rs10859871 — VEZT

VEZT rs10859871 — Vezatin, Adherens Junctions, and Endometriosis Risk

Endometriosis — in which tissue resembling the uterine lining implants and grows outside the uterus — affects approximately 10% of women of reproductive age and accounts for a disproportionate burden of pelvic pain, dyspareunia, infertility, and diagnostic delay. The condition is strongly heritable; genetic factors explain roughly 50% of susceptibility variance. rs10859871, an intronic variant near the VEZT gene at chromosome 12q22, is one of the most robustly replicated genome-wide association signals for endometriosis, confirmed across multiple independent datasets in European and Japanese populations.

VEZT encodes vezatin¹¹ vezatin
a ubiquitous transmembrane protein of adherens junctions — the intercellular adhesion structures that link neighboring epithelial and endothelial cells via the cadherin–catenin–actin axis. Vezatin is a 779 amino acid protein embedded in the transmembrane domain of adherens junctions; it interacts with myosin VIIa and the cadherin–catenin complex to stabilize cell-cell contacts and regulate cytoskeletal tension. Disruption of adherens junction integrity is a recognized feature of endometriotic stromal cells, enabling the detachment, peritoneal transit, and ectopic re-implantation that characterize endometriosis.

The Mechanism

rs10859871 sits in an intron of VEZT and does not alter the vezatin protein sequence. Its clinical relevance lies in its function as a cis-eQTL²² cis-eQTL
an expression quantitative trait locus — a genetic variant that regulates the expression level of a nearby gene in cis, meaning on the same chromosome. The endometriosis risk allele (C) is associated with increased VEZT mRNA levels in both blood and endometrial tissue, as demonstrated by Holdsworth-Carson et al. using samples from 228 women across four endometrial compartments. This upregulation suggests that the C allele alters transcription factor binding or chromatin accessibility at the intronic locus, shifting vezatin expression toward levels that may paradoxically destabilize adherens junction dynamics rather than reinforce them — possibly through titrating junction components or activating feedback suppression.

In endometriotic stromal cells, adherens junction weakening reduces E-cadherin-mediated cohesion, facilitating epithelial–mesenchymal transition and invasive behavior analogous to metastatic cancer cells. Vezatin's role in connecting myosin VIIa to the cadherin complex places it at the intersection of mechanosensing and junction stability: altered vezatin levels could shift the balance between adhesion and contractility-driven detachment in endometrial cells shed during retrograde menstruation. Protein-level confirmation of the eQTL effect in endometrial tissue has not yet been published, and functional studies directly testing vezatin's causal role in endometriosis pathogenesis remain warranted.

The Evidence

The initial genome-wide significant association was reported by Nyholt et al. in Nature Genetics (2012)³³ Nyholt et al. in Nature Genetics (2012)
GWAS meta-analysis of 4,604 cases and 9,393 controls from Japanese and European cohorts identified seven endometriosis loci; rs10859871 at 12q22/VEZT reached P = 5 × 10⁻¹³, OR ~1.2 (95% CI 1.14–1.26). The signal was independent of the other known endometriosis loci and consistent across both ancestral groups studied.

A subsequent replication and meta-analysis by Pagliardini et al. (Human Reproduction, 2015)⁴⁴ replication and meta-analysis by Pagliardini et al. (Human Reproduction, 2015)
confirmed rs10859871 as the locus with the single strongest statistical support for endometriosis association; OR = 1.19, P = 7.9 × 10⁻²⁰ across combined datasets. Effect sizes were stronger in Stage III/IV disease than in milder stages, suggesting this locus is particularly implicated in moderate-to-severe and ovarian disease.

The Rahmioglu et al. meta-analysis (Human Reproduction Update, 2014)⁵⁵ Rahmioglu et al. meta-analysis (Human Reproduction Update, 2014)
11,506 cases and 32,678 controls across eight GWAS datasets; rs10859871 genome-wide significant at P = 4.7 × 10⁻¹⁵; all nine replicated loci showed stronger effects in Stage III/IV reached the same conclusion. The C allele's effect is consistent across European and East Asian populations, adding cross-ancestry evidence to the association.

A systematic review of endometriosis GWAS studies (Cardoso et al., 2020)⁶⁶ systematic review of endometriosis GWAS studies (Cardoso et al., 2020)
15 studies reviewed; VEZT rs10859871 was one of five variants highlighted as having the highest frequency of replication across independent datasets ranked rs10859871 among the five most consistently replicated endometriosis genetic signals alongside WNT4, GREB1, FN1, and IL1A loci.

Practical Implications

Carrying the C allele at rs10859871 confers a modest but well-established increase in endometriosis susceptibility, with an odds ratio of approximately 1.19 per C allele. The absolute risk contribution of a single locus is modest relative to the condition's overall ~10% population prevalence, but this signal combines additively with risk alleles at other confirmed loci (WNT4, GREB1, FN1, CDKN2B-AS1, IL1A, and HOXA10/11 loci).

The clearest clinical implication is awareness: the diagnostic delay for endometriosis averages 4–11 years from symptom onset, and genetic risk signals support a lower threshold for specialist evaluation when relevant symptoms are present. C allele carriers with symptoms consistent with endometriosis benefit from proactive gynecological referral rather than normalization of pelvic pain.

Interactions

rs7521902 (WNT4 locus, 1p36.12): WNT4 regulates Müllerian duct development and ovarian sex-steroid production. WNT4 and VEZT risk alleles are among the most replicated endometriosis loci; additive polygenic burden across these loci is expected under the established polygenic architecture, though formal interaction testing between rs10859871 and rs7521902 has not been published.

rs13394619 (GREB1, 2p25.1): GREB1 is an estrogen-responsive gene involved in endometrial proliferation. The combination of GREB1 and VEZT risk alleles likely contributes additively to endometriosis susceptibility through distinct pathways (hormonal regulation vs. adhesion junction mechanics).

rs1537377 (CDKN2B-AS1/ANRIL, 9p21.3): This locus near the cell-cycle regulatory genes CDKN2A/CDKN2B on chromosome 9 is a separate endometriosis GWAS signal. The CDKN2B-AS1 locus and the VEZT locus represent distinct genetic contributions to endometriosis risk — both have been confirmed in the same multi-locus meta-analyses.

rs1250248 (FN1, 2q34): The fibronectin gene is a confirmed endometriosis locus with particularly strong effects in Stage III/IV disease. Fibronectin-mediated ECM remodeling and vezatin-mediated adherens junction regulation both affect how ectopic endometrial cells adhere, invade, and persist — pathway-level convergence between these two loci is plausible.