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Connecting genetic risk to disease endpoints through the human blood plasma proteome

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Locus annotations

Locus 52

Top associations per target

Target cis/​trans Study SNP SNP location Maj/​min allele MAF N βinv seinv Pinv fclog Plog Praw
VEGF sR3 trans Discovery rs10935480 3:98,431,986 C/T 0.46 995 -0.727 0.038 9.9×10-70 -1.180 9.2×10-73 3.4×10-69
VEGF sR3 trans Replication rs10935473 3:98,416,900 C/A 0.41 337 -0.547 0.060 1.2×10-17 -1.160 7.7×10-19 9.6×10-18

 

Regional association plots

Vascular endothelial growth factor receptor 3 (VEGF sR3)

Download the association data used to generate this plot

 

Boxplots and histograms for top associations

Vascular endothelial growth factor receptor 3 (VEGF sR3)

inverse-normalized probe levels log2 transformed probe levels raw probe levels
Discovery study
Replication study

Vascular endothelial growth factor receptor 3 (VEGF sR3)

Target (abbrv.) VEGF sR3
Target (full name) Vascular endothelial growth factor receptor 3
Somalogic ID (Sequence ID) SL003322 (2358-19_2)
Entrez Gene Symbol FLT4
UniProt ID P35916
UniProt Comment
  • Tyrosine-protein kinase that acts as a cell-surface receptor for VEGFC and VEGFD, and plays an essential role in adult lymphangiogenesis and in the development of the vascular network and the cardiovascular system during embryonic development. Promotes proliferation, survival and migration of endothelial cells, and regulates angiogenic sprouting. Signaling by activated FLT4 leads to enhanced production of VEGFC, and to a lesser degree VEGFA, thereby creating a positive feedback loop that enhances FLT4 signaling. Modulates KDR signaling by forming heterodimers. The secreted isoform 3 may function as a decoy receptor for VEGFC and/or VEGFD and play an important role as a negative regulator of VEGFC-mediated lymphangiogenesis and angiogenesis. Binding of vascular growth factors to isoform 1 or isoform 2 leads to the activation of several signaling cascades; isoform 2 seems to be less efficient in signal transduction, because it has a truncated C-terminus and therefore lacks several phosphorylation sites. Mediates activation of the MAPK1/ERK2, MAPK3/ERK1 signaling pathway, of MAPK8 and the JUN signaling pathway, and of the AKT1 signaling pathway. Phosphorylates SHC1. Mediates phosphorylation of PIK3R1, the regulatory subunit of phosphatidylinositol 3-kinase. Promotes phosphorylation of MAPK8 at 'Thr-183' and 'Tyr-185', and of AKT1 at 'Ser-473'.
Targeted by drugs (based on IPA annotation)
  • sunitinib
  • pazopanib
  • axitinib
  • CEP 7055
  • tivozanib
  • motesanib
  • telatinib
  • cabozantinib
  • nintedanib
  • regorafenib
  • bortezomib/sorafenib
  • dexamethasone/lenalidomide/sorafenib
  • bevacizumab/sorafenib
  • cabozantinib/erlotinib
  • sorafenib
  • vandetanib
Biomarker applications (based on IPA annotation)
  • diagnosis
  • disease progression
  • efficacy
  • prognosis
Pathway Interaction Database
  • VEGF and VEGFR signaling network
  • VEGFR3 signaling in lymphatic endothelium
Reactome
  • VEGF binds to VEGFR leading to receptor dimerization
Pathway Studio
  • VEGFR → AP-1/CREB/MYC signaling
  • VEGFR → ATF/CREB/ELK-SRF signaling
  • VEGFR → CTNNB signaling
  • VEGFR → FOXO3A signaling

All locus annotations are based on the sentinel SNP (rs10935480) and 9 proxy variant(s) that is/are in linkage disequilibrium r2 ≥ 0.8. Linkage disequilibrium is based on data from the 1000 Genomes Project, phase 3 version 5, European population and was retrieved using SNiPA's Block Annotation feature.
Download the detailed results of SNiPA's block annotation (PDF)

Linked genes


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Genes hit or close-by
eQTL genes
  • DCBLD2 discoidin, CUB and LCCL domain containing 2
  • CPOX coproporphyrinogen oxidase
  • ST3GAL6 ST3 beta-galactoside alpha-2,3-sialyltransferase 6
  • ST3GAL6-AS1 ST3GAL6 antisense RNA 1

 

Results from other genome-wide association studies

Trait P Study Source
cg18690922 (chr3:98429463) 5.5×10-7 10.1101/033084 (DOI) BIOS QTL cis-meQTLs
HbA1c 3.6×10-4 20858683 (PMID) Supplemental file

Genetic variant linking VEGF sR3 to protein sialylation.

This locus harbours a replicated trans-association with Vascular endothelial growth factor receptor 3 (FLT4, aka VEGF sR3); SNP rs10935480 is in ST3 Beta-Galactoside Alpha-2,3-Sialyltransferase 6 (ST3GAL6); a trans-association (p=7.5×10-6) with Sialic acid-binding Ig-like lectin 9 (SIGLEC9) is observed when eliminating samples with very low SIGLEC9 levels (epitope effect, see Locus 49), and a correlation between SIGLEC9 and FLT4 is then also found.

The information gathered here is a result of an attempt to keep track of all interesting information that we encountered while investigating these loci. Please bear in mind that the annotation given here is neither complete nor free of errors, and that all information provided here should be confirmed by additional literature research before being used as a basis for firm conclusions or further experiments.