Genetic Association of Circulating Proteins and Gene Transcripts With Spontaneous Coronary Artery Dissection

BACKGROUND: Spontaneous coronary artery dissection (SCAD) is an uncommon cause of myocardial infarction that disproportionately affects women, particularly during pregnancy and the peripartum period. Limited understanding of its underlying pathophysiology hinders the development of effective preventive and therapeutic strategies. METHODS: This study investigated associations between genetically predicted circulating proteins and tissue-specific RNA levels with genetically predicted SCAD risk using Mendelian randomization and Bayesian colocalization. Genetic scores for >1500 circulating proteins were derived from the UK Biobank (n=34 557) and deCODE (n=35 559). Scores for 13 848 gene transcripts in arterial and fibroblast tissues were generated from Genotype-Tissue Expression data. Associations between these scores and SCAD were assessed in a genome-wide association study meta-analysis of 1917 individuals with SCAD and 9292 controls. Findings were validated in vitro using mass spectrometry-based proteomic analysis of extracellular vesicles from 50 patients with SCAD and 50 healthy controls. RESULTS: Genetic associations of 4 circulating proteins with SCAD (AFAP1 actin filament–associated protein 1, ECM1 extracellular matrix protein 1, SPON1 spondin 1, and STAT6 signal transducer and activator of transcription 6) were identified. Two were supported by gene expression data (AFAP1 and ECM1), and one by tissue-specific Bayesian colocalization analyses (ECM1). Protein interaction mapping identified potential shared pathways through the JAK-STAT signaling pathway and inflammatory regulation. Mass spectrometry-based proteomic analysis demonstrated that ECM1 was significantly upregulated in SCAD cases versus controls. CONCLUSIONS: Integrative analysis of proteomic, transcriptomic, and experimental data revealed 4 circulating proteins genetically associated with SCAD risk, with ECM1 emerging as a key protein with a likely causal role in SCAD pathogenesis. These findings highlight biological pathways for mechanistic studies and protein targets for potential therapeutic interventions.