HelmholtzZentrum munich
WCMC

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

ONLINE SUPPLEMENTARY INFORMATION

Ideogram
Proteome annotation
Locus annotations

Locus 8

Top associations per target

Target cis/​trans Study SNP SNP location Maj/​min allele MAF N βinv seinv Pinv fclog Plog Praw
MAPKAPK3 trans Discovery rs1926447 13:46,629,944 G/A 0.29 989 1.104 0.036 2.2×10-145 1.400 9.6×10-146 2.1×10-133
MAPKAPK3 trans Replication rs1926447 13:46,629,944 G/A 0.32 337 0.161 0.039 4.3×10-5 1.100 2.3×10-5 0.035
MIF trans Discovery rs1926447 13:46,629,944 G/A 0.29 989 0.348 0.048 1×10-12 1.060 5×10-8 0.003
MIF trans Replication rs1926447 13:46,629,944 G/A 0.32 337 0.151 0.046 0.001 1.040 0.01 0.395

 

Regional association plots

MAP kinase-activated protein kinase 3 (MAPKAPK3)

Macrophage migration inhibitory factor (MIF)

 

Boxplots and histograms for top associations

MAP kinase-activated protein kinase 3 (MAPKAPK3)

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

Macrophage migration inhibitory factor (MIF)

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

MAP kinase-activated protein kinase 3 (MAPKAPK3)

Target (abbrv.) MAPKAPK3
Target (full name) MAP kinase-activated protein kinase 3
Somalogic ID (Sequence ID) SL004765 (3822-54_2)
Entrez Gene Symbol MAPKAPK3
UniProt ID Q16644
UniProt Comment
  • Stress-activated serine/threonine-protein kinase involved in cytokines production, endocytosis, cell migration, chromatin remodeling and transcriptional regulation. Following stress, it is phosphorylated and activated by MAP kinase p38-alpha/MAPK14, leading to phosphorylation of substrates. Phosphorylates serine in the peptide sequence, Hyd-X-R-X(2)-S, where Hyd is a large hydrophobic residue. MAPKAPK2 and MAPKAPK3, share the same function and substrate specificity, but MAPKAPK3 kinase activity and level in protein expression are lower compared to MAPKAPK2. Phosphorylates HSP27/HSPB1, KRT18, KRT20, RCSD1, RPS6KA3, TAB3 and TTP/ZFP36. Mediates phosphorylation of HSP27/HSPB1 in response to stress, leading to dissociate HSP27/HSPB1 from large small heat-shock protein (sHsps) oligomers and impair their chaperone activities and ability to protect against oxidative stress effectively. Involved in inflammatory response by regulating tumor necrosis factor (TNF) and IL6 production post-transcriptionally: acts by phosphorylating AU-rich elements (AREs)-binding proteins, such as TTP/ZFP36, leading to regulate the stability and translation of TNF and IL6 mRNAs. Phosphorylation of TTP/ZFP36, a major post-transcriptional regulator of TNF, promotes its binding to 14-3-3 proteins and reduces its ARE mRNA affinity leading to inhibition of dependent degradation of ARE-containing transcript. Involved in toll-like receptor signaling pathway (TLR) in dendritic cells: required for acute TLR-induced macropinocytosis by phosphorylating and activating RPS6KA3. Also acts as a modulator of Polycomb-mediated repression.
Biomarker applications (based on IPA annotation)
  • unspecified application
Wiki Pathways
  • FAS pathway and Stress induction of HSP regulation
  • Serotonin HTR1 Group and FOS Pathway
Pathway Interaction Database
  • Signaling mediated by p38-alpha and p38-beta
  • p38 signaling mediated by MAPKAP kinases
Reactome
  • Oxidative Stress Induced Senescence
  • VEGFA-VEGFR2 Pathway
  • activated TAK1 mediates p38 MAPK activation
  • p38MAPK events
Pathway Studio
  • ADRA1A → IL6 production
  • AngiotensinR → CREB/ELK-SRF/TP53 signaling
  • CHRM1 → IL2 production
  • CNR1/2 → IL1B/2/4/6/10 production
  • CannabinoidR → AP-1/EGR signaling
  • CholinergicRm → CREB/ELK-SRF signaling
  • DopamineR2 → AP-1/CREB/ELK-SRF signaling
  • EDNRA/B → vascular motility
  • EGFR → AP-1/CREB/ELK-SRF/MYC signaling
  • EndothelinRa → AP-1/CREB signaling
  • EndothelinRb → AP-1/CREB/ELK-SRF signaling
  • ErythropoietinR → AP-1/CREB/MYC signaling
  • FGFR → AP-1/CREB/CREBBP/ELK-SRF/MYC signaling
  • GRM1/5 → CREB signaling
  • HGFR → AP-1/CREB/MYC signaling
  • HTR1 → IL6 production
  • HTR5 → TNF production
  • ICAM1 → AP-1/CREB/ELK-SRF signaling
  • NGFR → AP-1/CEBPB/CREB/ELK-SRF/TP53 signaling
  • NTRK → AP-1/CREB/ELK-SRF/MYC/SMAD3/TP53 signaling
  • Nociception-related DRD2 expression targets
  • PTAFR → AP-1/ATF1/CREB/ERK-SRF signaling
  • SerotoninR1 → FOS signaling
  • Summarized nociception-related expression targets
  • T-cell receptor → ATF/CREB signaling
  • TGFBR → CREB/ELK-SRF signaling
  • TNFR → CREB/ELK-SRF signaling
  • TNFRSF1A → CREB/ELK-SRF signaling
  • ThrombinR → AP-1/CREB/ELK-SRF/SP1 signaling
  • ThrombopoietinR → AP-1/CREB/ELK-SRF/MYC 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

Macrophage migration inhibitory factor (MIF)

Target (abbrv.) MIF
Target (full name) Macrophage migration inhibitory factor
Somalogic ID (Sequence ID) SL003080 (5356-2_3)
Entrez Gene Symbol MIF
UniProt ID P14174
UniProt Comment
  • Pro-inflammatory cytokine. Involved in the innate immune response to bacterial pathogens. The expression of MIF at sites of inflammation suggests a role as mediator in regulating the function of macrophages in host defense. Counteracts the anti-inflammatory activity of glucocorticoids. Has phenylpyruvate tautomerase and dopachrome tautomerase activity (in vitro), but the physiological substrate is not known. It is not clear whether the tautomerase activity has any physiological relevance, and whether it is important for cytokine activity.
Biomarker applications (based on IPA annotation)
  • diagnosis
  • prognosis
  • response to therapy
Wiki Pathways
  • Adipogenesis

All locus annotations are based on the sentinel SNP (rs1926447) and 71 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
  • ZC3H13 zinc finger CCCH-type containing 13
  • CPB2 carboxypeptidase B2 (plasma)
  • CPB2-AS1 CPB2 antisense RNA 1
eQTL genes
  • LCP1 lymphocyte cytosolic protein 1 (L-plastin)

 

Results from other genome-wide association studies

Trait P Study Source
Bipolar disorder 9.5×10-5 17554300 (PMID) GRASP2 nonQTL

Strong trans-pQTL with MAPKAPK3 may be used to identify link to cis-encoded genes.

This locus harbours a replicated trans-pQTL to MAP kinase-activated protein kinase 3 (MAPKAPK3). A second trans-pQTL Macrophage migration inhibitory factor (MIF) did not have sufficient replication power in QMDiab, but was still nominally significant (p=1.2×10-3).

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.