Expressive

rs12331869 (KDR): VEGF Receptor 2 Gene Variant

Key takeaways

  • GTEx data from 953 donors links this variant to reduced KDR expression in the brain putamen, an unexpected finding for a gene best known for blood vessel biology
  • rs12331869 sits near KDR, the gene encoding VEGF receptor 2, and the pseudogene RN7SL822P
  • The same variant also alters expression of two other genes in thyroid tissue: one reduced, one increased
  • Genome-wide pQTL studies in cancer patients confirm that germline variants in the broader VEGF receptor region can measurably shift circulating angiogenic protein levels
  • Evidence specific to this variant is limited to tissue expression data; no disease-outcome associations are yet reported

Key takeaways

  • GTEx data from 953 donors links this variant to reduced KDR expression in the brain putamen, an unexpected finding for a gene best known for blood vessel biology
  • rs12331869 sits in the region flanked by KDR (which encodes VEGF receptor 2, a protein central to blood vessel formation and angiogenesis) and the pseudogene RN7SL822P
  • The same variant also alters expression of two other genes in thyroid tissue: one reduced, one increased
  • Genome-wide pQTL studies in cancer patients confirm that germline variants in the broader VEGF receptor region can measurably shift circulating angiogenic protein levels
  • Evidence specific to rs12331869 is limited to tissue expression data; no large-scale disease-outcome associations are reported in the available studies

What the research says GTEx v11 data from 953 donors links rs12331869 to reduced KDR expression in the brain putamen basal ganglia (slope -0.20, p=7.1e-5), reduced RN7SKP30 expression in thyroid (slope -0.25, p=3.2e-5), and increased expression of ENSG00000296485 in thyroid (slope +0.17, p=6.8e-5), all passing the FDR<0.05 threshold used for that dataset GTEx Portal. Genome-wide pQTL analyses in patients with metastatic colorectal cancer (n=869) and prostate cancer (n=538) validated associations between germline variants in the VEGF receptor region and circulating levels of angiogenic proteins including VEGF-A, VEGF-R3, and CD73, establishing that common variation near the KDR locus can regulate these proteins in plasma. A separate lung function genome-wide association study across 400,102 individuals of European ancestry identified 279 spirometric signals (139 novel), highlighting vascular and angiogenic pathways as contributors to lung function variability.

Reported associations

  • KDR expression in brain putamen basal ganglia: The alternate allele is linked to reduced KDR (VEGF receptor 2) expression in this brain region (slope -0.20, p=7.1e-5) GTEx Portal
  • RN7SKP30 expression in thyroid: The alternate allele is linked to reduced expression of the nearby pseudogene RN7SKP30 in thyroid tissue (slope -0.25, p=3.2e-5) GTEx Portal
  • ENSG00000296485 expression in thyroid: The alternate allele is linked to increased expression of ENSG00000296485 in thyroid tissue (slope +0.17, p=6.8e-5) GTEx Portal
  • VEGF pathway protein levels (region-level evidence): Germline variants in the VEGF receptor region are associated with circulating VEGF-A, VEGF-R3, and CD73 levels in cancer patient cohorts (n=869 colorectal cancer, n=538 prostate cancer), though the studies available do not report results specific to rs12331869

Evidence quality The most direct evidence for rs12331869 comes from GTEx v11 (953 donors, cis-window analysis, FDR<0.05), which provides tissue-specific expression associations passing genome-wide correction in thyroid and near-threshold significance in brain putamen. The pQTL cancer literature (metastatic colorectal cancer n=869; prostate cancer n=538) validates the broader principle that common germline variation near the KDR locus influences circulating angiogenic proteins with replication across independent cohorts, but these analyses report region-level findings and do not single out rs12331869. The lung function GWAS (n=400,102, two-stage design with P<5x10-9 threshold) establishes pathway-level relevance without variant-level specificity. Cross-population pQTL work found that approximately 81.8% of pQTL signals colocalize between European and Arab populations, suggesting expression associations at this locus may generalize across ancestries, but rs12331869 has not been tested in non-European cohorts specifically. Taken together, evidence for this variant is preliminary and expression-centric, with no reported disease-outcome associations in the available literature.

Tissue-specific expression effects

  • KDR: Reduced expression in brain putamen basal ganglia for carriers of the alternate allele GTEx Portal
  • RN7SKP30: Reduced expression in thyroid for carriers of the alternate allele GTEx Portal
  • ENSG00000296485: Increased expression in thyroid for carriers of the alternate allele GTEx Portal

Lifestyle considerations No lifestyle considerations on file for this variant.

Frequently asked questions

What does the KDR gene do?

KDR encodes VEGF receptor 2 (VEGFR2), a protein on blood vessel cell surfaces that receives signals promoting the growth of new blood vessels (angiogenesis). It plays a central role in vascular development and is a target of several approved cancer therapies.

What is rs12331869 associated with?

Based on GTEx tissue expression data from 953 donors, rs12331869 is linked to reduced KDR expression in the brain putamen basal ganglia and to altered expression of two nearby genes in thyroid tissue. Broader studies of this genomic region connect it to regulation of circulating angiogenic proteins including VEGF-A and VEGF-R3 in cancer patient cohorts.

Is rs12331869 linked to any disease?

The available studies do not report a direct association between rs12331869 and a specific disease outcome. Evidence is currently limited to gene expression changes observed in specific tissues. Related studies of the VEGF pathway region have been conducted in cancer patients, but results specific to this variant have not yet been published.

Why does this variant affect the brain putamen?

KDR is expressed not only in blood vessel cells but also in brain tissue, including the putamen - a region involved in motor control and learning. GTEx data shows this variant specifically reduces KDR expression there, though the functional consequences of that reduction are not yet established.

What is a pQTL and why does it matter for this region?

A pQTL (protein quantitative trait locus) is a genetic variant that predicts the circulating level of a protein. Studies in cancer patient cohorts have shown that germline variants near the KDR locus influence circulating VEGF-pathway proteins, suggesting that rs12331869 may have downstream effects on protein levels beyond the gene expression changes observed in GTEx.