HelmholtzZentrum munich
WCMC

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

ONLINE SUPPLEMENTARY INFORMATION

Ideogram
Proteome annotation
Locus annotations

Locus 31

Top associations per target

Target cis/​trans Study SNP SNP location Maj/​min allele MAF N βinv seinv Pinv fclog Plog Praw
HRG cis Discovery rs2228243 3:186,395,113 A/G 0.21 997 1.007 0.044 4.7×10-94 1.240 7.4×10-90 2.2×10-101
HRG cis Replication rs2228243 3:186,395,113 A/G 0.23 337 0.845 0.075 2.7×10-25 1.290 4×10-16 5.3×10-25
MP2K4 trans Discovery rs2228243 3:186,395,113 A/G 0.21 997 0.942 0.045 4.2×10-82 1.310 1.2×10-78 6×10-88
MP2K4 trans Replication rs16860974 3:186,387,299 A/C 0.21 337 0.719 0.078 6×10-18 1.280 3.9×10-13 1.5×10-18
CD27 trans Discovery rs2228243 3:186,395,113 A/G 0.21 997 0.730 0.049 1.7×10-45 1.130 1.9×10-29 2.2×10-17
CD27 trans Replication rs2228243 3:186,395,113 A/G 0.23 337 0.323 0.088 2.6×10-4 1.090 0.014 0.136
Semaphorin 3A trans Discovery rs2228243 3:186,395,113 A/G 0.21 997 0.335 0.053 3.3×10-10 1.050 5.5×10-5 0.028
Semaphorin 3A trans Replication rs16860974 3:186,387,299 A/C 0.21 337 0.053 0.080 0.51 1.010 0.783 0.95

 

Regional association plots

Histidine-rich glycoprotein (HRG)

Dual specificity mitogen-activated protein kinase kinase 4 (MP2K4)

CD27 antigen (CD27)

Semaphorin-3A (Semaphorin 3A)

 

Boxplots and histograms for top associations

Histidine-rich glycoprotein (HRG)

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

Dual specificity mitogen-activated protein kinase kinase 4 (MP2K4)

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

CD27 antigen (CD27)

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

Semaphorin-3A (Semaphorin 3A)

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

Histidine-rich glycoprotein (HRG)

Target (abbrv.) HRG
Target (full name) Histidine-rich glycoprotein
Somalogic ID (Sequence ID) SL006448 (4996-66_1)
Entrez Gene Symbol HRG
UniProt ID P04196
UniProt Comment
  • Plasma glycoprotein that binds a number of ligands such as heme, heparin, heparan sulfate, thrombospondin, plasminogen, and divalent metal ions. Binds heparin and heparin/glycosaminoglycans in a zinc-dependent manner. Binds heparan sulfate on the surface of liver, lung, kidney and heart endothelial cells. Binds to N-sulfated polysaccharide chains on the surface of liver endothelial cells. Inhibits rosette formation. Acts as an adapter protein and is implicated in regulating many processes such as immune complex and pathogen clearance, cell chemotaxis, cell adhesion, angiogenesis, coagulation and fibrinolysis. Mediates clearance of necrotic cells through enhancing the phagocytosis of necrotic cells in a heparan sulfate-dependent pathway. This process can be regulated by the presence of certain HRG ligands such as heparin and zinc ions. Binds to IgG subclasses of immunoglobins containing kappa and lambda light chains with different affinities regulating their clearance and inhibiting the formation of insoluble immune complexes. Tethers plasminogen to the cell surface. Binds T-cells and alters the cell morphology. Modulates angiogenesis by blocking the CD6-mediated antiangiongenic effect of thrombospondins, THBS1 and THBS2. Acts as a regulator of the vascular endothelial growth factor (VEGF) signaling pathway; inhibits endothelial cell motility by reducing VEGF-induced complex formation between PXN/paxillin and ILK/integrin-linked protein kinase and by promoting inhibition of VEGF-induced tyrosine phosphorylation of focal adhesion kinases and alpha-actinins in endothelial cells. Also plays a role in the regulation of tumor angiogenesis and tumor immune surveillance. Normalizes tumor vessels and promotes antitumor immunity by polarizing tumor-associated macrophages, leading to decreased tumor growth and metastasis.
Reactome
  • Dissolution of Fibrin Clot
  • Platelet degranulation

Dual specificity mitogen-activated protein kinase kinase 4 (MP2K4)

Target (abbrv.) MP2K4
Target (full name) Dual specificity mitogen-activated protein kinase kinase 4
Somalogic ID (Sequence ID) SL007237 (5242-37_3)
Entrez Gene Symbol MAP2K4
UniProt ID P45985
UniProt Comment
  • Dual specificity protein kinase which acts as an essential component of the MAP kinase signal transduction pathway. Essential component of the stress-activated protein kinase/c-Jun N-terminal kinase (SAP/JNK) signaling pathway. With MAP2K7/MKK7, is the one of the only known kinase to directly activate the stress-activated protein kinase/c-Jun N-terminal kinases MAPK8/JNK1, MAPK9/JNK2 and MAPK10/JNK3. MAP2K4/MKK4 and MAP2K7/MKK7 both activate the JNKs by phosphorylation, but they differ in their preference for the phosphorylation site in the Thr-Pro-Tyr motif. MAP2K4 shows preference for phosphorylation of the Tyr residue and MAP2K7/MKK7 for the Thr residue. The phosphorylation of the Thr residue by MAP2K7/MKK7 seems to be the prerequisite for JNK activation at least in response to proinflammatory cytokines, while other stimuli activate both MAP2K4/MKK4 and MAP2K7/MKK7 which synergistically phosphorylate JNKs. MAP2K4 is required for maintaining peripheral lymphoid homeostasis. The MKK/JNK signaling pathway is also involved in mitochondrial death signaling pathway, including the release cytochrome c, leading to apoptosis. Whereas MAP2K7/MKK7 exclusively activates JNKs, MAP2K4/MKK4 additionally activates the p38 MAPKs MAPK11, MAPK12, MAPK13 and MAPK14.
Wiki Pathways
  • Apoptosis
  • FAS pathway and Stress induction of HSP regulation
  • IL-1 signaling pathway
  • IL-6 signaling pathway
  • Insulin Signaling
  • MAPK Cascade
  • MAPK signaling pathway
  • MicroRNAs in cardiomyocyte hypertrophy
  • Regulation of toll-like receptor signaling pathway
  • TGF beta Signaling Pathway
  • TNF alpha Signaling Pathway
  • Toll-like receptor signaling pathway
  • angiogenesis overview
  • p38 MAPK Signaling Pathway
Pathway Interaction Database
  • CD40/CD40L signaling
  • CDC42 signaling events
  • Cellular roles of Anthrax toxin
  • Ceramide signaling pathway
  • Ephrin B reverse signaling
  • ErbB1 downstream signaling
  • Fc-epsilon receptor I signaling in mast cells
  • IL6-mediated signaling events
  • JNK signaling in the CD4+ TCR pathway
  • Nephrin/Neph1 signaling in the kidney podocyte
  • PDGFR-beta signaling pathway
  • RAC1 signaling pathway
  • Regulation of Androgen receptor activity
  • Regulation of p38-alpha and p38-beta
  • RhoA signaling pathway
  • Signaling events mediated by Hepatocyte Growth Factor Receptor (c-Met)
  • Signaling events mediated by focal adhesion kinase
  • TRAIL signaling pathway
  • VEGFR3 signaling in lymphatic endothelium
Reactome
  • FCERI mediated MAPK activation
  • Interleukin-1 signaling
  • JNK (c-Jun kinases) phosphorylation and activation mediated by activated human TAK1
  • Oxidative Stress Induced Senescence
  • Uptake and function of anthrax toxins
Pathway Studio
  • ADRA1A → IL6 production
  • AngiopoietinR → AP-1 signaling
  • CNR1/2 → IL1B/2/4/6/10 production
  • CannabinoidR → AP-1/EGR signaling
  • DopamineR2 → AP-1/CREB/ELK-SRF signaling
  • EDG3/5 → AP-1/ELK-SRF signaling
  • EDNRA/B → vascular motility
  • EGFR → AP-1/ATF2 signaling
  • EGFR → AP-1/CREB/ELK-SRF/MYC signaling
  • EGFR/ERBB2 → TP53 signaling
  • EctodysplasinR → AP-1 signaling
  • EndothelinRa → AP-1/CREB signaling
  • EndothelinRb → AP-1/CREB/ELK-SRF signaling
  • EphrinB → JUN signaling
  • ErythropoietinR → AP-1/CREB/MYC signaling
  • FGFR → AP-1/CREB/CREBBP/ELK-SRF/MYC signaling
  • FibronectinR → AP-1/ELK-SRF/SREBF signaling
  • FibronectinR → NF-kB signaling
  • FrizzledR → JUN/PAX2 signaling
  • GDNF → HSF1 signaling
  • GNRHR → ELK-SRF signaling
  • HGFR → AP-1/CREB/MYC signaling
  • IL1R → STAT3 signaling
  • NGFR → AP-1/CEBPB/CREB/ELK-SRF/TP53 signaling
  • NGFR → MEF signaling
  • NTRK → AP-1/CREB/ELK-SRF/MYC/SMAD3/TP53 signaling
  • Nociception-related DRD2 expression targets
  • Notch → TCF3 signaling
  • PDGFR → AP-1/MYC signaling
  • PTAFR → AP-1/ATF1/CREB/ERK-SRF signaling
  • PTGER2/3 → inflammation-related expression targets
  • Summarized nociception-related expression targets
  • T-cell receptor → ATF/CREB signaling
  • TGFBR → AP-1 signaling
  • TGFBR → ATF/GADD/MAX/TP53 signaling
  • TGFBR → CREB/ELK-SRF signaling
  • TGFBR → MEF/MYOD/MYOG signaling
  • TLR → AP-1 signaling
  • TLR4 Signaling in Leukocytes
  • TNFR → AP-1/ATF/TP53 signaling
  • TNFR → CREB/ELK-SRF signaling
  • TNFRSF1A → AP-1/ATF/TP53 signaling
  • TNFRSF1A → CREB/ELK-SRF signaling
  • TNFRSF6 → DDIT3 signaling
  • TNFRSF6 → HSF1 signaling
  • ThrombinR → AP-1/CREB/ELK-SRF/SP1 signaling
  • ThrombopoietinR → AP-1/CREB/ELK-SRF/MYC signaling
  • ThrombopoietinR → SPI1 signaling
  • Toll-like Receptors Act through MYD88-TIRAP Signaling
  • VEGFR → AP-1/CREB/MYC signaling
  • VEGFR → ATF/CREB/ELK-SRF signaling
  • VasopressinR1 → CREB/ELK-SRF/AP-1/EGR signaling
  • VasopressinR2 → CREB/ELK-SRF/AP-1/EGR signaling

CD27 antigen (CD27)

Target (abbrv.) CD27
Target (full name) CD27 antigen
Somalogic ID (Sequence ID) SL004134 (5412-53_3)
Entrez Gene Symbol CD27
UniProt ID P26842
UniProt Comment
  • Receptor for CD70/CD27L. May play a role in survival of activated T-cells. May play a role in apoptosis through association with SIVA1.
Biomarker applications (based on IPA annotation)
  • unspecified application

Semaphorin-3A (Semaphorin 3A)

Target (abbrv.) Semaphorin 3A
Target (full name) Semaphorin-3A
Somalogic ID (Sequence ID) SL010379 (3222-11_2)
Entrez Gene Symbol SEMA3A
UniProt ID Q14563
UniProt Comment
  • Involved in the development of the olfactory system and in neuronal control of puberty. Induces the collapse and paralysis of neuronal growth cones. Could serve as a ligand that guides specific growth cones by a motility-inhibiting mechanism. Binds to the complex neuropilin-1/plexin-1.
Wiki Pathways
  • angiogenesis overview
Reactome
  • CRMPs in Sema3A signaling
  • SEMA3A-Plexin repulsion signaling by inhibiting Integrin adhesion
  • Sema3A PAK dependent Axon repulsion

All locus annotations are based on the sentinel SNP (rs2228243) and 1 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

 

Results from other genome-wide association studies

Trait P Study Source
Activated partial thromboplastin time 7.2×10-26 22703881 (PMID) GRASP2 nonQTL
Activated protein C resistance 9.6×10-15 23188048 (PMID) GRASP2 nonQTL

HRG may have a regulatory role on MAP2K4, possibly also on CD27 and ESR1.

Locus 31 harbours a replicated trans-association with Dual specificity mitogen-activated protein kinase kinase 4 (MAP2K4) and a replicated cis-association with Histidine-rich glycoprotein (HRG). Elevated levels of HRG are associated with thrombophilia (OMIM #613116). Locus 43 harbours a second replicated trans-association with MAP2K4 in the same genetic region. The associated SNP rs1042445 is a coding variant in HRG. In addition, there are two non-replicated, but in QMDiab still nominally significant trans-pQTL with CD27 antigen (CD27, p=4.7×10-3 in QMDiab) and Estrogen receptor (ESR1, p=8.3×10-4 in QMDiab).

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.