From Blood to Heartbeat: Plasma Proteins and Brugada Syndrome Revealed by Mendelian Randomization.

Background: Brugada syndrome (BrS) is a hereditary arrhythmia characterized by distinctive electrocardiographic patterns and a high risk of sudden cardiac death. While SCN5A mutations account for 20-30% of cases, the majority remain unexplained. Recent evidence suggests plasma proteins may contribute to BrS pathogenesis through non-ion channel mechanisms such as inflammation and metabolism, though causal roles are unclear.

Objective: To assess the causal relationship between plasma proteins and BrS using Mendelian randomization (MR) and explore underlying molecular mechanisms.

Methods: Using pQTL proteomic data from a Finnish cohort, we evaluated causal associations between 4,185 plasma proteins and BrS via MR. The inverse variance weighted (IVW) method served as the primary analysis, supported by additional MR methods and sensitivity tests to ensure robustness. MR-CAUSE was used to identify proteins with unique causal patterns. For significant proteins, we constructed PPI networks and performed Gene Ontology and KEGG enrichment analyses. A machine learning-based model integrated these results to prioritize candidate proteins.

Results: Twenty plasma proteins were identified as potentially associated with BrS. Sensitivity analyses supported the robustness of these findings. HSPB1, MAPKAPK2, PDLIM4, and MMP1 emerged as top candidates based on causal strength, biological relevance, and network centrality.

Conclusion: This study provides insight into the molecular landscape of BrS and identifies high-priority plasma proteins for further investigation. Experimental and clinical validation is needed to evaluate their diagnostic and therapeutic potential.