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

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Locus annotations

Locus 101

Top associations per target

Target cis/​trans Study SNP SNP location Maj/​min allele MAF N βinv seinv Pinv fclog Plog Praw
TIMD3 cis Discovery rs4704846 5:156,513,344 A/G 0.19 997 0.687 0.050 1.8×10-39 1.160 6×10-24 6.5×10-26
TIMD3 cis Replication rs919747 5:156,531,330 G/A 0.12 337 0.608 0.064 4.4×10-19 1.210 3.1×10-19 1.6×10-15

 

Regional association plots

Hepatitis A virus cellular receptor 2 (TIMD3)

Download the association data used to generate this plot

 

Boxplots and histograms for top associations

Hepatitis A virus cellular receptor 2 (TIMD3)

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

Hepatitis A virus cellular receptor 2 (TIMD3)

Target (abbrv.) TIMD3
Target (full name) Hepatitis A virus cellular receptor 2
Somalogic ID (Sequence ID) SL007547 (5134-52_2)
Entrez Gene Symbol HAVCR2
UniProt ID Q8TDQ0
UniProt Comment
  • Cell surface receptor implicated in modulating innate and adaptive immune responses. Generally accepted to have an inhibiting function. Reports on stimulating functions suggest that the activity may be influenced by the cellular context and/or the respective ligand (PubMed:24825777). Regulates macrophage activation (PubMed:11823861). Inhibits T-helper type 1 lymphocyte (Th1)-mediated auto- and alloimmune responses and promotes immunological tolerance (PubMed:14556005). In CD8+ cells attenuates TCR-induced signaling, specifically by blocking NF-kappaB and NFAT promoter activities resulting in the loss of IL-2 secretion. The function may implicate its association with LCK proposed to impair phosphorylation of TCR subunits, and/or LGALS9-dependent recruitment of PTPRC to the immunological synapse (PubMed:24337741, PubMed:26492563). In contrast, shown to activate TCR-induced signaling in T cells probably implicating ZAP70, LCP2, LCK and FYN (By similarity). Expressed on Treg cells can inhibit Th17 cell responses (PubMed:24838857). Receptor for LGALS9 (PubMed:16286920, PubMed:24337741). Binding to LGALS9 is believed to result in suppression of T cell responses; the resulting apoptosis of antigen-specific cells may implicate HAVCR2 phosphorylation and disruption of its association with BAG6. Binding to LGALS9 is proposed to be involved in innate immune response to intracellular pathogens. Expressed on Th1 cells interacts with LGALS9 expressed on Mycobacterium tuberculosis-infected macrophages to stimulate antibactericidal activity including IL-1 beta secretion and to restrict intracellular bacterial growth (By similarity). However, the function as receptor for LGALS9 has been challenged (PubMed:23555261). Also reported to enhance CD8+ T cell responses to an acute infection such as by Listeria monocytogenes (By similarity). Receptor for phosphatidylserine (PtSer); PtSer-binding is calcium-dependent. May recognize PtSer on apoptotic cells leading to their phagocytosis. Mediates the engulfment of apoptotic cells by dendritic cells. Expressed on T cells, promotes conjugation but not engulfment of apoptotic cells. Expressed on dendritic cells (DCs) positively regulates innate immune response and in synergy with Toll-like receptors promotes secretion of TNF-alpha. In tumor-imfiltrating DCs suppresses nucleic acid-mediated innate immune repsonse by interaction with HMGB1 and interfering with nucleic acid-sensing and trafficking of nucleid acids to endosomes (By similarity). Expressed on natural killer (NK) cells acts as a coreceptor to enhance IFN-gamma production in response to LGALS9 (PubMed:22323453). In contrast, shown to suppress NK cell-mediated cytotoxicity (PubMed:22383801). Negatively regulates NK cell function in LPS-induced endotoxic shock (By similarity).
Biomarker applications (based on IPA annotation)
  • unspecified application
Reactome
  • Interleukin-2 signaling

All locus annotations are based on the sentinel SNP (rs4704846) and 48 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
Potentially regulated genes
eQTL genes
  • HAVCR1 hepatitis A virus cellular receptor 1
  • HAVCR2 hepatitis A virus cellular receptor 2
  • MED7 mediator complex subunit 7

 

Results from other genome-wide association studies

Trait P Study Source
cg18374914 (chr5:156513836) 6.1×10-49 10.1101/033084 (DOI) BIOS QTL cis-meQTLs
cg19646897 (chr5:156536355) 2.3×10-30 10.1101/033084 (DOI) BIOS QTL cis-meQTLs
cg19110684 (chr5:156536979) 1×10-13 10.1101/033084 (DOI) BIOS QTL cis-meQTLs
Gene expression of HAVCR2 in blood 3×10-8 21829388 (PMID) GRASP2 eQTL
PC aa C30:0 / PC ae C30:0 9.5×10-8 20037589 (PMID) GRASP2 metabQTL
Triglycerides 1.6×10-4 24097068 (PMID) Supplemental file
PC aa C40:4 3.6×10-4 20037589 (PMID) GRASP2 metabQTL