Beautiful story of how human population genetic and proteomic studies have led to the discovery of SVEP1 as the natural ligand of the receptor PEAR1. It's been a while since I read such a fantastic paper. 🧵
nature.com/articles/s41467-023-36486-0
I am big fan of GWAS of molecular traits as they often reveal clear and interpretable cis and trans signals reiterating the known biology of the trait.
For e.g. a GWAS of a protein will reveal genetic variants that directly modify the protein expression in cis and also, genetic variants that indirectly modify the protein expression in trans.
twitter.com/doctorveera/status/1514381131990413321?s=20
But I've always wondered, if the cis and trans pQTL signals can reveal known molecular interactions/connections (receptor-ligand, protein-TF), they should also be able to reveal previously unknown molecular interactions.
SVEP1-PEAR1 is one such examples where a receptor-ligand discovery has been made via human proteomics (and also genetic) studies. Just for this fact, the paper by Elenbaas et al. will serve as an important reference in proteomics literature.
nature.com/articles/s41467-023-36486-0
The background story of GWASs identifying disease associations for SVEP1 and PEAR1 in parallel without any knowledge of the secret affair between the two is fascinating.
The story begins with the discovery of an association between a missense variant in SVEP1 (p.D2702G) and coronary artery disease that appeared to be mediated not via the classical risk factor, lipids, but via something else, a novel mechanism.
nejm.org/doi/10.1056/NEJMoa1507652
SVEP1 codes for sushi, von Willebrand factor type A, EGF, and pentraxin domain-containing protein 1 (what an interesting name!), which is an extracellular matrix protein.
The authors followed up the association via functional studies to understand more about the role of SVEP1 in CAD. They found SVEP1 is expressed is vascular smooth muscle cells and acts as a proatherogenic factor and a potential target.
science.org/doi/10.1126/scitranslmed.abe0357
Meanwhile studies linked SVEP1 genetic variants with other diseases including blood pressure, type 2 diabetes, septic shock and glaucoma.
nature.com/articles/s41467-020-20851-4
As the proteomics started catching up with SVEP1 links with CAD and other diseases (T2D) became stronger with the ability to identify stronger genetic instruments that are cis pQTLs of SVEP1.
For e.g. this Icelandic study by Emilsson et al. mapped the genetics of ~5k proteins in ~5k individuals and chose to highlight the SVEP1 associations among others.
nature.com/articles/s41467-022-28081-6
GWAS of SVEP1 revealed two hits. One cis (near SVEP1) and one trans (near PEAR1). The authors focussed only on the cis variants and ignored the trans variants (they had no idea the trans signal was actually pointing to the very receptor that SVEP1 binds to)
While SVEP1 associations were evolving, in a parallel world, scientists were learning about PEAR1 through its strong associations with platelet aggregation response (an important biological process in relation to atherosclerotic plaque formation & rupture)
PEAR1 association with platelet response to agonists such as ADP is so strong it was found in an early study in mere 500 individuals published in 2009.
Unlike cis signals, trans signals will have small effect sizes and so will require large sample sizes. The trans signal at SVEP1 for platelet aggregation appeared only in 2021 in a pQTL study of 3.8k individuals (that too only via gene based test).
nature.com/articles/s41467-021-23470-9
In the current paper, Elenbaas et al. connected all the dots, guessed that SVEP1 and PEAR1 are receptor-ligand pairs, and went on prove the same using a series of proteomics, genomics and functional experiments.
nature.com/articles/s41467-023-36486-0
The authors reproduce the strong cis signal at SVEP1 and trans signal at PEAR1 for SVEP1 using the pQTLs data from INTERVAL study.
Remarkably the trans association in Chr 1 with PEAR1 missense variant is seen only with SVEP1 among the 2994 proteins assayed in INTERVAL study.
Based on pQTL results from an independent study ( by deCODE) the authors show strong inverse relationship between PEAR1 and SVEP1 and also show that the causality direction is from receptor (PEAR1) to ligand (SVEP1) (i.e. increase in receptor decreases ligand and vice versa)
Through molecular assay, the authors show that indeed SVEP1 binds to PEAR1 with high affinity and this affinity drops down my many folds in the presence of PEAR1 missense variant that associates with SVEP1 levels in trans.
Then the authors go on to map the molecular pathways downstream of SVEP1-PEAR1 binding: AKT and mTOR signaling in vascular smooth muscle cells.
Given that human genetic studies suggest that SVEP1 inhibition might be cardioprotective, the authors studied SVEP1 KO mice. While loss of SVEP1 is lethal, partial loss seems to be well tolerated in mice in normal and disease backgrounds. But no evidence for cardioprotective role
Given the strong human genetic associations that increased SVEP1 is deleterious, the authors suspect that there might be "a safe therapeutic window exists to target SVEP1 and/or PEAR1 and potentially reduce their associated disease"
Though therapeutic value of the findings is still not clear, how the discovery that SVEP1 is the physiological ligand for PEAR1 unfolded was extremely fascinating. A great example of human genetic findings leading to incredible biological insight.