Causal Association Between Plasma Proteins and Pericarditis: A Mendelian Randomization Study With Therapeutic Target Identification.

Abstract

Background: Observational studies demonstrate that pro-inflammatory cytokines play a critical role in pericarditis. However, the causal association between circulating plasma proteins and pericarditis remains unestablished.

Objective: This research aimed to assess the causal association between plasma proteins and pericarditis and to investigate potential therapeutic targets.

Methods: A genome-wide association study (GWAS) involving 35,559 individuals of European ancestry was conducted using 4907 plasma proteins as instrumental variables (IVs). The causal relationship between plasma proteins and pericarditis was examined using inverse weighted median, variance weighting, and Mendelian randomization (MR)-Egger methods. Horizontal pleiotropy was evaluated via MR-Egger regression, and heterogeneity was quantified by Cochran's Q statistic. In addition, enrichment analyses, construction of a protein-protein interaction (PPI) network, and single-cell RNA sequencing (scRNA-seq) analysis were performed. Molecular docking was used to predict potential drug targets.

Results: MR analyses identified 67 plasma proteins with potential causal relationships with pericarditis, such as NEU1, GDNF, LAT, CASP8, ZFYVE27, and NAPA. Among them, elevated levels of NEU1, GDNF, and LAT increased the risk of pericarditis, whereas higher levels of CASP8, ZFYVE27, and NAPA decreased the risk of pericarditis. Pleiotropy tests and sensitivity analyses confirmed the stability of the findings. Moreover, scRNA-seq analysis revealed that genes such as extracellular matrix protein 1 (ECM1), CASP8, EPHA4, and CCL2 were specifically expressed in cardiac progenitor cells (CPCs). Molecular docking further identified compounds with anti-inflammatory, antioxidant, or immunomodulatory potential, including phorbol 12-myristate 13-acetate (PMA), cerivastatin, and melatonin.

Conclusion: This research examined the causal association between plasma proteins and pericarditis by MR analysis and identified several potential therapeutic targets. These findings provide theoretical evidence for targeted drug development and clinical prevention strategies for pericarditis.