Assessing the causal effect of inflammation‐related genes on myocarditis: A Mendelian randomization study

Abstract Aims Prior evidence has shown a significant link between inflammation and the development of myocarditis. This study aimed to investigate the causal relationship between inflammation‐related genes (IRGs) and myocarditis. Methods and results In this study, the causal relationship between 167 IRGs and myocarditis were investigated using datasets from the Gene Set Enrichment Analysis and Integrative Epidemiology Unit open genome‐wide association study (IEU OpenGWAS) databases. The GWAS data (finn‐b‐I9 MYOCARD) contained single nucleotide polymorphisms (SNPs) data from 117 755 myocarditis samples (16 379 455 SNPs, 829 cases vs. 116 926 controls). Five algorithms [MR‐Egger, weighted median, inverse variance weighted (IVW), simple mode, and weighted mode regression] were employed for the MR analysis, with IVW as the primary method, and sensitivity analysis was conducted. Subcellular localization and protein–protein interaction (PPI) network analyses were performed for selected biomarkers. Results were verified in ebi‐a‐GCST90018882 (24 180 570 SNPs, 633 cases vs. 427 278 controls) and finn‐b‐I9 MYOCARD EXNONE (16 380 466 SNPs, 829 cases vs. 217 963 controls) to enhance reliability. Results IRF7 and ADORA2B were shown to be two exposure factors after screening. Univariable MR (UVMR) analysis revealed that IRF7 was a risk factor for myocarditis [IVW: odd ratio (OR) = 1.041, 95% confidence interval (CI) = 1.018–1.955, P = 0.039], while ADORA2B was a protective factors for myocarditis (IVW: OR = 0.799, 95% CI = 0.640–0.997, P = 0.047). Sensitivity analysis confirmed the robustness of these findings. Multivariable MR (MVMR) analysis further demonstrated a direct causal role of ADORA2B in preventing myocarditis. Subcellular localization analysis indicated predominant cytoplasmic expression and limited mitochondrial expression for both genes. The results of PPI analysis showed that 20 genes were predicted to be associated with IRF7 function, such as response to type I interferon, pattern recognition receptor signalling pathway, and toll‐like receptor signalling pathway. The results in finn‐b‐I9 MYOCARD EXNONE were consistent with MR analysis. Conclusions The findings indicated there was a causal connection between IRGs (IRF7 and ADORA2B) and myocarditis, which offered a crucial point of reference and guidance for future studies and myocarditis treatment.