Connecting genetic risk to disease endpoints through the human blood plasma proteome
ONLINE SUPPLEMENTARY INFORMATION
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)
| 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 |
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| Targeted by drugs (based on IPA annotation) |
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| Biomarker applications (based on IPA annotation) |
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| Wiki Pathways |
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| Pathway Interaction Database |
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| Reactome |
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| Pathway Studio |
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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 |
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| Potentially regulated genes | |
| eQTL genes |
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.