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WCMC

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

ONLINE SUPPLEMENTARY INFORMATION

Ideogram
Proteome annotation
Locus annotations

Locus 88

Top associations per target

Target cis/​trans Study SNP SNP location Maj/​min allele MAF N βinv seinv Pinv fclog Plog Praw
HCC-1 cis Discovery rs41341749 17:34,310,702 A/G 0.06 997 -1.171 0.081 3×10-43 -1.360 5×10-48 8.3×10-34
HCC-1 cis Replication rs41341749 17:34,310,702 A/G 0.07 337 -0.795 0.117 4.9×10-11 -1.370 4.5×10-10 7.8×10-6
MPIF-1 cis Discovery rs41341749 17:34,310,702 A/G 0.06 997 1.032 0.084 3.1×10-32 1.360 3.3×10-35 9.6×10-40
MPIF-1 cis Replication rs9892586 17:34,313,915 A/G 0.07 337 0.934 0.128 2.4×10-12 1.340 1.6×10-12 1.9×10-12
PARC cis Discovery rs41341749 17:34,310,702 A/G 0.06 997 0.755 0.083 6.3×10-19 1.390 2.6×10-20 4.1×10-22
PARC cis Replication rs41341749 17:34,310,702 A/G 0.07 337 0.212 0.144 0.142 1.080 0.173 0.25
MIP-1a cis Discovery rs41341749 17:34,310,702 A/G 0.06 997 0.544 0.088 1×10-9 1.100 2×10-4 0.981
MIP-1a cis Replication rs41341749 17:34,310,702 A/G 0.07 337 0.146 0.142 0.304 1.040 0.468 0.964

 

Regional association plots

 

Boxplots and histograms for top associations

C-C motif chemokine 14 (HCC-1)

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

C-C motif chemokine 23 (MPIF-1)

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

C-C motif chemokine 18 (PARC)

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

C-C motif chemokine 3 (MIP-1a)

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

C-C motif chemokine 14 (HCC-1)

Target (abbrv.) HCC-1
Target (full name) C-C motif chemokine 14
Somalogic ID (Sequence ID) SL003329 (2900-53_3)
Entrez Gene Symbol CCL14
UniProt ID Q16627
UniProt Comment
  • Has weak activities on human monocytes and acts via receptors that also recognize MIP-1 alpha. It induced intracellular Ca(2+) changes and enzyme release, but no chemotaxis, at concentrations of 100-1,000 nM, and was inactive on T-lymphocytes, neutrophils, and eosinophil leukocytes. Enhances the proliferation of CD34 myeloid progenitor cells. The processed form HCC-1(9-74) is a chemotactic factor that attracts monocytes eosinophils, and T-cells and is a ligand for CCR1, CCR3 and CCR5.
Pathway Studio
  • CCR1 → STAT signaling
  • CCR2/5 → STAT signaling
  • CCR5 → TP53 signaling
  • Nociception-related CCR1 expression targets
  • Summarized nociception-related expression targets

C-C motif chemokine 23 (MPIF-1)

Target (abbrv.) MPIF-1
Target (full name) C-C motif chemokine 23
Somalogic ID (Sequence ID) SL003302 (2913-1_2)
Entrez Gene Symbol CCL23
UniProt ID P55773
UniProt Comment
  • Shows chemotactic activity for monocytes, resting T-lymphocytes, and neutrophils, but not for activated lymphocytes. Inhibits proliferation of myeloid progenitor cells in colony formation assays. This protein can bind heparin. Binds CCR1. CCL23(19-99), CCL23(22-99), CCL23(27-99), CCL23(30-99) are more potent chemoattractants than the small-inducible cytokine A23.
Reactome
  • Formyl peptide receptors bind formyl peptides and many other ligands
  • G alpha (i) signalling events
  • G alpha (q) signalling events
Pathway Studio
  • CCR1 → STAT signaling
  • Nociception-related CCR1 expression targets
  • Summarized nociception-related expression targets

C-C motif chemokine 18 (PARC)

Target (abbrv.) PARC
Target (full name) C-C motif chemokine 18
Somalogic ID (Sequence ID) SL003323 (3044-3_2)
Entrez Gene Symbol CCL18
UniProt ID P55774
UniProt Comment
  • Chemotactic factor that attracts lymphocytes but not monocytes or granulocytes. May be involved in B-cell migration into B-cell follicles in lymph nodes. Attracts naive T-lymphocytes toward dendritic cells and activated macrophages in lymph nodes, has chemotactic activity for naive T-cells, CD4+ and CD8+ T-cells and thus may play a role in both humoral and cell-mediated immunity responses.
Biomarker applications (based on IPA annotation)
  • efficacy
  • safety

C-C motif chemokine 3 (MIP-1a)

Target (abbrv.) MIP-1a
Target (full name) C-C motif chemokine 3
Somalogic ID (Sequence ID) SL000519 (3040-59_1)
Entrez Gene Symbol CCL3
UniProt ID P10147
UniProt Comment
  • Monokine with inflammatory and chemokinetic properties. Binds to CCR1, CCR4 and CCR5. One of the major HIV-suppressive factors produced by CD8+ T-cells. Recombinant MIP-1-alpha induces a dose-dependent inhibition of different strains of HIV-1, HIV-2, and simian immunodeficiency virus (SIV).
Biomarker applications (based on IPA annotation)
  • diagnosis
  • efficacy
  • prognosis
Wiki Pathways
  • Regulation of toll-like receptor signaling pathway
  • Senescence and Autophagy
  • Toll-like receptor signaling pathway
Pathway Interaction Database
  • IL12-mediated signaling events
Reactome
  • Chemokine receptors bind chemokines
Pathway Studio
  • CCR1 → STAT signaling
  • CCR2/5 → STAT signaling
  • CCR5 → TP53 signaling
  • Nociception-related CCR1 expression targets
  • Summarized nociception-related expression targets

All locus annotations are based on the sentinel SNP (rs41341749) 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
Potentially regulated genes

 

Results from other genome-wide association studies

Trait P Study Source
Adiponectin levels 2.3×10-4 22479202 (PMID) GRASP2 nonQTL

Increased CCL14 may induce decrease in CCL23 protein levels.

This locus includes two replicated cis-associations, with C-C motif chemokine 14 (CCL14, aka HCC1) and C-C motif chemokine 23 (CCL23, aka MPIF-1). Two further associations with CCL18 and CCL3 did not have sufficient replication power and were not replicated – note that Locus 87 harbours replicated cis-QTLs for these two chemokines. The association of rs41341749 with CCL14 and CCL23 has opposite direction, and the strength of association for the ratio of both increases by 35 orders of magnitude (p-gain=2.3×1035 in KORA, replicated 7.5×1012 in QMDiab). Note that there are multiple C-C motif chemokines encoded at this locus, including CCL3/4/5/7/14/15/16/18/23. SNiPA annotation identifies several variants that are tagged by rs41341749 and that regulate CCL14.



Boxplots of C-C motif chemokine 14 (CCL14, aka HCC-1) (A), C-C motif chemokine 23 (CCL23, aka MPIF-1) (B) and the ratio between both (C) as a function of rs41341749 (Locus 88); Scatterplot of CCL14 against CCL23, colored by genotype; black = major allele homozygotes, red = heterozygotes, green = minor allele homozygotes; means by genotype = large filled circles (D).

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.