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

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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