rs17697515 — VEGFC

The vascular endothelial growth factor C (VEGF-C) is best known as the master regulator of lymphangiogenesis — the growth of new lymphatic vessels — but its role extends into pathological angiogenesis in the eye and into cardiac repair after injury. In the retina, where there are no lymphatic vessels, VEGF-C stimulates pathological blood vessel growth through a distinct signaling cascade that VEGFA cannot replicate¹¹ VEGFA cannot replicate
VEGFC activates the p38MAPK–CREB–DLL4/NOTCH1 axis in retinal endothelial tip cells, whereas VEGFA fails to induce DLL4 and NOTCH1 expression despite causing CREB phosphorylation; this non-redundant pathway makes VEGFC an independent driver of retinal neovascularization. The rs17697515 variant is an intronic SNP that marks a protective haplotype: carriers of the T allele show substantially lower risk of developing diabetic retinopathy²² diabetic retinopathy
Diabetes-related damage to the retinal microvasculature; the leading cause of preventable blindness in working-age adults in high-income countries; classified as non-proliferative (microaneurysms, hemorrhages) or proliferative (new vessel growth into the vitreous) and diabetic macular edema — the two most common vision-threatening complications of diabetes.

rs17697515 is located in an intron of VEGFC on chromosome 4 (GRCh38 position 176,689,270). Like its neighbor rs7664413 (intron 5), this variant does not alter the VEGF-C protein sequence but likely influences VEGFC expression level, transcript isoform ratios, or mRNA stability through intronic regulatory elements. Under chronic hyperglycemia, retinal pericytes and Müller glia upregulate VEGF-C, which then activates VEGFR3 on retinal endothelial tip cells³³ tip cells
Tip cells are the leading endothelial cells at the growing end of a blood vessel sprout; they express VEGFR3 and DLL4 to guide directional vessel growth, driving sprouting angiogenesis via the p38MAPK–CREB–DLL4/NOTCH1 axis. If the protective T allele reduces effective VEGFC expression or activity at the regulatory level, it would lower the VEGF-C available to drive this cascade, explaining the protective genotype-phenotype relationship.

Beyond the eye, VEGF-C plays a critical role in cardiac repair. Following myocardial infarction, cardiac macrophages produce VEGF-C in response to efferocytosis⁴⁴ produce VEGF-C in response to efferocytosis
Efferocytosis is the phagocytic clearance of dying/apoptotic cells; when macrophages engulf dead cardiomyocytes after infarction, this triggers VEGFC transcription and secretion via CD36-STAT6 signaling. This macrophage-produced VEGF-C then acts in two modes: it suppresses proinflammatory macrophage activation (autocrine anti-inflammatory effect) and it drives cardiac lymphangiogenesis — growth of lymphatic vessels in the injured myocardium — enabling immune cell clearance and fluid drainage that are essential for healing. Reduced VEGFC activity, as might result from the common CC genotype at this locus, would impair this repair cascade, potentially exacerbating post-infarction inflammation and fibrosis.

The primary evidence for rs17697515 comes from a large candidate gene study of diabetic retinopathy⁵⁵ candidate gene study of diabetic retinopathy
2,899 white patients with type 1 or type 2 diabetes recruited from ophthalmology and endocrine clinics in Australia and the UK; cross-sectional case-control design; 980 with no retinopathy, 1,919 with any retinopathy; 9 VEGFC tag SNPs tested by Kaidonis et al. (2015). After logistic regression adjusting for diabetes duration, HbA1c, and clinical covariates, rs17697515 showed the strongest protective signal among the VEGFC SNPs tested:

• Any diabetic retinopathy: OR 0.62 (95% CI 0.47–0.81; p = 0.001)
• Diabetic macular edema in T2DM: OR 0.53 (95% CI 0.35–0.82; p = 0.004)

This makes rs17697515 the most strongly associated individual SNP among the three that reached significance (rs17697419: OR 0.67; rs2333526: OR 0.69). Haplotype analysis identified two protective VEGFC haplotypes against DR development. The neighboring rs17697419 is in close physical proximity (2,258 bp apart, both intronic on VEGFC), and both show similar protective effects, suggesting they tag the same or adjacent regulatory elements, though their independent significance when tested jointly was not reported.

A secondary line of evidence comes from an independent TGF-β pathway study⁶⁶ independent TGF-β pathway study
356 SNPs in 37 pathway genes; 801 bladder cancer cases and 801 cancer-free controls; Caucasian population; Wei et al. 2012, PLOS ONE, which found VEGFC haplotype H7 (containing rs17697515 along with rs1485762, rs6828869, rs3775194, and rs4557213) associated with 78% increased bladder cancer risk (OR 1.78, 95% CI 1.13–2.82). This finding is in the opposite direction — risk-elevating for the H7 haplotype — and reflects the context dependency of VEGFC's function: in the retina under hyperglycemia, the T allele reduces pathological VEGF-C signaling; in the bladder tumor microenvironment, different haplotype configurations may alter VEGF-C-driven lymphangiogenesis that enables tumor dissemination. The bladder cancer finding is for a multi-SNP haplotype, so its relationship to rs17697515 alone is not established.

A review of VEGF-C in cardiac disease⁷⁷ review of VEGF-C in cardiac disease
PMC8421775 — The Role of the VEGF Family in Coronary Heart Disease; comprehensive mechanistic review of VEGF-C/VEGFR-3 cardiac biology and the JCI experimental study by Glinton et al. (2022) provide the mechanistic rationale for why VEGFC variants matter in the heart-inflammation context, even though no genome-wide association study has yet linked rs17697515 to myocardial infarction outcomes specifically.

The overall evidence level is moderate: the diabetic retinopathy study is large (n=2,899) and well-adjusted, but conducted only in a white European population with no independent replication in other ancestry groups. The cardiac mechanism is strongly supported by experimental data but lacks a direct epidemiological study linking this specific variant to cardiac outcomes.

For individuals carrying the CC genotype, who lack the protective T allele, the primary implication is elevated baseline susceptibility to VEGF-C-driven diabetic microvascular complications. The most actionable step is glycemic optimization: because VEGF-C upregulation in the retina is driven by hyperglycemia, maintaining tight HbA1c control directly reduces the upstream signal that activates pathological neovascularization. Diabetic retinopathy screening should follow recommended intervals — typically annual dilated fundoscopy for most diabetic patients — without extending these intervals even if early assessments are clear, given the elevated susceptibility.

Because the same VEGF-C pathway mediates cardiac lymphangiogenesis and inflammation resolution after cardiac injury, CC homozygotes with diabetes carry compounded cardiovascular risk: impaired VEGF-C-mediated retinal control and potentially impaired cardiac repair signaling. Omega-3 fatty acids (EPA and DHA) have documented anti-inflammatory effects on macrophage activation and lymphangiogenesis pathways and may partially support the VEGF-C/VEGFR3 anti-inflammatory axis in the heart.

rs17697515 and rs17697419 are 2,258 bp apart in VEGFC introns. Both showed independent significance in the diabetic retinopathy study, which included both as separate predictors. The extent to which they are in linkage disequilibrium with each other (and thus partially redundant) was not fully reported. If an individual carries the protective T allele at both loci, the combined benefit is likely additive, but this has not been studied formally.

Both rs17697515 and rs7664413 (intron 5 VEGFC) are intronic VEGFC variants with regulatory implications, but they are associated with different phenotypes: rs7664413 with lymphedema and preeclampsia, rs17697515 with diabetic retinal disease. Their LD relationship and whether they compound each other's effects in the same individual has not been characterized.

Macrophage VEGFC production after efferocytosis is modulated by the CD36-STAT6 signaling axis. Individuals with the CC genotype at rs17697515 who also carry impaired macrophage function variants (e.g., in CD36, SR-A, or STAT6 pathway genes) would be expected to have further reduced post-infarction VEGF-C release, though this specific combination has not been studied.