HelmholtzZentrum munich
WCMC

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

ONLINE SUPPLEMENTARY INFORMATION

Ideogram
Proteome annotation
Locus annotations

Locus 43

Top associations per target

Target cis/​trans Study SNP SNP location Maj/​min allele MAF N βinv seinv Pinv fclog Plog Praw
MP2K4 trans Discovery rs1042445 3:186,395,436 C/T 0.23 997 -0.879 0.043 8.4×10-78 -1.300 1.3×10-80 6×10-67
MP2K4 trans Replication rs1042445 3:186,395,436 G/A 0.26 337 -0.726 0.069 1.2×10-22 -1.340 2.6×10-23 3.4×10-22
CD27 trans Discovery rs1042445 3:186,395,436 C/T 0.23 997 -0.556 0.049 1.6×10-28 -1.090 2.3×10-17 9.2×10-10
CD27 trans Replication rs1042445 3:186,395,436 G/A 0.26 337 -0.234 0.082 0.005 -1.070 0.027 0.061
ER trans Discovery rs1042445 3:186,395,436 C/T 0.23 997 -0.438 0.050 6.2×10-18 -1.060 2.4×10-6 0.068
ER trans Replication rs1042445 3:186,395,436 G/A 0.26 337 -0.241 0.071 0.001 -1.060 0.015 0.103

 

Regional association plots

 

Boxplots and histograms for top associations

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

Estrogen receptor (ER)

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

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

Estrogen receptor (ER)

Target (abbrv.) ER
Target (full name) Estrogen receptor
Somalogic ID (Sequence ID) SL000007 (2945-25_1)
Entrez Gene Symbol ESR1
UniProt ID P03372
UniProt Comment
  • Nuclear hormone receptor. The steroid hormones and their receptors are involved in the regulation of eukaryotic gene expression and affect cellular proliferation and differentiation in target tissues. Ligand-dependent nuclear transactivation involves either direct homodimer binding to a palindromic estrogen response element (ERE) sequence or association with other DNA-binding transcription factors, such as AP-1/c-Jun, c-Fos, ATF-2, Sp1 and Sp3, to mediate ERE-independent signaling. Ligand binding induces a conformational change allowing subsequent or combinatorial association with multiprotein coactivator complexes through LXXLL motifs of their respective components. Mutual transrepression occurs between the estrogen receptor (ER) and NF-kappa-B in a cell-type specific manner. Decreases NF-kappa-B DNA-binding activity and inhibits NF-kappa-B-mediated transcription from the IL6 promoter and displace RELA/p65 and associated coregulators from the promoter. Recruited to the NF-kappa-B response element of the CCL2 and IL8 promoters and can displace CREBBP. Present with NF-kappa-B components RELA/p65 and NFKB1/p50 on ERE sequences. Can also act synergistically with NF-kappa-B to activate transcription involving respective recruitment adjacent response elements; the function involves CREBBP. Can activate the transcriptional activity of TFF1. Also mediates membrane-initiated estrogen signaling involving various kinase cascades. Isoform 3 is involved in activation of NOS3 and endothelial nitric oxide production. Isoforms lacking one or several functional domains are thought to modulate transcriptional activity by competitive ligand or DNA binding and/or heterodimerization with the full length receptor. Essential for MTA1-mediated transcriptional regulation of BRCA1 and BCAS3. Isoform 3 can bind to ERE and inhibit isoform 1.
Targeted by drugs (based on IPA annotation)
  • 17-alpha-ethinylestradiol
  • fulvestrant
  • beta-estradiol
  • estradiol 17beta-cypionate
  • estriol
  • estrone
  • estradiol valerate
  • mestranol
  • CHF-4227
  • bazedoxifene
  • estradiol valerate/testosterone enanthate
  • TAS-108
  • ethinyl estradiol/ethynodiol diacetate
  • estradiol acetate
  • esterified estrogens
  • estradiol cypionate/medroxyprogesterone acetate
  • estradiol/norethindrone acetate
  • synthetic conjugated estrogens
  • A
  • estradiol cypionate/testosterone cypionate
  • B
  • etonogestrel
  • CC8490
  • MITO-4509
  • cyproterone acetate/ethinyl estradiol
  • ethinyl estradiol/etonogestrel
  • chlorotrianisene
  • megestrol acetate/tamoxifen
  • sulindac/tamoxifen
  • sulindac/toremifene
  • raloxifene/sulindac
  • ethynodiol
  • goserelin/tamoxifen
  • raloxifene/teriparatide
  • desogestrel/ethinyl estradiol
  • drospirenone/ethinyl estradiol
  • premarin
  • ethinyl estradiol/norelgestromin
  • ethinyl estradiol/norethindrone
  • ethinyl estradiol/levonorgestrel
  • ethinyl estradiol/norgestrel
  • ethinyl estradiol/norgestimate
  • conjugated estrogen/medroxyprogesterone acetate
  • diethylstilbestrol
  • ospemifene
  • toremifene
  • tamoxifen
  • raloxifene
  • arzoxifene
  • clomiphene
  • estramustine phosphate
  • diethylstilbestrol diphosphate
  • estropipate
  • dienestrol
  • estramustine
  • medroxyprogesterone acetate
  • desogestrel
  • danazol
  • trilostane
  • fluoxymesterone
  • norgestimate
  • progesterone
Biomarker applications (based on IPA annotation)
  • diagnosis
  • disease progression
  • efficacy
  • prognosis
  • response to therapy
Wiki Pathways
  • Estrogen signaling pathway
  • Integrated Breast Cancer Pathway
  • Leptin signaling pathway
  • Muscle cell TarBase
  • Nuclear Receptors
Pathway Interaction Database
  • AP-1 transcription factor network
  • ATF-2 transcription factor network
  • FOXA1 transcription factor network
  • FOXM1 transcription factor network
  • LKB1 signaling events
  • Plasma membrane estrogen receptor signaling
  • Regulation of Telomerase
  • Regulation of nuclear SMAD2/3 signaling
  • Signaling events mediated by HDAC Class II
  • Signaling mediated by p38-alpha and p38-beta
  • Validated nuclear estrogen receptor alpha network
Reactome
  • Nuclear Receptor transcription pathway
  • Nuclear signaling by ERBB4

All locus annotations are based on the sentinel SNP (rs1042445) and 4 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 6.6×10-53 22703881 (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.