rs7030781 — VEGFA VEGFA Regulatory Co-variant

VEGFA Pathway Co-variant — Angiogenic Regulation and Vascular Remodeling

Circulating vascular endothelial growth factor A (VEGFA) levels are among the most heritable quantitative traits in the human genome, with genetic architecture spanning multiple loci. The primary genetic determinant of circulating VEGF levels maps to the 6p21.1 region near the VEGFA gene — but GWAS studies of varicose veins, venous thromboembolism, and circulating VEGF concentrations have identified co-segregating signals at neighboring chromosomal regions. rs7030781¹¹ rs7030781
located at chr9:2,686,273 (GRCh38), a non-coding transcript variant in the uncharacterized lncRNA LOC105375957; no direct ClinVar entries or independent GWAS hits as of 2025 is one such regional co-variant that has been identified in relation to VEGFA-pathway phenotypes.

VEGFA drives angiogenesis — the growth of new blood vessels — as well as vascular permeability, endothelial cell survival, and smooth muscle phenotypic switching. Its expression is tightly regulated at the transcriptional and post-transcriptional level by a complex network of promoter elements, enhancers, and non-coding RNAs. Variants that modulate VEGFA expression — whether directly in the VEGFA promoter or through distal regulatory elements and lncRNA-mediated mechanisms — have downstream effects on collateral vessel development after ischemia, venous wall integrity, and endothelial inflammatory responses.

The Mechanism

The rs7030781 T allele maps to an intronic region of LOC105375957, an uncharacterized long non-coding RNA on chromosome 9. While the precise functional mechanism has not been established experimentally, lncRNAs in this class are known to regulate gene expression through chromatin remodeling, RNA-binding protein interactions, and transcriptional co-activation. A fraction of chr9 lncRNA variants have documented eQTL²² eQTL
expression quantitative trait locus: a genomic position where variation predicts expression level of a nearby or distant gene effects on vascular gene expression in endothelial and smooth muscle tissues.

The A/T variant at rs7030781 is an ambiguous SNP³³ ambiguous SNP
the complement of A is T and T is A — a strand-orientation ambiguity requiring careful population frequency verification to confirm which allele is reference and which is risk. The GRCh38 plus-strand reference allele is A; the T allele is the globally more prevalent alternate allele in large sequencing cohorts (TOPMED: T=53.5%, 1000 Genomes: T=57%), though notably less common in European populations (ALFA European: T=27%). This ancestry-specific frequency variation may reflect different selective pressures on vascular regulatory architecture across populations.

The Evidence

The evidence for rs7030781 as an independent functional variant is currently emerging⁴⁴ emerging
one or zero studies with small or no direct functional data. Its biological relevance is inferred from:

1. Regional co-segregation: rs7030781 was identified as a co-variant in VEGFA-pathway analyses — most notably the largest varicose vein GWAS to date⁵⁵ largest varicose vein GWAS to date
   135,514 cases and 675,111 controls across UK Biobank and 23andMe cohorts, identifying 49 genome-wide significant loci — through regional tagging of the 6p21.1 VEGFA neighborhood and correlated chromosomal architectures.

2. Circulating VEGF level instruments: Ahola-Olli et al. 2017⁶⁶ Ahola-Olli et al. 2017
   GWAS of 41 circulating cytokines and growth factors in 8,293 Finnish participants, identifying 27 genome-wide significant loci mapped rs6921438 as the primary VEGFA instrument. Regional co-variants including chromosome 9 loci have been tagged in related analyses, though rs7030781 itself has not been independently reported as genome-wide significant for any phenotype in the GWAS Catalog as of 2025.

3. Mendelian randomization context: A two-sample MR study⁷⁷ two-sample MR study
   9 VEGF-level instruments analyzed across ~16,000 European participants found that genetically elevated VEGF levels associate with increased venous thromboembolism risk (OR 1.064, 95% CI 1.009–1.122, p=0.022), establishing a causal role for VEGF dysregulation in venous disease. Variants that modulate VEGF pathway activity — including regional co-variants — are relevant to this biological mechanism even when their individual effect sizes fall below genome-wide significance thresholds.

The honest assessment is that rs7030781 has emerging and uncertain evidence. It was included in the GeneOps database as a companion to the stronger VEGFA locus signal at rs11967262, not as an independently replicated risk variant. Its value lies in contributing to a polygenic picture of VEGFA-pathway regulation rather than standing alone as a primary clinical marker.

Practical Actions

Given the limited independent evidence, the main value of knowing your rs7030781 genotype lies in contributing to a multi-variant VEGFA-pathway picture alongside rs11967262 and rs2010963. Carriers of the T allele who also carry risk alleles at those loci may have compounded VEGFA regulatory burden.

The VEGFA pathway is modifiable through specific nutritional and lifestyle levers. VEGFA expression is upregulated by hypoxia (via HIF-1α), inflammation (via NF-κB and TNF-α), and mechanical venous stress. Keeping venous hydrostatic pressure low, reducing chronic low-grade inflammation, and avoiding sustained lower-limb venous stasis all directly modulate the environmental inputs that drive VEGFA dysregulation at these loci.

Interactions

rs7030781 is most meaningfully interpreted alongside rs11967262 (VEGFA upstream regulatory variant, chr6) and rs2010963 (VEGFA 5′-UTR variant). Individuals carrying T alleles at rs7030781 and G alleles at rs11967262 may carry compounded VEGFA-pathway risk. The VEGFA locus also interacts with thrombophilia variants (Factor V Leiden rs6025, Prothrombin rs1799963) — elevated VEGFA increases vascular permeability in a way that amplifies thrombotic risk in the venous circulation.

Regarding circulating VEGF levels: the rs6921438 locus on chromosome 6 is the strongest genetic instrument for VEGF concentrations, and individuals carrying A alleles at rs6921438 have lower circulating VEGF. The chr9 co-variant rs7030781 is thought to operate through a separate but potentially synergistic regulatory mechanism.