriotic lesion growth; ectopic implants express elevated levels of aromatase, generating their own local estrogen supply and sustained by immune tolerance at ectopic implant sites. Roughly half of endometriosis susceptibility is heritable, and rs13394619 in GREB1 is one of the most consistently replicated common genetic risk signals discovered to date.

GREB1 — Growth Regulation by Estrogen in Breast Cancer 1 — was first identified as an early estrogen response gene in breast cancer cell lines. It encodes a nuclear co-factor that physically interacts with hormone receptors to amplify their transcriptional activity. The gene sits on chromosome 2p25.1, and rs13394619 lies in an intronic region between exons 9 and 10 with predicted effects on local splicing activity.

The Mechanism

GREB1 operates as a pan-steroid hormone cofactor²² GREB1 operates as a pan-steroid hormone cofactor
Chadchan et al. Nature Communications, 2024 that behaves differently depending on the hormonal and cellular context. In healthy endometrium during the secretory phase, GREB1 is progesterone-responsive: it physically binds the progesterone receptor and amplifies expression of downstream targets including WNT4 and FOXO1A, which drive the stromal decidualization required for embryo implantation.

In endometriotic lesions the circuit flips. Ectopic tissue accumulates estrogen through locally upregulated aromatase, and in this estrogen-dominant environment GREB1 switches to functioning as an estrogen receptor cofactor — amplifying estrogen-driven gene expression and proliferation of ectopic cells. Mouse models with GREB1 knockout show significantly reduced endometriotic lesion volume and mass. Human endometriotic cells with GREB1 knockdown proliferate more slowly when exposed to estrogen.

The intronic rs13394619 variant may influence how GREB1 is spliced or expressed in endometrial tissue. Although eQTL analyses have not identified a single dramatically altered transcript, fine-mapping studies have identified multiple nearby variants with stronger individual associations, suggesting the region contains regulatory elements relevant to endometrial gene expression. 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, supporting GREB1 as a functionally active contributor to estrogen-dependent lesion growth.

The Evidence

rs13394619 was identified in a genome-wide association meta-analysis of 4,604 endometriosis cases and 9,393 controls of Japanese and European ancestry⁴⁴ genome-wide association meta-analysis of 4,604 endometriosis cases and 9,393 controls of Japanese and European ancestry
Nyholt et al. Nature Genetics, 2012. The G allele reached genome-wide significance (OR 1.15, 95% CI 1.09–1.20, P = 6.1 × 10⁻⁸) in the combined analysis, with consistent direction of effect across all contributing cohorts.

A subsequent meta-analysis of eight GWAS datasets encompassing European and Japanese populations⁵⁵ meta-analysis of eight GWAS datasets encompassing European and Japanese populations
Rahmioglu et al. Human Reproduction Update, 2014 confirmed the association: OR 1.13 (95% CI 1.07–1.20, P = 2.9 × 10⁻⁸). Notably, five of the six confirmed endometriosis loci — including the GREB1 locus — showed stronger effects when restricted to Stage III/IV (moderate-to-severe) disease, with the Stage III/IV enriched estimate for rs13394619 reaching P = 3.5 × 10⁻⁸ and OR = 1.15.

Independent replication in a Belgian cohort of 998 cases and 783 controls⁶⁶ Belgian cohort of 998 cases and 783 controls
Sapkota et al. Twin Research and Human Genetics, 2015 confirmed nominally significant association, which reached genome-wide significance in the updated meta-analysis. The G allele frequency shows marked ancestry stratification: approximately 0.51 in Europeans and 0.50 in East Asians, but only approximately 0.14 in African populations.

Practical Implications

Carrying G alleles at rs13394619 raises the population-level probability of developing endometriosis, with the greatest estimated effect on moderate-to-severe disease. The absolute risk added by a single common variant of this effect size (OR ~1.13–1.15 per allele) is modest, but the biological pathway — GREB1's estrogen-driven amplification of ectopic tissue growth — points to concrete surveillance and specialist engagement strategies.

The most actionable implication is awareness of cardinal symptoms and willingness to escalate evaluation early. Endometriosis average diagnostic delay remains approximately 7–9 years in many healthcare systems. Severe dysmenorrhea, deep dyspareunia, cyclic bowel or bladder symptoms, and unexplained infertility are the key presentations to act on rather than normalize.

For GG homozygotes — who carry the highest common genetic load at this locus — the elevated probability of moderate-to-severe disease specifically supports proactive fertility counseling, early ovarian reserve assessment, and lower thresholds for specialist referral if symptoms emerge.

Interactions

rs12700667 (7p15.2, near HOXA10/HOXA11): rs12700667 is the other major replicated endometriosis GWAS locus, operating through a distinct candidate pathway — long-range regulation of homeobox genes that orchestrate endometrial development and receptivity. While formal statistical interaction testing between rs13394619 and rs12700667 has not been published, both variants show independent additive genome-wide significant effects on endometriosis risk, both show stronger effects for Stage III/IV disease, and women carrying risk alleles at both loci may represent a subgroup with substantially elevated cumulative susceptibility.

For a supervisor compound action proposal: women carrying the G risk allele at rs13394619 (GG or AG) AND the A risk allele at rs12700667 (AA or AG) carry the two strongest and most replicated common endometriosis GWAS signals simultaneously. The combined recommendation would be: lower threshold for specialist gynecological referral for any pelvic symptoms, earlier baseline ovarian reserve testing (AMH + antral follicle count), and proactive fertility counseling by age 28–30. Evidence level: moderate (both loci independently established; combined effect inferred from consistent additive direction rather than formal interaction analysis).

rs11674184 (GREB1): A second intronic GREB1 variant also associated with endometriosis risk. Studies in Greek populations testing rs11674184 as a proxy for the GREB1 locus found non-significant results in a small cohort, illustrating the population-level heterogeneity in this region. Both variants lie within GREB1 and may tag overlapping haplotypes.