Uncovering Potential Druggable Targets in Coronary Atherosclerosis: A Proteome‐Wide Mendelian Randomization Study With Cross‐Platform and Experimental Validation
TL;DR
This study identified PARP1, SDCCAG8, FST, FOLH1, and NCAN as genetically prioritized candidate proteins for CA, with PARP1 showing the most consistent evidence across analyses.
Abstract
Background Coronary atherosclerosis (CA) is a leading cause of cardiovascular morbidity and mortality worldwide. This study is aimed at identifying candidate plasma proteins and potential therapeutic targets for CA. Methods We performed a proteome‐wide Mendelian randomization (MR) analysis using integrated protein quantitative trait loci (pQTLs) and genome‐wide association study (GWAS) summary data. Forward two‐sample MR was first performed using cis‐pQTLs from the UK Biobank Pharma Proteomics Project (UKB‐PPP), followed by reverse MR analysis to exclude potential reverse causality. Bayesian colocalization analysis was conducted to ensure that the associations between proteins and CA were driven by shared genetic variants. Summary‐data‐based MR (SMR) combined with HEIDI testing was used to prioritize proteins and eliminate linkage bias. Significant proteins were cross‐referenced with a curated druggable genome to identify their potential therapeutic relevance. Cross‐platform validation was performed using the SomaScan‐based pQTL dataset from deCODE genetics. An oxidized low‐density lipoprotein (ox‐LDL)–induced human umbilical vein endothelial cell (HUVEC) injury model was used for the evaluation of prioritized proteins. Results Forward MR analysis using UKB‐PPP cis‐pQTL data identified 45 CA‐associated proteins (23 protective, 22 risk‐related; FDR < 0.05), with no reverse causality observed. Five proteins—PARP1, SDCCAG8, FST, FOLH1, and NCAN—were prioritized through MR (FDR < 0.05), colocalization analysis (PP.H4 > 0.50), and SMR analysis with HEIDI filtering (p_SMR < 0.05; p_HEIDI > 0.05). All five proteins were included in the druggable genome list, supporting their potential therapeutic relevance. PARP1 showed consistent associations across Olink and SomaScan platforms and was upregulated in an ox‐LDL‐induced HUVEC model as assessed by western blot. Conclusions This study identified PARP1, SDCCAG8, FST, FOLH1, and NCAN as genetically prioritized candidate proteins for CA, with PARP1 showing the most consistent evidence across analyses. Further validation and mechanistic studies are warranted.