HelmholtzZentrum munich
WCMC

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

ONLINE SUPPLEMENTARY INFORMATION

Ideogram
Proteome annotation
Locus annotations

Locus 448

Top associations per target

Target cis/​trans Study SNP SNP location Maj/​min allele MAF N βinv seinv Pinv fclog Plog Praw
TLR4:MD-2 complex cis Discovery rs1159787 9:120,327,400 C/T 0.21 996 -0.349 0.053 7.6×10-11 -1.080 9.6×10-11 1.5×10-7
TLR4:MD-2 complex cis Replication rs7858743 9:120,341,514 G/A 0.20 337 -0.157 0.066 0.018 -1.040 0.047 0.042

 

Regional association plots

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

 

Boxplots and histograms for top associations

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

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 TLR4LY96
UniProt ID O00206Q9Y6Y9
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

All locus annotations are based on the sentinel SNP (rs1159787) and 2 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

Potentially regulated genes

 

Results from other genome-wide association studies

Trait P Study Source
Gene expression of TLR4 in blood 3.6×10-16 21829388 (PMID) GRASP2 eQTL
Gene expression of CMPK2 in peripheral blood monocytes 2.1×10-6 20502693 (PMID) GRASP2 eQTL