HelmholtzZentrum munich
WCMC

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

ONLINE SUPPLEMENTARY INFORMATION

Ideogram
Proteome annotation
Locus annotations

Locus 26

Top associations per target

Target cis/​trans Study SNP SNP location Maj/​min allele MAF N βinv seinv Pinv fclog Plog Praw
Kininogen, HMW cis Discovery rs2304456 3:186,445,052 T/G 0.10 996 -1.366 0.058 2.9×10-97 -1.370 6.2×10-129 2.2×10-95
Kininogen, HMW cis Replication rs2304456 3:186,445,052 A/C 0.16 337 -1.159 0.075 2.8×10-40 -1.400 1.3×10-49 2.4×10-36
LCMT1 trans Discovery rs2304456 3:186,445,052 T/G 0.10 996 0.456 0.070 1.4×10-10 1.040 0.001 0.891
LCMT1 trans Replication rs5030044 3:186,449,122 A/G 0.16 337 0.380 0.077 1.5×10-6 1.090 9.1×10-5 0.001

 

Regional association plots

 

Boxplots and histograms for top associations

Kininogen-1 (Kininogen, HMW)

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

Leucine carboxyl methyltransferase 1 (LCMT1)

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

Kininogen-1 (Kininogen, HMW)

Target (abbrv.) Kininogen, HMW
Target (full name) Kininogen-1
Somalogic ID (Sequence ID) SL017189 (4495-33_2)
Entrez Gene Symbol KNG1
UniProt ID P01042
UniProt Comment
  • (1) Kininogens are inhibitors of thiol proteases; (2) HMW-kininogen plays an important role in blood coagulation by helping to position optimally prekallikrein and factor XI next to factor XII; (3) HMW-kininogen inhibits the thrombin- and plasmin-induced aggregation of thrombocytes; (4) the active peptide bradykinin that is released from HMW-kininogen shows a variety of physiological effects: (4A) influence in smooth muscle contraction, (4B) induction of hypotension, (4C) natriuresis and diuresis, (4D) decrease in blood glucose level, (4E) it is a mediator of inflammation and causes (4E1) increase in vascular permeability, (4E2) stimulation of nociceptors (4E3) release of other mediators of inflammation (e.g. prostaglandins), (4F) it has a cardioprotective effect (directly via bradykinin action, indirectly via endothelium-derived relaxing factor action); (5) LMW-kininogen inhibits the aggregation of thrombocytes; (6) LMW-kininogen is in contrast to HMW-kininogen not involved in blood clotting.
Wiki Pathways
  • ACE Inhibitor Pathway
  • Complement and Coagulation Cascades
Pathway Interaction Database
  • Beta2 integrin cell surface interactions
  • Syndecan-2-mediated signaling events
Reactome
  • G alpha (i) signalling events
  • G alpha (q) signalling events
  • Intrinsic Pathway of Fibrin Clot Formation
  • Peptide ligand-binding receptors
  • Platelet degranulation
Pathway Studio
  • BDKRB1/2 → interleukins production
  • BDKRB1/2 → ion channels
  • BDKRB1/2 → prostaglandin generation
  • BDKRB1/2 → vasodilation
  • Coagulation Cascade

Leucine carboxyl methyltransferase 1 (LCMT1)

Target (abbrv.) LCMT1
Target (full name) Leucine carboxyl methyltransferase 1
Somalogic ID (Sequence ID) SL011770 (4237-70_3)
Entrez Gene Symbol LCMT1
UniProt ID Q9UIC8
UniProt Comment
  • Methylates the carboxyl group of the C-terminal leucine residue of protein phosphatase 2A catalytic subunits to form alpha-leucine ester residues.

All locus annotations are based on the sentinel SNP (rs2304456) and 3 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

 

Results from other genome-wide association studies

Trait P Study Source
Methylation levels at chr3:187917754-187917804 [hg18 coord, probe cg12454167] in Frontal cortex 1.6×10-11 20485568 (PMID) GRASP2 meQTL
P01042 protein abundance levels 1.1×10-5 22595970 (PMID) GRASP2 pQTL
Serum creatinine 3.1×10-5 20383146 (PMID) GRASP2 nonQTL
Plasma factor XI level and activated partial thromboplastin time 4.9×10-4 22701019 (PMID) GRASP2 nonQTL

Co-association of KNG1 and LCMT1 suggests a possible link between the kininogen/bradykinin and the PP2A pathways.

This locus harbours a replicated trans-association with Leucine carboxyl methyltransferase 1 (LCMT1) and a cis-association with Kininogen-1 (KNG1). LCMT1 methylates Human protein phosphatase 2A (PP2A), a key regulator of many cellular processes, and a potential cancer-therapeutic target.

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.