Identification of candidate host susceptibility genes for viral myocarditis through integrated transcriptomic and mendelian randomization analyses

This study investigated the genetic mechanisms underlying myocardial inflammatory responses related to Coxsackievirus B3 (CVB3) infection through an integrative transcriptomic and genetic approach. Gene expression profiles from the Gene Expression Omnibus (GEO) database were analyzed to identify differentially expressed genes (DEGs) between CVB3-infected and control myocardial tissues. These genes were subsequently evaluated using Mendelian randomization (MR) based on publicly available expression quantitative trait loci (eQTL) data and genome-wide association study (GWAS) data for myocarditis. MR analysis prioritized four candidate genes whose genetically predicted expression levels were significantly associated with myocarditis susceptibility. To ensure the robustness of these findings, multiple sensitivity analyses were performed to assess potential pleiotropy and heterogeneity. Functional analyses suggested that the priority candidate genes (PCGs) were associated with immune regulation, inflammatory signaling, and cellular metabolic processes. In addition, immune cell infiltration analysis suggested alterations in the myocardial immune microenvironment and associations between PCG expression and estimated immune cell proportions. An independent GEO dataset was used for external validation, and in vitro experiments further confirmed the significant upregulation of these genes following CVB3 infection. This integrative strategy combining transcriptomic profiling, human genetic analyses, and experimental validation identified four genetically prioritized candidate genes associated with myocarditis susceptibility and provided preliminary insights into the immune-regulatory mechanisms underlying cardiac inflammatory responses.