Identification of Potential Therapeutic Targets for Coronary Atherosclerosis from an Inflammatory Perspective Through Integrated Proteomics and Single-Cell Omics

Coronary atherosclerosis (CAS) is a major cause of cardiovascular morbidity worldwide. The understanding of atherosclerosis has shifted from a cholesterol deposition disorder to an inflammation-driven disease, with anti-inflammatory therapies demonstrating clinical efficacy. Identifying inflammatory protein targets is crucial for developing targeted therapies. A proteome-wide Mendelian randomization (MR) analysis was performed to explore therapeutic targets for CAS by integrating inflammatory proteomics data from the UK-PPP (54,219 participants, 2923 proteins) and Iceland cohorts (35,559 participants, 4907 proteins) as exposures and outcome data for CAS, atherosclerosis, and carotid atherosclerosis from FinnGen. Replication MR employed meta-analysis of six proteomics datasets and CAS data from three sources, while the impact of the identified proteins on four cardiovascular diseases was also investigated. Colocalization analysis (PPH₄ > 0.9), reverse MR, and SMR were used to ensure robust causal inference. Proteome-wide MR identified 11 proteins significantly associated with CAS (<i>p</i> < 3.52 × 10^-5), with all but CD4 linked to cardiovascular disease risk. Notably, colocalization confirmed the causal roles of PCSK9, IL6R, CELSR2, FN1, and SPARCL1 in CAS, and single-cell RNA-seq analysis revealed that five genes (TGFB1, SPARCL1, IL6R, FN1, and CELSR2) were exclusively expressed in smooth muscle cells of either coronary plaques or healthy vasculature. Druggability assessments were subsequently conducted for these targets. The three most promising targets (CELSR2, FN1, and SPARCL1), along with the other identified proteins and their biological functions, exhibit robust causal associations with CAS. FN1 and TGFB1 have the potential for drug repurposing in atherosclerosis treatment.