rs1903068 — KDR KDR/VEGFR2 Endometriosis Angiogenesis Variant

KDR/VEGFR2 — When Blood Vessel Wiring Determines Where Endometriosis Survives

Endometriosis requires blood. Ectopic lesions — fragments of endometrial-like tissue that implant on the peritoneum, ovaries, and bowel — cannot grow beyond a few millimetres without recruiting their own vascular supply. VEGFR2 (vascular endothelial growth factor receptor 2)¹¹ VEGFR2 (vascular endothelial growth factor receptor 2)
Also called KDR (kinase insert domain receptor) or FLK1; the primary tyrosine kinase receptor through which VEGF-A drives endothelial proliferation, survival, migration, and tubular morphogenesis is the central throttle on this neovascularization. Variants in its regulatory region that subtly raise VEGFR2 expression — or lower the signaling threshold — make it easier for ectopic tissue to establish a durable blood supply and survive.

rs1903068 sits approximately 17 kilobases upstream of the KDR gene on chromosome 4q12. It is intergenic and carries no protein-coding consequence; its effect is regulatory — it lies in a region implicated in long-range transcriptional control of KDR expression. The nearby variant rs17773813 (492 bp away in the same regulatory zone) was the lead GWAS signal for this locus in the original Icelandic discovery cohort, and rs1903068 tags the same haplotype block.

The Mechanism

[KDR encodes VEGFR2 | A type III receptor tyrosine kinase; upon VEGF-A or VEGF-C binding, it autophosphorylates and activates the PI3K–AKT and MAPK–ERK cascades driving endothelial proliferation, survival, and tube formation], the dominant mediator of angiogenic signalling in endothelial cells. In women with endometriosis, peritoneal fluid and ectopic lesions contain substantially elevated VEGF concentrations, creating a permissive neovascular environment. The upstream regulatory variants at the KDR locus likely modulate baseline VEGFR2 expression in endometrial and endothelial cells — even modest upregulation of receptor density amplifies the response to the elevated VEGF milieu, allowing nascent ectopic implants to vascularise more efficiently and progress to established lesions.

The effect size is larger in moderate-to-severe (Stage III/IV) endometriosis than in minimal-to-mild disease, consistent with an angiogenesis-dependent mechanism: deep infiltrating lesions and endometriomas require more extensive neovascularisation than superficial peritoneal implants, making the VEGFR2 pathway a proportionally greater determinant of whether disease progresses to advanced stages.

The Evidence

The strongest genomic evidence for the KDR/4q12 locus comes from two large GWAS:

Steinthorsdottir et al. (2016)²² Steinthorsdottir et al. (2016)
Common variants upstream of KDR encoding VEGFR2 and in TTC39B associate with endometriosis. Nature Communications 7:12350 conducted a whole-genome sequencing–based GWAS of 1,840 Icelandic endometriosis cases and 129,016 controls, identifying rs17773813[G] upstream of KDR at genome-wide significance (OR = 1.28, P = 3.8 × 10⁻¹¹). Crucially, the variant stratified disease severity — the G allele was significantly enriched in moderate-to-severe versus minimal-to-mild cases (P = 0.0046), making it one of the few endometriosis loci with an explicit severity-dependency signal.

Rahmioglu et al. (2023)³³ Rahmioglu et al. (2023)
The genetic basis of endometriosis and comorbidity with other pain and inflammatory conditions. Nature Genetics 55:423–436 meta-analysed data from 60,674 endometriosis cases and 701,926 controls — the largest endometriosis genetics study to date. Among the 42 genome-wide significant loci identified, KDR/4q12 was one of six showing non-overlapping confidence intervals between stage I/II and stage III/IV analyses, confirming that the locus exerts its largest effects in advanced disease. rs1903068 tags this same KDR regulatory haplotype.

Practical Actions

The KDR pathway is directly targetable by dietary polyphenols. Epigallocatechin-3-gallate (EGCG), the primary catechin in green tea, has well-characterised anti-angiogenic effects specific to the VEGFR2 pathway. Xu et al. (2011)⁴⁴ Xu et al. (2011)
Fertil Steril 96:1021–28 demonstrated that EGCG selectively suppresses VEGFC and VEGFR2 expression in experimental endometriosis, inhibiting microvessel formation in ectopic implants in vivo — with VEGFC supplementation reversing the inhibitory effect, confirming pathway specificity. Wang et al. (2013)⁵⁵ Wang et al. (2013)
Angiogenesis 16:59–69 showed a prodrug form of EGCG with enhanced bioavailability significantly reduced lesion size and vascular density over 4 weeks in a mouse model.

Resveratrol (found in red grape skin, blueberries, and dark chocolate) acts through complementary anti-angiogenic mechanisms: Madanes et al. (2022)⁶⁶ Madanes et al. (2022)
Reprod Biomed Online 44:891–901 demonstrated dose-dependent reduction in VEGF mRNA and angiopoietin-1 (Ang-1) expression in endometriotic cell cultures alongside reduced cell migration and viability.

For G allele carriers — particularly GG homozygotes — supporting awareness of endometriosis symptoms and ensuring early specialist evaluation if symptoms arise is the most clinically meaningful action from this result.

Interactions

rs17773813 (KDR upstream region): The lead Icelandic GWAS variant is at the same regulatory locus, 492 bp from rs1903068. These two variants are likely in strong LD and tag the same biological effect. Carrying G at rs1903068 is equivalent to tagging the rs17773813-G haplotype.

rs12700667 (7p15.2 / HOXA10-HOXA11 region): The most robustly replicated endometriosis locus acts through a different pathway (HOX gene regulation of endometrial development). Women carrying risk alleles at both KDR/4q12 and 7p15.2 would accumulate risk through distinct biological axes — angiogenesis competence and endometrial developmental programming. No formal gene-gene interaction paper exists, but additive risk is biologically plausible.

For a supervisor compound action proposal: women carrying the G risk allele at rs1903068 (KDR angiogenesis locus) who also carry the A risk allele at rs12700667 (HOX developmental locus) represent a biologically coherent high-risk combination for moderate-to-severe endometriosis. The combined recommendation would be earlier specialist evaluation, proactive disease-severity monitoring, and supplementation with EGCG to target the VEGFR2 pathway that the KDR variant specifically sensitises. Evidence level: emerging for the combination (no published interaction paper); each locus is independently strong-to-established.