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

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Locus annotations

Locus 28

Top associations per target

Target cis/​trans Study SNP SNP location Maj/​min allele MAF N βinv seinv Pinv fclog Plog Praw
sE-Selectin trans Discovery rs651007 9:136,153,875 C/T 0.23 997 -0.944 0.040 1.2×10-96 -1.400 7.2×10-108 3×10-90
sE-Selectin trans Replication rs507666 9:136,149,399 G/A 0.16 337 -0.823 0.077 8.2×10-23 -1.400 8×10-24 5.2×10-15
IR trans Discovery rs651007 9:136,153,875 C/T 0.23 997 -0.696 0.047 3.9×10-44 -1.180 6.3×10-41 1.8×10-28
IR trans Replication rs579459 9:136,154,168 A/G 0.17 337 -0.558 0.068 5.2×10-15 -1.220 1.1×10-15 2.2×10-12
VEGF sR3 trans Discovery rs651007 9:136,153,875 C/T 0.23 997 -0.593 0.049 1.1×10-31 -1.150 2.3×10-33 2.4×10-31
VEGF sR3 trans Replication rs507666 9:136,149,399 G/A 0.16 337 -0.472 0.081 1.4×10-8 -1.140 8×10-10 2.6×10-8
CD36 ANTIGEN trans Discovery rs651007 9:136,153,875 C/T 0.23 997 -0.535 0.046 1.3×10-29 -1.160 1.4×10-29 5.2×10-27
CD36 ANTIGEN trans Replication rs507666 9:136,149,399 G/A 0.16 337 -0.168 0.093 0.072 -1.030 0.615 0.187
Endoglin cis Discovery rs651007 9:136,153,875 C/T 0.23 997 -0.536 0.049 6×10-26 -1.110 2.6×10-24 1.9×10-21
Endoglin cis Replication rs507666 9:136,149,399 G/A 0.16 337 -0.207 0.073 0.005 -1.070 0.016 0.136
Met trans Discovery rs651007 9:136,153,875 C/T 0.23 997 -0.437 0.048 3.3×10-19 -1.080 2.2×10-19 1.8×10-18
Met trans Replication rs579459 9:136,154,168 A/G 0.17 337 -0.476 0.076 1.2×10-9 -1.100 4.5×10-9 1×10-8
sICAM-2 trans Discovery rs651007 9:136,153,875 C/T 0.23 997 -0.402 0.051 7.5×10-15 -1.050 8×10-6 0.308
sICAM-2 trans Replication rs579459 9:136,154,168 A/G 0.17 337 -0.184 0.071 0.01 -1.010 0.578 0.407
VEGF sR2 trans Discovery rs651007 9:136,153,875 C/T 0.23 997 -0.367 0.050 3.1×10-13 -1.060 4.4×10-13 6.8×10-13
VEGF sR2 trans Replication rs507666 9:136,149,399 G/A 0.16 337 -0.346 0.080 1.9×10-5 -1.070 4.8×10-5 6×10-5
ST4S6 trans Discovery rs651007 9:136,153,875 C/T 0.23 997 -0.365 0.050 6.7×10-13 -1.060 6.2×10-12 3.5×10-10
ST4S6 trans Replication rs507666 9:136,149,399 G/A 0.16 337 -0.052 0.067 0.44 -1.000 0.826 0.272
P-Selectin trans Discovery rs651007 9:136,153,875 C/T 0.23 997 -0.373 0.051 7.4×10-13 -1.070 2.5×10-11 7.6×10-12
P-Selectin trans Replication rs507666 9:136,149,399 G/A 0.16 337 -0.262 0.055 3.4×10-6 -1.090 9×10-6 0.001
TLR4:MD-2 complex trans Discovery rs651007 9:136,153,875 C/T 0.23 997 -0.364 0.052 3.4×10-12 -1.080 2.7×10-11 1.7×10-8
TLR4:MD-2 complex trans Replication rs507666 9:136,149,399 G/A 0.16 337 -0.189 0.068 0.006 -1.050 0.017 0.059
Cadherin-5 trans Discovery rs651007 9:136,153,875 C/T 0.23 997 -0.359 0.051 4.8×10-12 -1.070 3.6×10-11 3.7×10-9
Cadherin-5 trans Replication rs507666 9:136,149,399 G/A 0.16 337 -0.257 0.077 0.001 -1.060 0.001 0.001
JAG1 trans Discovery rs651007 9:136,153,875 C/T 0.23 997 -0.336 0.050 4.7×10-11 -1.040 3.9×10-11 1.7×10-10
JAG1 trans Replication rs579459 9:136,154,168 A/G 0.17 337 -0.192 0.066 0.004 -1.020 0.082 0.457
OX2G trans Discovery rs651007 9:136,153,875 C/T 0.23 997 -0.328 0.050 8×10-11 -1.050 1.7×10-5 0.116
OX2G trans Replication rs507666 9:136,149,399 G/A 0.16 337 -0.348 0.077 8.2×10-6 -1.060 0.034 0.458
CD109 trans Discovery rs651007 9:136,153,875 C/T 0.23 997 -0.300 0.052 8.4×10-9 -1.070 1.5×10-8 1.2×10-7
CD109 trans Replication rs507666 9:136,149,399 G/A 0.16 337 -0.151 0.075 0.044 -1.060 0.072 0.061

 

Regional association plots

 

Boxplots and histograms for top associations

E-Selectin (sE-Selectin)

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

Insulin receptor (IR)

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

Vascular endothelial growth factor receptor 3 (VEGF sR3)

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

Platelet glycoprotein 4 (CD36 ANTIGEN)

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

Endoglin

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

Hepatocyte growth factor receptor (Met)

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

Intercellular adhesion molecule 2 (sICAM-2)

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

Vascular endothelial growth factor receptor 2 (VEGF sR2)

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

Carbohydrate sulfotransferase 15 (ST4S6)

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

P-Selectin

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

Toll-like receptor 4:Lymphocyte antigen 96 complex (TLR4:MD-2 complex)

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

Cadherin-5

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

Protein jagged-1 (JAG1)

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

OX-2 membrane glycoprotein (OX2G)

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

CD109 antigen (CD109)

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

E-Selectin (sE-Selectin)

Target (abbrv.) sE-Selectin
Target (full name) E-Selectin
Somalogic ID (Sequence ID) SL001945 (3470-1_2)
Entrez Gene Symbol SELE
UniProt ID P16581
UniProt Comment
  • Cell-surface glycoprotein having a role in immunoadhesion. Mediates in the adhesion of blood neutrophils in cytokine-activated endothelium through interaction with PSGL1/SELPLG. May have a role in capillary morphogenesis.
Biomarker applications (based on IPA annotation)
  • diagnosis
  • disease progression
  • efficacy
  • unspecified application
Pathway Interaction Database
  • ATF-2 transcription factor network
  • Glucocorticoid receptor regulatory network
  • Thromboxane A2 receptor signaling
Reactome
  • Cell surface interactions at the vascular wall
Pathway Studio
  • Leukocyte Adhesion to Endothelial Cell
  • SELE → ELK-SRF signaling

Insulin receptor (IR)

Target (abbrv.) IR
Target (full name) Insulin receptor
Somalogic ID (Sequence ID) SL004125 (3448-13_2)
Entrez Gene Symbol INSR
UniProt ID P06213
UniProt Comment
  • Receptor tyrosine kinase which mediates the pleiotropic actions of insulin. Binding of insulin leads to phosphorylation of several intracellular substrates, including, insulin receptor substrates (IRS1, 2, 3, 4), SHC, GAB1, CBL and other signaling intermediates. Each of these phosphorylated proteins serve as docking proteins for other signaling proteins that contain Src-homology-2 domains (SH2 domain) that specifically recognize different phosphotyrosines residues, including the p85 regulatory subunit of PI3K and SHP2. Phosphorylation of IRSs proteins lead to the activation of two main signaling pathways: the PI3K-AKT/PKB pathway, which is responsible for most of the metabolic actions of insulin, and the Ras-MAPK pathway, which regulates expression of some genes and cooperates with the PI3K pathway to control cell growth and differentiation. Binding of the SH2 domains of PI3K to phosphotyrosines on IRS1 leads to the activation of PI3K and the generation of phosphatidylinositol-(3, 4, 5)-triphosphate (PIP3), a lipid second messenger, which activates several PIP3-dependent serine/threonine kinases, such as PDPK1 and subsequently AKT/PKB. The net effect of this pathway is to produce a translocation of the glucose transporter SLC2A4/GLUT4 from cytoplasmic vesicles to the cell membrane to facilitate glucose transport. Moreover, upon insulin stimulation, activated AKT/PKB is responsible for: anti-apoptotic effect of insulin by inducing phosphorylation of BAD; regulates the expression of gluconeogenic and lipogenic enzymes by controlling the activity of the winged helix or forkhead (FOX) class of transcription factors. Another pathway regulated by PI3K-AKT/PKB activation is mTORC1 signaling pathway which regulates cell growth and metabolism and integrates signals from insulin. AKT mediates insulin-stimulated protein synthesis by phosphorylating TSC2 thereby activating mTORC1 pathway. The Ras/RAF/MAP2K/MAPK pathway is mainly involved in mediating cell growth, survival and cellular differentiation of insulin. Phosphorylated IRS1 recruits GRB2/SOS complex, which triggers the activation of the Ras/RAF/MAP2K/MAPK pathway. In addition to binding insulin, the insulin receptor can bind insulin-like growth factors (IGFI and IGFII). Isoform Short has a higher affinity for IGFII binding. When present in a hybrid receptor with IGF1R, binds IGF1. PubMed:12138094 shows that hybrid receptors composed of IGF1R and INSR isoform Long are activated with a high affinity by IGF1, with low affinity by IGF2 and not significantly activated by insulin, and that hybrid receptors composed of IGF1R and INSR isoform Short are activated by IGF1, IGF2 and insulin. In contrast, PubMed:16831875 shows that hybrid receptors composed of IGF1R and INSR isoform Long and hybrid receptors composed of IGF1R and INSR isoform Short have similar binding characteristics, both bind IGF1 and have a low affinity for insulin.
Targeted by drugs (based on IPA annotation)
  • insulin detemir
  • INS
  • canakinumab/INS
  • insulin aspart/insulin detemir
  • ceritinib
  • insulin glargine/insulin lispro
  • insulin aspart
  • insulin glulisine
  • insulin lispro
  • insulin glargine
  • protamine zinc insulin
Biomarker applications (based on IPA annotation)
  • prognosis
Wiki Pathways
  • AMPK signaling
  • DNA damage response (only ATM dependent)
  • Folate Metabolism
  • Insulin Signaling
  • Selenium Pathway
  • Type II diabetes mellitus
  • Vitamin B12 Metabolism
Pathway Interaction Database
  • Insulin Pathway
  • Insulin-mediated glucose transport
  • Signaling events mediated by PTP1B
  • Signaling events mediated by TCPTP
Reactome
  • IRS activation
  • Insulin receptor recycling
  • SHC activation
  • Signal attenuation
  • Signaling by Insulin receptor
Pathway Studio
  • InsulinR → CTNNB/FOXA/FOXO signaling
  • InsulinR → ELK-SRF/SREBF signaling
  • InsulinR → STAT signaling

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

Platelet glycoprotein 4 (CD36 ANTIGEN)

Target (abbrv.) CD36 ANTIGEN
Target (full name) Platelet glycoprotein 4
Somalogic ID (Sequence ID) SL000668 (2973-15_2)
Entrez Gene Symbol CD36
UniProt ID P16671
UniProt Comment
  • Multifunctional glycoprotein that acts as receptor for a broad range of ligands. Ligands can be of proteinaceous nature like thrombospondin, fibronectin, collagen or amyloid-beta as well as of lipidic nature such as oxidized low-density lipoprotein (oxLDL), anionic phospholipids, long-chain fatty acids and bacterial diacylated lipopeptides. They are generally multivalent and can therefore engage multiple receptors simultaneously, the resulting formation of CD36 clusters initiates signal transduction and internalization of receptor-ligand complexes. The dependency on coreceptor signaling is strongly ligand specific. Cellular responses to these ligands are involved in angiogenesis, inflammatory response, fatty acid metabolism, taste and dietary fat processing in the intestine (Probable). Binds long-chain fatty acids and facilitates their transport into cells, thus participating in muscle lipid utilization, adipose energy storage, and gut fat absorption (By similarity) (PubMed:18353783, PubMed:21610069). In the small intestine, plays a role in proximal absorption of dietary fatty acid and cholesterol for optimal chylomicron formation, possibly through the activation of MAPK1/3 (ERK1/2) signaling pathway (By similarity) (PubMed:18753675). Involved in oral fat perception and preferences (PubMed:22240721, PubMed:25822988). Detection into the tongue of long-chain fatty acids leads to a rapid and sustained rise in flux and protein content of pancreatobiliary secretions (By similarity). In taste receptor cells, mediates the induction of an increase in intracellulare calcium levels by long-chain fatty acids, leading to the activation of the gustatory neurons in the nucleus of the solitary tract (By similarity). Important factor in both ventromedial hypothalamus neuronal sensing of long-chain fatty acid and the regulation of energy and glucose homeostasis (By similarity). Receptor for thombospondins, THBS1 and THBS2, mediating their antiangiogenic effects (By similarity). As a coreceptor for TLR4:TLR6 heterodimer, promotes inflammation in monocytes/macrophages. Upon ligand binding, such as oxLDL or amyloid-beta 42, interacts with the heterodimer TLR4:TLR6, the complex is internalized and triggers inflammatory response, leading to NF-kappa-B-dependent production of CXCL1, CXCL2 and CCL9 cytokines, via MYD88 signaling pathway, and CCL5 cytokine, via TICAM1 signaling pathway, as well as IL1B secretion, through the priming and activation of the NLRP3 inflammasome (By similarity) (PubMed:20037584). Selective and nonredundant sensor of microbial diacylated lipopeptide that signal via TLR2:TLR6 heterodimer, this cluster triggers signaling from the cell surface, leading to the NF-kappa-B-dependent production of TNF, via MYD88 signaling pathway and subsequently is targeted to the Golgi in a lipid-raft dependent pathway (By similarity) (PubMed:16880211).
Biomarker applications (based on IPA annotation)
  • efficacy
Wiki Pathways
  • Vitamin A and carotenoid metabolism
Reactome
  • Cross-presentation of particulate exogenous antigens (phagosomes)
  • IRAK4 deficiency (TLR2/4)
  • MyD88 deficiency (TLR2/4)
  • MyD88:Mal cascade initiated on plasma membrane
  • PPARA activates gene expression
  • Platelet degranulation
  • Scavenging by Class B Receptors
  • Toll Like Receptor TLR6:TLR2 Cascade
  • Transcriptional regulation of white adipocyte differentiation

Endoglin

Target (abbrv.) Endoglin
Target (full name) Endoglin
Somalogic ID (Sequence ID) SL004482 (4908-6_1)
Entrez Gene Symbol ENG
UniProt ID P17813
UniProt Comment
  • Major glycoprotein of vascular endothelium. Involved in the regulation of angiogenesis. May play a critical role in the binding of endothelial cells to integrins and/or other RGD receptors. Acts as TGF-beta coreceptor and is involved in the TGF-beta/BMP signaling cascade. Required for GDF2/BMP9 signaling through SMAD1 in endothelial cells and modulates TGF-beta1 signaling through SMAD3.
Biomarker applications (based on IPA annotation)
  • disease progression
  • efficacy
Wiki Pathways
  • TGF Beta Signaling Pathway
Pathway Interaction Database
  • ALK1 signaling events
  • HIF-1-alpha transcription factor network

Hepatocyte growth factor receptor (Met)

Target (abbrv.) Met
Target (full name) Hepatocyte growth factor receptor
Somalogic ID (Sequence ID) SL000134 (2837-3_2)
Entrez Gene Symbol MET
UniProt ID P08581
UniProt Comment
  • Receptor tyrosine kinase that transduces signals from the extracellular matrix into the cytoplasm by binding to hepatocyte growth factor/HGF ligand. Regulates many physiological processes including proliferation, scattering, morphogenesis and survival. Ligand binding at the cell surface induces autophosphorylation of MET on its intracellular domain that provides docking sites for downstream signaling molecules. Following activation by ligand, interacts with the PI3-kinase subunit PIK3R1, PLCG1, SRC, GRB2, STAT3 or the adapter GAB1. Recruitment of these downstream effectors by MET leads to the activation of several signaling cascades including the RAS-ERK, PI3 kinase-AKT, or PLCgamma-PKC. The RAS-ERK activation is associated with the morphogenetic effects while PI3K/AKT coordinates prosurvival effects. During embryonic development, MET signaling plays a role in gastrulation, development and migration of muscles and neuronal precursors, angiogenesis and kidney formation. In adults, participates in wound healing as well as organ regeneration and tissue remodeling. Promotes also differentiation and proliferation of hematopoietic cells.
Targeted by drugs (based on IPA annotation)
  • crizotinib
  • tivantinib
  • cabozantinib
  • INC280
  • cabozantinib/erlotinib
Biomarker applications (based on IPA annotation)
  • diagnosis
  • disease progression
  • efficacy
  • prognosis
  • response to therapy
  • unspecified application
Wiki Pathways
  • Epithelium TarBase
  • Focal Adhesion
  • Lymphocyte TarBase
  • Muscle cell TarBase
  • Squamous cell TarBase
Pathway Interaction Database
  • Arf6 signaling events
  • Direct p53 effectors
  • FGF signaling pathway
  • Posttranslational regulation of adherens junction stability and dissassembly
  • Regulation of retinoblastoma protein
  • Signaling events mediated by Hepatocyte Growth Factor Receptor (c-Met)
  • Signaling events mediated by TCPTP
  • Stabilization and expansion of the E-cadherin adherens junction
  • Syndecan-1-mediated signaling events
  • a6b1 and a6b4 Integrin signaling
Reactome
  • Sema4D mediated inhibition of cell attachment and migration
Pathway Studio
  • Adherens Junction Assembly (Cadherins)
  • HGFR → AP-1/CREB/MYC signaling
  • HGFR → FOXO3A signaling
  • HGFR → STAT signaling

Intercellular adhesion molecule 2 (sICAM-2)

Target (abbrv.) sICAM-2
Target (full name) Intercellular adhesion molecule 2
Somalogic ID (Sequence ID) SL003177 (2842-68_1)
Entrez Gene Symbol ICAM2
UniProt ID P13598
UniProt Comment
  • ICAM proteins are ligands for the leukocyte adhesion protein LFA-1 (integrin alpha-L/beta-2). ICAM2 may play a role in lymphocyte recirculation by blocking LFA-1-dependent cell adhesion. It mediates adhesive interactions important for antigen-specific immune response, NK-cell mediated clearance, lymphocyte recirculation, and other cellular interactions important for immune response and surveillance.

Vascular endothelial growth factor receptor 2 (VEGF sR2)

Target (abbrv.) VEGF sR2
Target (full name) Vascular endothelial growth factor receptor 2
Somalogic ID (Sequence ID) SL003201 (3651-50_5)
Entrez Gene Symbol KDR
UniProt ID P35968
UniProt Comment
  • Tyrosine-protein kinase that acts as a cell-surface receptor for VEGFA, VEGFC and VEGFD. Plays an essential role in the regulation of angiogenesis, vascular development, vascular permeability, and embryonic hematopoiesis. Promotes proliferation, survival, migration and differentiation of endothelial cells. Promotes reorganization of the actin cytoskeleton. Isoforms lacking a transmembrane domain, such as isoform 2 and isoform 3, may function as decoy receptors for VEGFA, VEGFC and/or VEGFD. Isoform 2 plays an important role as negative regulator of VEGFA- and VEGFC-mediated lymphangiogenesis by limiting the amount of free VEGFA and/or VEGFC and preventing their binding to FLT4. Modulates FLT1 and FLT4 signaling by forming heterodimers. Binding of vascular growth factors to isoform 1 leads to the activation of several signaling cascades. Activation of PLCG1 leads to the production of the cellular signaling molecules diacylglycerol and inositol 1,4,5-trisphosphate and the activation of protein kinase C. Mediates activation of MAPK1/ERK2, MAPK3/ERK1 and the MAP kinase signaling pathway, as well as of the AKT1 signaling pathway. Mediates phosphorylation of PIK3R1, the regulatory subunit of phosphatidylinositol 3-kinase, reorganization of the actin cytoskeleton and activation of PTK2/FAK1. Required for VEGFA-mediated induction of NOS2 and NOS3, leading to the production of the signaling molecule nitric oxide (NO) by endothelial cells. Phosphorylates PLCG1. Promotes phosphorylation of FYN, NCK1, NOS3, PIK3R1, PTK2/FAK1 and SRC.
Targeted by drugs (based on IPA annotation)
  • AEE 788
  • sunitinib
  • cediranib
  • pazopanib
  • axitinib
  • XL647
  • CEP 7055
  • brivanib alaninate
  • CHIR-265
  • tivozanib
  • motesanib
  • OSI-930
  • telatinib
  • ramucirumab
  • cabozantinib
  • nintedanib
  • regorafenib
  • bortezomib/sorafenib
  • lapatinib/pazopanib
  • dexamethasone/lenalidomide/sorafenib
  • bevacizumab/sorafenib
  • cabozantinib/erlotinib
  • docetaxel/ramucirumab
  • vatalanib
  • sorafenib
  • vandetanib
  • pegaptanib
Biomarker applications (based on IPA annotation)
  • disease progression
  • efficacy
  • prognosis
  • response to therapy
  • safety
Wiki Pathways
  • Angiogenesis
  • Focal Adhesion
  • angiogenesis overview
Pathway Interaction Database
  • Beta3 integrin cell surface interactions
  • HIF-2-alpha transcription factor network
  • Integrins in angiogenesis
  • Notch-mediated HES/HEY network
  • S1P1 pathway
  • SHP2 signaling
  • Signaling events mediated by TCPTP
  • Signaling events mediated by VEGFR1 and VEGFR2
  • VEGF and VEGFR signaling network
Reactome
  • EPHA-mediated growth cone collapse
  • Integrin cell surface interactions
  • Neurophilin interactions with VEGF and VEGFR
  • VEGF binds to VEGFR leading to receptor dimerization
  • VEGFA-VEGFR2 Pathway
  • VEGFR2 mediated cell proliferation
Pathway Studio
  • Transcytosis
  • VEGFR → AP-1/CREB/MYC signaling
  • VEGFR → ATF/CREB/ELK-SRF signaling
  • VEGFR → CTNNB signaling
  • VEGFR → CTNND signaling
  • VEGFR → FOXO3A signaling
  • VEGFR → NFATC signaling
  • VEGFR → STAT signaling

Carbohydrate sulfotransferase 15 (ST4S6)

Target (abbrv.) ST4S6
Target (full name) Carbohydrate sulfotransferase 15
Somalogic ID (Sequence ID) SL007502 (4469-78_2)
Entrez Gene Symbol CHST15
UniProt ID Q7LFX5
UniProt Comment
  • Sulfotransferase that transfers sulfate from 3'-phosphoadenosine 5'-phosphosulfate (PAPS) to the C-6 hydroxyl group of the GalNAc 4-sulfate residue of chondroitin sulfate A and forms chondroitin sulfate E containing GlcA-GalNAc(4,6-SO(4)) repeating units. It also transfers sulfate to a unique non-reducing terminal sequence, GalNAc(4SO4)-GlcA(2SO4)-GalNAc(6SO4), to yield a highly sulfated structure similar to the structure found in thrombomodulin chondroitin sulfate. May also act as a B-cell receptor involved in BCR ligation-mediated early activation that mediate regulatory signals key to B-cell development and/or regulation of B-cell-specific RAG expression; however such results are unclear in vivo.
Reactome
  • Chondroitin sulfate biosynthesis

P-Selectin

Target (abbrv.) P-Selectin
Target (full name) P-Selectin
Somalogic ID (Sequence ID) SL000560 (4154-57_2)
Entrez Gene Symbol SELP
UniProt ID P16109
UniProt Comment
  • Ca(2+)-dependent receptor for myeloid cells that binds to carbohydrates on neutrophils and monocytes. Mediates the interaction of activated endothelial cells or platelets with leukocytes. The ligand recognized is sialyl-Lewis X. Mediates rapid rolling of leukocyte rolling over vascular surfaces during the initial steps in inflammation through interaction with PSGL1.
Biomarker applications (based on IPA annotation)
  • efficacy
  • safety
  • unspecified application
Pathway Interaction Database
  • IL4-mediated signaling events
  • amb2 Integrin signaling
Reactome
  • Cell surface interactions at the vascular wall
  • Platelet degranulation
Pathway Studio
  • Leukocyte Adhesion to Endothelial Cell

Toll-like receptor 4:Lymphocyte antigen 96 complex (TLR4:MD-2 complex)

Target (abbrv.) TLR4:MD-2 complex
Target (full name) Toll-like receptor 4:Lymphocyte antigen 96 complex
Somalogic ID (Sequence ID) SL018625 (3647-49_4)
Entrez Gene Symbol TLR4, LY96
UniProt ID O00206, Q9Y6Y9
UniProt Comment
  • O00206: Cooperates with LY96 and CD14 to mediate the innate immune response to bacterial lipopolysaccharide (LPS). Acts via MYD88, TIRAP and TRAF6, leading to NF-kappa-B activation, cytokine secretion and the inflammatory response (PubMed:9237759, PubMed:10835634). Also involved in LPS-independent inflammatory responses triggered by free fatty acids, such as palmitate, and Ni(2+). Responses triggered by Ni(2+) require non-conserved histidines and are, therefore, species-specific (PubMed:20711192). In complex with TLR6, promotes sterile inflammation in monocytes/macrophages in response to oxidized low-density lipoprotein (oxLDL) or amyloid-beta 42. In this context, the initial signal is provided by oxLDL- or amyloid-beta 42-binding to CD36. This event induces the formation of a heterodimer of TLR4 and TLR6, which is rapidly internalized and triggers inflammatory response, leading to the NF-kappa-B-dependent production of CXCL1, CXCL2 and CCL9 cytokines, via MYD88 signaling pathway, and CCL5 cytokine, via TICAM1 signaling pathway, as well as IL1B secretion. Binds electronegative LDL (LDL(-)) and mediates the cytokine release induced by LDL(-) (PubMed:23880187).
  • Q9Y6Y9: Binds bacterial lipopolysaccharide (LPS) (PubMed:17803912, PubMed:17569869). Cooperates with TLR4 in the innate immune response to bacterial lipopolysaccharide (LPS), and with TLR2 in the response to cell wall components from Gram-positive and Gram-negative bacteria (PubMed:11160242, PubMed:11593030). Enhances TLR4-dependent activation of NF-kappa-B (PubMed:10359581). Cells expressing both LY96 and TLR4, but not TLR4 alone, respond to LPS (PubMed:10359581).
Wiki Pathways
  • Regulation of toll-like receptor signaling pathway
  • Toll-like receptor signaling pathway
Pathway Interaction Database
  • Endogenous TLR signaling
Reactome
  • Activation of IRF3/IRF7 mediated by TBK1/IKK epsilon
  • IKK complex recruitment mediated by RIP1
  • IRAK4 deficiency (TLR2/4)
  • Ligand-dependent caspase activation
  • MyD88 deficiency (TLR2/4)
  • MyD88-independent TLR3/TLR4 cascade
  • MyD88:Mal cascade initiated on plasma membrane
  • TRAF6 mediated induction of TAK1 complex
  • TRIF-mediated programmed cell death
  • Toll Like Receptor 4 (TLR4) Cascade
Pathway Studio
  • TLR → AP-1 signaling
  • TLR4 → IRF signaling
  • TLR4/5/7/9 → NF-kB signaling

Cadherin-5

Target (abbrv.) Cadherin-5
Target (full name) Cadherin-5
Somalogic ID (Sequence ID) SL002081 (2819-23_2)
Entrez Gene Symbol CDH5
UniProt ID P33151
UniProt Comment
  • Cadherins are calcium-dependent cell adhesion proteins. They preferentially interact with themselves in a homophilic manner in connecting cells; cadherins may thus contribute to the sorting of heterogeneous cell types. This cadherin may play a important role in endothelial cell biology through control of the cohesion and organization of the intercellular junctions. It associates with alpha-catenin forming a link to the cytoskeleton. Acts in concert with KRIT1 to establish and maintain correct endothelial cell polarity and vascular lumen. These effects are mediated by recruitment and activation of the Par polarity complex and RAP1B. Required for activation of PRKCZ and for the localization of phosphorylated PRKCZ, PARD3, TIAM1 and RAP1B to the cell junction.
Biomarker applications (based on IPA annotation)
  • diagnosis
Pathway Interaction Database
  • S1P2 pathway
  • Signaling events mediated by VEGFR1 and VEGFR2
Reactome
  • Adherens junctions interactions
  • VEGFR2 mediated vascular permeability
Pathway Studio
  • Leukocyte Adhesion to Endothelial Cell

Protein jagged-1 (JAG1)

Target (abbrv.) JAG1
Target (full name) Protein jagged-1
Somalogic ID (Sequence ID) SL007328 (5092-51_3)
Entrez Gene Symbol JAG1
UniProt ID P78504
UniProt Comment
  • Ligand for multiple Notch receptors and involved in the mediation of Notch signaling. May be involved in cell-fate decisions during hematopoiesis. Seems to be involved in early and late stages of mammalian cardiovascular development. Inhibits myoblast differentiation (By similarity). Enhances fibroblast growth factor-induced angiogenesis (in vitro).
Biomarker applications (based on IPA annotation)
  • efficacy
Wiki Pathways
  • Notch Signaling Pathway
  • Proteins and DNA Sequences in Cardicac Structures
Pathway Interaction Database
  • Notch signaling pathway
  • Validated transcriptional targets of TAp63 isoforms
Reactome
  • Activated NOTCH1 Transmits Signal to the Nucleus
  • Constitutive Signaling by NOTCH1 HD Domain Mutants
  • Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants
  • Constitutive Signaling by NOTCH1 PEST Domain Mutants
  • Constitutive Signaling by NOTCH1 t(7
  • NOTCH2 Activation and Transmission of Signal to the Nucleus
  • Signaling by NOTCH3
  • Signaling by NOTCH4
Pathway Studio
  • Notch → EP300/ASCL signaling
  • Notch → LEF1 signaling
  • Notch → MEF/MYOD signaling
  • Notch → NF-kB signaling
  • Notch → RBPJ/HES/HEY signaling
  • Notch → SMAD3 signaling
  • Notch → TCF3 signaling

OX-2 membrane glycoprotein (OX2G)

Target (abbrv.) OX2G
Target (full name) OX-2 membrane glycoprotein
Somalogic ID (Sequence ID) SL014268 (5112-73_3)
Entrez Gene Symbol CD200
UniProt ID P41217
UniProt Comment
  • Costimulates T-cell proliferation. May regulate myeloid cell activity in a variety of tissues.
Reactome
  • Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell

CD109 antigen (CD109)

Target (abbrv.) CD109
Target (full name) CD109 antigen
Somalogic ID (Sequence ID) SL008773 (3290-50_2)
Entrez Gene Symbol CD109
UniProt ID Q6YHK3
UniProt Comment
  • Modulates negatively TGFB1 signaling in keratinocytes.

All locus annotations are based on the sentinel SNP (rs651007) 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

Genes hit or close-by
  • ABO ABO blood group (transferase A, alpha 1-3-N-acetylgalactosaminyltransferase; transferase B, alpha 1-3-galactosyltransferase)
Potentially regulated genes
  • CELP carboxyl ester lipase pseudogene
  • DBH dopamine beta-hydroxylase (dopamine beta-monooxygenase)
  • ADAMTSL2 ADAMTS-like 2
  • SARDH sarcosine dehydrogenase
  • RALGDS ral guanine nucleotide dissociation stimulator
eQTL genes
  • ABO ABO blood group (transferase A, alpha 1-3-N-acetylgalactosaminyltransferase; transferase B, alpha 1-3-galactosyltransferase)
  • SURF1 surfeit 1
  • SURF6 surfeit 6
  • GBGT1 globoside alpha-1,3-N-acetylgalactosaminyltransferase 1

 

Results from other genome-wide association studies

Trait P Study Source
von Willebrand factor (vWF) 1.4×10-161 21534939 (PMID) GRASP2 nonQTL
Alkaline phosphatase (ALP) in plasma 2.6×10-123 22001757 (PMID) GRASP2 nonQTL
Liver enzyme levels (alkaline phosphatase) 3×10-123 22001757 (PMID) GWAS Catalog via SNiPA
E-selectin levels 2×10-82 20147318 (PMID) GWAS Catalog via SNiPA
Blood soluble E-selectin levels (female) 2.4×10-82 20147318 (PMID) GRASP2 nonQTL
Activated partial thromboplastin time 4.7×10-75 22703881 (PMID) GRASP2 nonQTL
Alkaline phosphatase (ALP) 4.2×10-59 20139978 (PMID) GRASP2 nonQTL
Serum alkaline phosphatase levels 1×10-56 24094242 (PMID) GWAS Catalog via SNiPA
LDL cholesterol 2.4×10-44 24097068 (PMID) Supplemental file
Triglycerides 8.8×10-42 24097068 (PMID) Supplemental file
Soluble P-selectin 1.9×10-41 20167578 (PMID) GRASP2 nonQTL
Soluble levels of adhesion molecules 2×10-41 20167578 (PMID) GWAS Catalog via SNiPA
Blood metabolite ratios 6×10-34 24816252 (PMID) GWAS Catalog via SNiPA
Soluble E-selectin levels 1×10-29 19729612 (PMID) GWAS Catalog via SNiPA
cg18718102 (chr9:136203313) 1.3×10-29 10.1101/033084 (DOI) BIOS QTL cis-meQTLs
Serum soluble E-selectin 1.3×10-29 19729612 (PMID) GRASP2 nonQTL
E-selectin 1.3×10-29 pha002871 (dbGaP) dbGaP via SNiPA
Venous thrombosis 5.6×10-29 22675575 (PMID) GRASP2 nonQTL
Urinary metabolites (H-NMR features) 1×10-28 24586186 (PMID) GWAS Catalog via SNiPA
Blood soluble E-selectin levels (in non-diabetic females) 7.6×10-26 20147318 (PMID) GRASP2 nonQTL
Factor XIII antigen 1.9×10-25 23381943 (PMID) GRASP2 nonQTL
End-stage coagulation 2×10-25 23381943 (PMID) GWAS Catalog via SNiPA
Total cholesterol 1×10-21 20686565 (PMID) GRASP2 nonQTL
Plasma carcinoembryonic antigen (CEA) levels 1.8×10-21 23300138 (PMID) GRASP2 nonQTL
Cholesterol, total 9×10-21 20686565 (PMID) GWAS Catalog via SNiPA
Blood soluble E-selectin levels (in diabetic females) 1.5×10-20 20147318 (PMID) GRASP2 nonQTL
Blood metabolite levels 6×10-20 24816252 (PMID) GWAS Catalog via SNiPA
ADpSGEGDFXAEGGGVR* 6.3×10-20 24816252 (PMID) gwas.eu via SNiPA
Red blood cell traits 9×10-18 23222517 (PMID) GWAS Catalog via SNiPA
Red blood cell count (RBC) 9.3×10-18 23222517 (PMID) GRASP2 nonQTL
Venous thromboembolism 1.2×10-17 22672568 (PMID) GRASP2 nonQTL
Hemoglobin (Hb) 1.4×10-15 23222517 (PMID) GRASP2 nonQTL
Coronary heart disease 4×10-14 21378990 (PMID) GWAS Catalog via SNiPA
Coronary artery disease (CAD) 4.1×10-14 23364394 (PMID) GRASP2 nonQTL
Hematocrit (Hct) 7.6×10-14 23222517 (PMID) GRASP2 nonQTL
Angiotensin-converting enzyme (ACE) activity 2×10-13 20066004 (PMID) GRASP2 nonQTL
cg14560040 (chr9:136203329) 3×10-13 10.1101/033084 (DOI) BIOS QTL cis-meQTLs
Interleukin-6 (IL-6) levels 3.6×10-13 22291609 (PMID) GRASP2 nonQTL
Red blood cell count 3×10-12 20139978 (PMID) GWAS Catalog via SNiPA
Hematological and biochemical traits 1×10-11 20139978 (PMID) GWAS Catalog via SNiPA
Serum metabolite (mass spec peak: 512.2 m/z) 4.1×10-11 23281178 (PMID) GRASP2 metabQTL
Circulating galectin-3 levels 1.9×10-10 23056639 (PMID) GRASP2 nonQTL
Serum metabolite (mass spec peak: 765.4 m/z) 2.9×10-10 23281178 (PMID) GRASP2 metabQTL
cg13040392 (chr9:136075369) 1.5×10-9 10.1101/033084 (DOI) BIOS QTL cis-meQTLs
Coronary artery disease or ischemic stroke 2×10-9 24262325 (PMID) GWAS Catalog via SNiPA
Metabolite levels 6×10-9 21909109 (PMID) GWAS Catalog via SNiPA
Iron status biomarkers (ferritin levels) 1×10-8 25352340 (PMID) GWAS Catalog via SNiPA
Coronary artery disease (CAD) (males) 2.8×10-8 23202125 (PMID) GRASP2 nonQTL
Angiotensin-converting enzyme activity 3×10-8 20066004 (PMID) GWAS Catalog via SNiPA
Coronary artery disease or large artery stroke 3×10-8 24262325 (PMID) GWAS Catalog via SNiPA
Coronary artery disease and myocardial infarction 7.1×10-8 23202125 (PMID) Supplemental file
Fasting serum interleukin-6 (IL-6) (pg/mL) in children 1.7×10-7 23251661 (PMID) GRASP2 nonQTL
Coronary Artery Disease 2×10-7 24262325 (PMID) GWAS Catalog via SNiPA
Coronary artery disease (CAD) with myocardial infarction (MI) 2.2×10-7 23202125 (PMID) GRASP2 nonQTL
Coronary artery disease (CAD) (men) 2.6×10-7 21378990 (PMID) GRASP2 nonQTL
Myocardial infarction (MI) 5.2×10-7 21378990 (PMID) GRASP2 nonQTL
Pancreatic cancer 8.2×10-7 19648918 (PMID) GRASP2 nonQTL
Gene expression of ABO (probeID ILMN_1656979) in cerebellum in non-Alzheimer's disease samples 2.9×10-6 22685416 (PMID) GRASP2 eQTL
Gene expression of ABO in lymphoblastoid cell lines 4.5×10-6 21378990 (PMID) GRASP2 nonQTL
Gene expression of ABO (probeID ILMN_1656979) in cerebellum in Alzheimer's disease cases and controls 5.3×10-6 22685416 (PMID) GRASP2 eQTL
Gamma-glutamyl transferase (GGT) 2.4×10-5 22001757 (PMID) GRASP2 nonQTL
Fasting glucose 3.3×10-5 22885924 (PMID) Supplemental file
Gene expression of SURF1 in blood 9.9×10-5 21829388 (PMID) GRASP2 eQTL
Coronary artery disease (CAD) age <=50 1.2×10-4 23202125 (PMID) GRASP2 nonQTL
Gene expression of SURF6 in blood 1.8×10-4 21829388 (PMID) GRASP2 eQTL
Coronary artery disease (CAD) with age of onset <=50 2×10-4 21378990 (PMID) GRASP2 nonQTL
2h glucose 2.1×10-4 22885924 (PMID) Supplemental file
Coronary artery disease (CAD) age >50 2.2×10-4 23202125 (PMID) GRASP2 nonQTL
Adiponectin levels 2.4×10-4 22479202 (PMID) GRASP2 nonQTL
Schizophrenia 3.7×10-4 19571809 (PMID) GRASP2 nonQTL

The pleiotropic ABO locus is discussed in the main paper.

This locus is discussed in the main paper. Here we report observations not mentioned in the paper: In Shin et al. [PubMed] SNP rs651007 associates with dipeptide levels (aspartylphenylalanine, p=2×10-7; X-14189, annotated as potential Leu-Ala, but Ser-Pro is also possible by mass alone, p=9.6×10-10; X14304, I/L-Ala or Ala-I/L?, p=1.8×10-8; X-14208, could be Cys-Met or Tyr-Ala or His-Pro or Ser-Phe by mass alone, p=1.5×10-7; X-14205; X14086: annotated as Thr-Glu, but mass is 25 too high; Val-Arg possible by mass alone). This SNP also associates in Raffler et al. [PubMed] (Urine NMR) with a signal at 2.0308 ppm (PM20308, p=5.1×10-20). It is also a marginal hit in CardioGram (7.1×10-8). He et al. [PubMed] report a genome wide association study of genetic loci that influence tumour biomarkers cancer antigen 19-9, carcinoembryonic antigen and α fetoprotein and their associations with cancer risk. The authors find strong association of SNP rs8176749 with carcinoembryonic antigen (CEA) levels – we find association with Cadherin-5. CD209 and MBL2 are both lectins. All associated ABO-associated proteins are glycoproteins, part of glycoprotein complex (LY96), or glycoprotein-binding (SELE), except for IL27RA (http://jcggdb.jp/rcmg/gpdb/index). According to Uniprot all proteins are glycoproteins (including associations non-replicated in QMDiab), while only half of all SomaLogic proteins are glycoproteins. The Panther classification system (http://pantherdb.org/tools/compareToRefList.jsp) reported a significant enrichment of the GO process "endothelial cell differentiation" (GO:0045446): 5 out of 17 annotated proteins were found (expected were 0.32, p=1.45×10-5).



Subnetwork of the ABO locus.Six replicated pQTLs at the ABO gene locus (red), including SNP identifiers that are linked to the the six loci (light green KORA SNPs, yellow QMDiab SNPs, bright green both), pQTLS (blue), proteins with significant partial correlation are connected, associations with GWAS endpoints are shown (grey) [NOTE: the anorexia is a false positive, checked this with the consortium].

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.