HelmholtzZentrum munich

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


Proteome annotation
Locus annotations

Locus 2

Top associations per target

Target cis/​trans Study SNP SNP location Maj/​min allele MAF N βinv seinv Pinv fclog Plog Praw
IL-6 sRa cis Discovery rs4129267 1:154,426,264 C/T 0.38 996 1.208 0.025 1.6×10-265 1.320 6.1×10-284 1.2×10-294
IL-6 sRa cis Replication rs4129267 1:154,426,264 G/A 0.37 337 1.051 0.038 2.1×10-87 1.330 9.6×10-90 1.6×10-95


Regional association plots

Interleukin-6 receptor subunit alpha (IL-6 sRa)


Boxplots and histograms for top associations

Interleukin-6 receptor subunit alpha (IL-6 sRa)

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

Interleukin-6 receptor subunit alpha (IL-6 sRa)

Target (abbrv.) IL-6 sRa
Target (full name) Interleukin-6 receptor subunit alpha
Somalogic ID (Sequence ID) SL001943 (4139-71_2)
Entrez Gene Symbol IL6R
UniProt ID P08887
UniProt Comment
  • Part of the receptor for interleukin 6. Binds to IL6 with low affinity, but does not transduce a signal. Signal activation necessitate an association with IL6ST. Activation may lead to the regulation of the immune response, acute-phase reactions and hematopoiesis.
Targeted by drugs (based on IPA annotation)
  • tocilizumab
Biomarker applications (based on IPA annotation)
  • efficacy
Wiki Pathways
  • IL-6 signaling pathway
  • SIDS Susceptibility Pathways
  • Senescence and Autophagy
Pathway Interaction Database
  • IL6-mediated signaling events
  • SHP2 signaling
  • ERK1 activation
  • ERK2 activation
  • Interleukin-6 signaling
Pathway Studio
  • IL6R → CEBP/ELK-SRF signaling
  • IL6R → STAT signaling
  • Nociception-related IL6 expression targets
  • Th17 Cell Differentiation

All locus annotations are based on the sentinel SNP (rs4129267) and 27 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
  • IL6R interleukin 6 receptor
Potentially regulated genes
  • IL6R interleukin 6 receptor
  • C1orf189 chromosome 1 open reading frame 189
  • UBAP2L ubiquitin associated protein 2-like
eQTL genes
  • AQP10 aquaporin 10
  • IL6R interleukin 6 receptor
  • UBE2Q1 ubiquitin-conjugating enzyme E2Q family member 1
  • POU5F1P4 POU class 5 homeobox 1 pseudogene 4


Results from other genome-wide association studies

Trait P Study Source
Soluble IL6R (sIL6R) 2.5×10-76 18464913 (PMID) GRASP2 nonQTL
Cerebrospinal fluid levels of Alzheimer's disease-related proteins 6×10-63 25340798 (PMID) GWAS Catalog via SNiPA
Interleukin-6R 4.9×10-60 23696881 (PMID) GRASP2 nonQTL
Protein quantitative trait loci 2×10-57 18464913 (PMID) GWAS Catalog via SNiPA
C-reactive protein levels 2×10-48 21300955 (PMID) GWAS Catalog via SNiPA
C-reactive protein (CRP) 2.1×10-48 21300955 (PMID) GRASP2 nonQTL
Fibrinogen 6×10-27 23969696 (PMID) GWAS Catalog via SNiPA
Interleukin-6 (IL-6) levels 9.6×10-22 23505291 (PMID) GRASP2 nonQTL
C-reactive protein 2×10-14 19567438 (PMID) GWAS Catalog via SNiPA
P08887 protein abundance levels 1.4×10-12 22595970 (PMID) GRASP2 pQTL
Plasma fibrinogen (females) 1.8×10-11 20031577 (PMID) GRASP2 nonQTL
Coronary artery disease (CAD) 1.7×10-8 23202125 (PMID) GRASP2 nonQTL
Coronary artery disease and myocardial infarction 1.7×10-8 23202125 (PMID) Supplemental file
Plasma C-reactive protein (female) 2×10-8 18439548 (PMID) GRASP2 nonQTL
Asthma 2×10-8 21907864 (PMID) GWAS Catalog via SNiPA
Gene expression of IL6R in blood 6.1×10-8 21829388 (PMID) GRASP2 eQTL
cg21262032 (chr1:154437669) 2.2×10-7 10.1101/033084 (DOI) BIOS QTL cis-meQTLs
Serum ratio of (decanoylcarnitine)/(sebacate (decanedioate)) 9.2×10-7 21886157 (PMID) GRASP2 metabQTL
PULMONARY FUNCTION 7×10-6 17903307 (PMID) GWAS Catalog via SNiPA
Gene expression of UBTF in blood 7.3×10-6 21829388 (PMID) GRASP2 eQTL
Lung function, predicted forced expiratory flow (FEF) 7.4×10-6 17903307 (PMID) GRASP2 nonQTL
Gene expression of IL6R in normal prepouch ileum 7.9×10-6 23474282 (PMID) GRASP2 eQTL
Gene expression of SHE (probeID ILMN_2133996) in temporal cortex in Alzheimer's disease cases and controls 1.5×10-5 22685416 (PMID) GRASP2 eQTL
Gene expression of SHE (probeID ILMN_2133996) in cerebellum in Alzheimer's disease cases and controls 2.6×10-5 22685416 (PMID) GRASP2 eQTL
Gene expression of SHE (probeID ILMN_2133996) in temporal cortex in Alzheimer's disease cases 3.8×10-5 22685416 (PMID) GRASP2 eQTL
Serum ratio of (laurylcarnitine)/(sebacate (decanedioate)) 4.6×10-5 21886157 (PMID) GRASP2 metabQTL
Gene expression of TDRD10///UBE2Q1 in blood 1.4×10-4 21829388 (PMID) GRASP2 eQTL
Cross-disorder, subset Attention-deficit/hyperactivity disorder 2.1×10-4 23453885 (PMID) Supplemental file
C-reactive protein [log (mg/l)] 4.4×10-4 19060910 (PMID) GRASP2 nonQTL

Two genetic signals at this locus may be used for drug target validation using genotype dependent drug-response curves.

cis-association with IL6R (rs4129267). The main genetic determinant of soluble interleukin 6 receptor (sIL-6R) levels is the missense variant rs2228145 that maps to the cleavage site of IL-6R [PubMed] (rs4129267 is a proxy SNP for rs2228145). Van Dongen et al. [PubMed] reported the association of rs2228145 IL6R, replicating earlier reports by Galicia et al. [PubMed]. Cells lacking IL6R can respond to IL6 using the trans-membrane signal transducer protein gp130 (IL6ST). Two molecules of gp130 are believed to bind the IL6/IL6R complex. We found no genetic variance in IL6, but SNP rs7730934 associated in our study in cis with gp130 (Locus 272). This SNP tags the coding SNP rs2228044 (G/R Ggt/Cgt). One might therefore investigate possible epistasis between SNPs rs2228145 (soluble IL6R) and rs2228044 (gp130) with an IL6 signalling related outcome. López-Mejías et al. [PubMed] could not find such a signal, but CardioGram found an association of rs4129267 with CVD (1.7×10-8). Prototype of a biomarker with a large effect size – unlikely to be an epitope effect since the functional SNP is known and affects the solubilisation of the protein. This variant associates with CVD at p=1.66×10-8 in CardiogramPlus.

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.