rs7664413 — VEGFC

VEGFC rs7664413 — A Lymphatic Growth Factor Variant Linked to Edema Risk

The lymphatic system is the body's drainage network — a parallel circulatory system that collects interstitial fluid, immune cells, and lipids from tissues and returns them to the bloodstream. Without functional lymphatic vessels, fluid accumulates in tissues, fat depots become inflamed, and lipedema¹¹ lipedema
A chronic condition characterized by abnormal, painful subcutaneous fat deposition predominantly in the lower limbs, with pathological fluid retention and inflammation; affects an estimated 10-17% of women progresses. At the center of lymphatic vessel formation stands VEGFC²² VEGFC
Vascular Endothelial Growth Factor C — the primary driver of lymphangiogenesis, the growth of new lymphatic vessels, signaling through its receptor VEGFR3 (encoded by FLT4). The rs7664413 variant falls in intron 5 of VEGFC, in a region annotated as a putative splicing regulatory element, and accumulating evidence links the T allele to reduced lymphatic vascular support and elevated edema-related disease risk.

The Mechanism

rs7664413 is an intron 5 variant — it does not change the VEGF-C protein sequence directly. Its location in a putative exonic splicing silencer region³³ putative exonic splicing silencer region
Exonic and intronic splicing silencers are RNA sequence elements that bind hnRNP proteins, suppressing nearby splice site recognition; when mutated, they alter the ratio of mRNA isoforms produced suggests it may alter the ratio of VEGFC transcript isoforms or affect overall VEGFC expression level. Lower effective VEGFC signaling through VEGFR3 (FLT4) reduces lymphatic endothelial cell proliferation, migration, and survival — reducing the formation, density, and function of lymphatic capillaries in tissues, particularly in adipose-rich areas.

Studies in lipedema patients have found decreased FLT4/VEGFR3 expression⁴⁴ decreased FLT4/VEGFR3 expression
The VEGFC receptor is markedly downregulated in lipedema thigh adipose tissue alongside increased macrophage infiltration and fibrosis markers, suggesting a systemic impairment in the VEGFC-VEGFR3 signaling axis in thigh subcutaneous fat compared to abdominal fat. Paradoxically, serum VEGF-C protein is elevated in lipedema, pointing to receptor-level dysfunction rather than ligand deficiency — a pattern consistent with intrinsic signaling inefficiency that a regulatory variant at the gene level could contribute to.

The Evidence

The strongest genetic evidence for rs7664413 comes from a candidate gene study of secondary lymphedema⁵⁵ candidate gene study of secondary lymphedema
n=407 DNA samples from breast cancer patients (110 with lymphedema, 297 without); 8 VEGFC SNPs analyzed; additive model across all genetic models tested after breast cancer surgery. Among the 8 VEGFC variants tested, rs7664413 was the only individual SNP reaching significance (p = 0.041, additive model), and a haplotype containing the nearby rs3775202 "G" rare allele and rs3775195 "C" common allele (haplotype B03) reduced lymphedema odds by 36% per dose (p = 0.027). Because this protective haplotype has no known functional annotation, it likely tags rs7664413 or another regulatory variant in linkage disequilibrium.

Additional evidence comes from two independent contexts. First, a case-control study of preeclampsia⁶⁶ case-control study of preeclampsia
124 tagging SNPs in angiogenic genes; white women only (32 cases, 85 controls); prospective recruitment found rs7664413 associated with preeclampsia risk in white women (OR 2.04; 95% CI, 0.99–4.17; p = 0.04) but not in Black women, pointing to population-specific effects and incomplete penetrance. Preeclampsia involves pathological placental lymphatic insufficiency and abnormal angiogenesis, mechanisms mechanistically convergent with lipedema and secondary lymphedema. Second, a prospective pilot study in diabetic patients⁷⁷ prospective pilot study in diabetic patients
n=125 type 2 diabetes patients with diabetic retinopathy, n=110 controls; aflibercept treatment arm found that VEGFC rs7664413 T carriers had significantly higher diabetic retinopathy risk (allelic OR 2.09, 95% CI 1.25–3.49). Diabetic retinopathy involves aberrant retinal lymphangiogenesis where VEGFC-VEGFR3 signaling drives pathological neovascularization.

The lipedema connection is supported by genome-wide expression data⁸⁸ genome-wide expression data
Subcutaneous fat biopsies from lipedema patients showed marked downregulation of VEGFC and FLT4 in thigh depots compared to abdominal fat and healthy controls and the UK Biobank GWAS of a lipedema phenotype⁹⁹ of a lipedema phenotype
n=448,436 UK Biobank women; leg fat % and waist:hip anthropometric criteria; 18 associated loci identified; VEGFA replicated in independent case-control cohort in 448,436 women showing pathway enrichment in lymphatic/vascular genes. However, rs7664413 itself has not yet appeared in a lipedema-specific GWAS, so its lipedema relevance currently rests on mechanistic and cross-phenotype evidence. Evidence level is preliminary: the lymphedema candidate gene study is relatively small (n=407), and none of the associations have been replicated in independent large cohorts yet.

Practical Actions

For individuals carrying the T allele, the primary concern is reduced lymphatic reserve — the margin between normal lymphatic transport capacity and what triggers fluid retention. This reserve can be supported through several specific, genotype-informed strategies. Compression garments applied early in conditions that stress the lymphatic system (prolonged standing, long-haul flights, post-surgical periods) reduce capillary filtration load and preserve the lymph transport gradient. Micronized purified flavonoid fraction (MPFF — diosmin 900 mg + hesperidin 100 mg) has documented effects on lymphatic contractility and capillary permeability in lymphedema and venous insufficiency, with evidence specifically for reducing edema-related symptoms in lymphedema-prone individuals. Bioimpedance screening before and after procedures that injure lymphatics (lymph node dissection, liposuction, radiation) detects subclinical lymphedema at a stage when compression intervention is most effective.

Interactions

VEGFC signals through VEGFR3, encoded by FLT4. Loss-of-function variants in FLT4 cause Milroy disease (primary hereditary lymphedema, OMIM #153100) through autosomal dominant inheritance. While rs7664413 is a common regulatory variant with modest effect size — not a rare Milroy-causing mutation — individuals carrying both a VEGFC T allele and any rare FLT4 variant would be expected to have further reduced VEGFC-VEGFR3 signaling capacity, compounding lymphatic insufficiency. This interaction is mechanistically sound but not yet studied in a genetic association context.

The nearby rs3775202 and rs3775195 define a protective VEGFC haplotype. Individuals who carry the minor G allele at rs3775202 together with the common C allele at rs3775195 show 36% reduced lymphedema odds per dose — a candidate for compound action analysis if those variants are genotyped. rs17697419 and rs17697515 are independently associated VEGFC SNPs in the diabetic retinopathy GWAS literature; their interaction with rs7664413 in lymphatic phenotypes has not been characterized.