Causal role of 731 immune cell types in atrial fibrillation: A bidirectional two-sample Mendelian randomization study

Mounting genetic evidence indicates that immune dysregulation may be a key driver in the development of atrial fibrillation (AF), yet the specific immune pathways involved remain poorly characterized. In this study, we applied advanced Mendelian randomization approaches to systematically assess the causal relationships between 731 precisely defined immune cell traits and susceptibility to AF. By integrating large-scale genetic datasets and employing rigorous statistical frameworks-including inverse variance weighting and weighted median analyses-we identified 2 immune signatures with significant causal associations. Genetically predicted increases in IgD-CD38^dim B-cell frequency were associated with a higher risk of AF (odds ratio = 1.049, 95% confidence interval 1.024-1.075, P = .0001), whereas elevated CD25 expression on IgD+CD38^dim B cells conferred a protective effect (odds ratio = 0.974, 95% confidence interval 0.962-0.986, P = 1.87 × 10-5). Both associations remained significant after stringent false discovery rate correction (post false discovery rate < 0.05). These findings provide the first genetic evidence linking specific B-cell regulatory mechanisms to AF pathogenesis, offering novel biological insights into the immune basis of atrial arrhythmogenesis. Beyond advancing mechanistic understanding, this work highlights the power of genetic epidemiology to uncover previously unrecognized immunomodulatory targets for AF prevention and therapy.