Identification of Novel Protein Biomarkers and Drug Targets for Large-Artery Atherosclerosis Stroke by Human Plasma Proteome with Genome
Author(s):
Min Zhang
Large artery atherosclerotic stroke (LAAS) represents the most common ischemic stroke subtype, yet its molecular mechanisms remain incompletely understood. In this study, we employed an integrative multi-omics approach to identify causal molecular biomarkers and therapeutic targets for LAAS. We conducted summary-data-based Mendelian randomization (SMR) and colocalization analyses using large-scale GWAS and quantitative trait loci (QTL) datasets (pQTL, mQTL, eQTL) from European-ancestry populations. Five plasma proteins showed significant associations with LAAS risk: LPA and ITGAV (increased risk) and MMP12, CD40, and DKKL1 (decreased risk). CD40 emerged as the most robust candidate, demonstrating consistent evidence across all omics levels (Tier 1), with two hypomethylated CpG sites (cg11841529, cg24575067) significantly associated with increased LAAS risk (OR = 1.58-2.13). Tissue-specific analyses revealed CD40's protective effects were strongest in transverse colon (OR = 0.52) and adipose tissues, while ITGAV showed risk-enhancing effects in visceral adipose (OR = 1.64). We identified 12 FDA-approved drugs targeting these proteins, including immunomodulators (aldesleukin) and lipid-lowering agents (rosuvastatin). These findings highlight CD40 as a key regulator in LAAS pathogenesis and suggest potential drug repurposing opportunities for stroke prevention and treatment.