Association of mTOR-dependent circulating protein with atrial fibrillation/flutter: A two-sample Mendelian randomization study

Background: The mechanistic target of rapamycin (mTOR) pathway is involved in the pathogenesis of atrial fibrillation, and however, the specific mechanism by which mTOR affects atrial fibrillation/atrial flutter is still unclear. Herein, this two-sample Mendelian randomization (MR) study aims to investigate the causal associations of mTOR-dependent circulating proteins with atrial fibrillation/flutter. Methods: Data of mTOR-dependent circulating proteins including eukaryotic initiation factor 4A (eIF4A), eIF4B, eIF4EBP, eIF4G and ribosomal protein S6 kinase (RP-S6K) were obtained from the genome-wide association studies (GWASs) on 3,301 participants of European ancestry. Data of atrial fibrillation and flutter were extracted from the FinnGen consortium. Inverse variance weighted (IVW), weighted-median, weighted mode, MR-Egger and simple mode methods were utilized to explore the causal association of mTOR-dependent circulating proteins with atrial fibrillation and flutter. The effect size was expressed by odds ratios (ORs) and 95% confidence intervals (CIs). In addition, MR-Pleiotropy RESidual Sum and Outlier (MR-PRESSO), MR steiger method and MR leave-one-out test were used for sensitivity analysis. Results: MR steiger test showed the direction of these causal associations is true. MR-PRESSO and MR leave-one-out test suggested there was no significant outlier among the selected IVs, indicating the causal associations of eIF4EBP and eIF4G with atrial fibrillation and flutter are robust. Additionally, no reverse causal association between mTOR-dependent circulating proteins and atrial fibrillation and flutter has been found. Conclusions: The mechanism that mTOR-dependent pathway involved in atrial fibrillation and flutter may be associated with mTOR-dependent circulating proteins, especially eIF4EBP and eIF4G.