Causal relationships between 4907 circulating proteins and heart failure and atrial fibrillation: A bidirectional Mendelian randomization study

The 5-year survival rate of patients with heart failure (HF) is comparable to that of malignant tumors, with a persistently high risk of mortality. Atrial fibrillation (AF) is a common cardiac arrhythmia, with its incidence rising annually due to the aging population. Therefore finding relevant therapeutic targets for both diseases is crucial. Firstly, instrumental variables were obtained from publicly available genome-wide association study databases. Secondly, 5 robust Mendelian randomization (MR) methods were employed to assess causal effects between exposure and outcome. Thirdly, we also performed multiple sensitivity analyses and corrected all inverse variance weighted results for false discovery rate (FDR). Fourthly, reverse MR analysis and Mediation MR analysis can improve the completeness of the study. Finally, the protective proteins were analyzed for pathway enrichment and potential drug targets were explored via the DrugBank website. This study identified a total of 23 circulating proteins associated with the diseases, among which defensin beta 135 (DEFB135, PIVW < .001, PFDR = .017) emerged as a shared protective protein against both diseases. Conversely, reverse MR analysis revealed no statistically significant impact of the diseases on these circulating proteins. Mediation MR analysis identified AF as the mediator between DEFB135 and HF. Enrichment analysis elucidated a series of pathways related to HF and AF. Finally, a total of 8 proteins were retrieved from the database. Our MR analysis identified 23 circulating proteins associated with the diseases, providing valuable references for clinical treatment.