Abstract
BACKGROUND: Dilated cardiomyopathy (DCM) is a significant contributor to heart failure, originating from complex interactions between genetic and environmental factors. Although the immune system has been implicated in various cardiovascular diseases, its precise role in DCM pathogenesis remains ambiguous. This study uses Mendelian randomisation (MR) to explore the causal relationship between diverse immune cell traits and DCM risk. METHODS: We conducted a two-sample MR analysis using summary-level data from genome-wide association studies of 731 immune cell traits and DCM. Our primary method employed fixed- and random-effects inverse-variance weighting, complemented by sensitivity analyses - such as MR-Egger, Mendelian Randomisation-Pleiotropy RESidual Sum and Outlier (MR-PRESSO) - to address potential pleiotropy. Additionally, genetic mapping and pathway enrichment analyses were performed on the key immune trait associated with DCM risk. RESULTS: Our analysis revealed that an increased relative count of CD4(+) regulatory T-cells (Tregs) is causally associated with a higher risk of DCM. Specifically, each unit increase in the genetically predicted proportion of CD4(+) Tregs corresponded to a 14.4% increase in the odds of developing DCM (OR 1.144; 95% CI [1.069-1.223], p=9.36E-05, false discovery rate (FDR) = 0.0684). No reverse causal effects were observed. Genetic mapping further indicated an association between this immune trait and several genes enriched in cardiovascular tissues, with involvement in inflammatory responses and leukocyte adhesion. CONCLUSION: These findings provide novel evidence supporting a causal role of elevated CD4(+) Treg levels in DCM development and highlight the critical impact of immune regulation in its pathogenesis. Future studies are warranted to validate these associations and elucidate the underlying biological mechanisms.