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

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Locus annotations

Locus 74

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 rs4986791 9:120,475,602 C/T 0.07 997 -1.269 0.080 1.8×10-50 -1.290 2.9×10-47 4.5×10-25
TLR4:MD-2 complex cis Replication rs4986791 9:120,475,602 G/A 0.06 337 -0.454 0.115 9.9×10-5 -1.120 0.002 0.001

 

Regional association plots

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

Download the association data used to generate this plot

 

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 TLR4, LY96
UniProt ID O00206, Q9Y6Y9
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 (rs4986791) and 7 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


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Genes hit or close-by
  • RNU6-1082P RNA, U6 small nuclear 1082, pseudogene
  • TLR4 toll-like receptor 4
eQTL genes
  • TLR4 toll-like receptor 4
  • BRINP1 bone morphogenetic protein/retinoic acid inducible neural-specific 1

 

Results from other genome-wide association studies

Trait P Study Source
Tetrology of fallot 4.4×10-4 23297363 (PMID) GRASP2 nonQTL