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

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Locus annotations

Locus 14

Top associations per target

Target cis/​trans Study SNP SNP location Maj/​min allele MAF N βinv seinv Pinv fclog Plog Praw
ARTS1 cis Discovery rs17482078 5:96,118,866 C/T 0.19 993 -1.142 0.044 3×10-115 -1.710 9.8×10-157 2.2×10-112
ARTS1 cis Replication rs17482078 5:96,118,866 G/A 0.09 337 -0.901 0.117 1.7×10-13 -1.550 1.4×10-12 1.6×10-12

 

Regional association plots

Endoplasmic reticulum aminopeptidase 1 (ARTS1)

Download the association data used to generate this plot

 

Boxplots and histograms for top associations

Endoplasmic reticulum aminopeptidase 1 (ARTS1)

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

Endoplasmic reticulum aminopeptidase 1 (ARTS1)

Target (abbrv.) ARTS1
Target (full name) Endoplasmic reticulum aminopeptidase 1
Somalogic ID (Sequence ID) SL007729 (4964-67_1)
Entrez Gene Symbol ERAP1
UniProt ID Q9NZ08
UniProt Comment
  • Aminopeptidase that plays a central role in peptide trimming, a step required for the generation of most HLA class I-binding peptides. Peptide trimming is essential to customize longer precursor peptides to fit them to the correct length required for presentation on MHC class I molecules. Strongly prefers substrates 9-16 residues long. Rapidly degrades 13-mer to a 9-mer and then stops. Preferentially hydrolyzes the residue Leu and peptides with a hydrophobic C-terminus, while it has weak activity toward peptides with charged C-terminus. May play a role in the inactivation of peptide hormones. May be involved in the regulation of blood pressure through the inactivation of angiotensin II and/or the generation of bradykinin in the kidney.
Reactome
  • Antigen Presentation: Folding, assembly and peptide loading of class I MHC

All locus annotations are based on the sentinel SNP (rs17482078) and 22 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
  • LIX1 Lix1 homolog (chicken)
  • ERAP1 endoplasmic reticulum aminopeptidase 1
  • CTD-2215E18.2
  • ERAP2 endoplasmic reticulum aminopeptidase 2
  • LNPEP leucyl/cystinyl aminopeptidase
eQTL genes

 

Results from other genome-wide association studies

Trait P Study Source
Gene expression of ERAP1 [probe 214012_at] in lymphoblastoid cell lines 1.4×10-22 17873877 (PMID) GRASP2 eQTL
Gene expression of ERAP1 [probe 209788_s_at] in lymphoblastoid cell lines 9.4×10-17 17873877 (PMID) GRASP2 eQTL
Gene expression of ARTS-1 in CD4+ lymphocytes 5.8×10-14 20833654 (PMID) GRASP2 eQTL
Ankylosing spondylitis (HLA-B27 positive) 1.5×10-10 21743469 (PMID) GRASP2 nonQTL
Gene expression of ERAP1 [probeset 214012_at] in sputum 1.7×10-10 21949713 (PMID) GRASP2 eQTL
Gene expression of ERAP1 (probeID ILMN_2336220) in temporal cortex in Alzheimer's disease cases and controls 2.7×10-9 22685416 (PMID) GRASP2 eQTL
Differential exon level expression of ERAP1 [probe 2868133] in peripheral blood mononuclear cells 3.5×10-9 19222302 (PMID) GRASP2 eQTL
Gene expression of ERAP1 in peripheral blood monocytes 5.6×10-9 20502693 (PMID) GRASP2 eQTL
Differential splicing of ARTS-1 [probeset 2868133] in lymphoblastoid cell lines 1×10-8 19052777 (PMID) GRASP2 eQTL
Ankylosing spondylitis 1.1×10-8 21743469 (PMID) GRASP2 nonQTL
Behcet's disease 4×10-8 23291587 (PMID) GWAS Catalog via SNiPA
Gene expression of ERAP1 in T cells 9.2×10-8 19644074 (PMID) GRASP2 eQTL
Differential exon level expression of ERAP1 [probe 2868144] in peripheral blood mononuclear cells 2.2×10-7 19222302 (PMID) GRASP2 eQTL
Differential exon level expression of ERAP1 [probe 2868145] in peripheral blood mononuclear cells 2.6×10-7 19222302 (PMID) GRASP2 eQTL
Gene expression of ERAP1 (probeID ILMN_2336220) in cerebellum in Alzheimer's disease cases and controls 6.3×10-7 22685416 (PMID) GRASP2 eQTL
Gene expression of ERAP1 in Lymphoblastoid cell lines 6.5×10-7 19644074 (PMID) GRASP2 eQTL
Differential exon level expression of ERAP1 [probe 2868142] in peripheral blood mononuclear cells 7.9×10-7 19222302 (PMID) GRASP2 eQTL
Gene expression of KCNH8 in peripheral blood monocytes 7.7×10-6 20502693 (PMID) GRASP2 eQTL
Differential exon level expression of ERAP1 [probe 2868161] in peripheral blood mononuclear cells 8×10-6 19222302 (PMID) GRASP2 eQTL
Gene expression of ERAP1 [probeset 210385_s_at] in sputum 1.4×10-4 21949713 (PMID) GRASP2 eQTL
Gene expression of LRAP in blood 4×10-4 21829388 (PMID) GRASP2 eQTL

Two independent pQTLs, confirmed by strong eQTLs, with additive effect, co-association to ankylosing spondylitis suggests additive risk.

Two strong cis-associations endoplasmic reticulum aminopeptidase 1 (ERAP1, aka ARTS1). SNP rs26496 (Locus 11) is associated with ankylosing spondylitis [PubMed]. SNP rs17482078 (Locus 14, r2=0.059 with rs26496) is associated with Behcet's disease. Hong et al. [PubMed] report an mQTL with SNP rs27529 (r2=0.46 with rs26496) with a metabolite of unknown identity (MS peaks 616.7 m/z, 666.3 m/z, 489.2 m/z). Imputed data reveals at least two independent hits with p<10-120. Interaction between ERAP1 and HLA-B27 was reported by Evans et al. [PubMed] . That paper also provides experimental evidence that rs30187 (r2=0.46 with rs26496) and rs17482078 have ~40% slower rates of substrate trimming than wild-type ERAP1, but results are based only on a small set of experiments (N=3). See Locus 251 for a non-replicated associations with IL23R in relation to ankylosing spondylitis. Evans et al. [PubMed] discuss the interaction of ERAP1 and IL23R.

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.