Comprehensive mendelian randomization reveals atrial fibrillation-breast cancer relationship and explores common druggable targets.

BACKGROUND

Atrial fibrillation (AF) and breast cancer pose significant risks to human health. The reasons behind the concurrent occurrence of AF and breast cancer remain unclear, leading to complex treatment approaches. Mendelian Randomization (MR) analyses aim to offer genetic evidence supporting the causation of AF and breast cancer and to investigate common druggable genes associated with both conditions.

METHODS

We used two-samples of MR to sequentially explore the causal relationship between atrial fibrillation and breast cancer, and between atrial fibrillation and breast cancer therapeutic drugs, and verified the stability of the results through colocalization analysis. We utilized the Connectivity map database to infer the direction of drug effects on disease. Finally, we explored druggable genes that play a role in AF and breast cancer and performed a Phenome-wide MR analysis to analyze the potential side effects of drug targets.

RESULTS

We found 15 breast cancer therapeutic drugs that significantly support a causal association between AF and breast cancer through expression in blood and/or atrial appendage tissue. Among these, activation of by Docetaxel, inhibition of by Fulvestrant, and inhibition of by Tamoxifen increased the risk of AF, while inhibition of by Gemcitabine and Vinorebine and inhibition of by Paclitaxel reduced the risk of AF. Inhibition of and by Cyclophosphamide, as well as inhibition of and and activation of and by Doxorubicin can have bidirectional effects on AF occurrence. can be used as a common druggable gene for AF and breast cancer, and there are no potential side effects of treatment against this target.

CONCLUSION

This study did not find a direct disease causality between AF and breast cancer but identified 40 target genes for 15 breast cancer therapeutic drugs associated with AF, clarified the direction of action of 8 breast cancer therapeutic drugs on AF, and finally identified one common druggable target for AF and breast cancer.