AUTHOR=Qi Fenglin , Yang Lunzhe , Chang Guanglei , Wang Xiangbin , Tao Guanghong , Xiao Hua 

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

JOURNAL=Frontiers in Pharmacology

VOLUME=15

YEAR=2024

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2024.1435545

DOI=10.3389/fphar.2024.1435545

ISSN=1663-9812

ABSTRACT=<sec><title>Background</title><p>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.</p></sec><sec><title>Methods</title><p>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.</p></sec><sec><title>Results</title><p>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 <italic>ANXA5</italic> by Docetaxel, inhibition of <italic>EIF5A</italic> by Fulvestrant, and inhibition of <italic>GNA12</italic> by Tamoxifen increased the risk of AF, while inhibition of <italic>ANXA5</italic> by Gemcitabine and Vinorebine and inhibition of <italic>PCGF6</italic> by Paclitaxel reduced the risk of AF. Inhibition of <italic>MSH6</italic> and <italic>SF3B1</italic> by Cyclophosphamide, as well as inhibition of <italic>SMAD4</italic> and <italic>PSMD2</italic> and activation of <italic>ASAH1</italic> and <italic>MLST8</italic> by Doxorubicin can have bidirectional effects on AF occurrence. <italic>XBP1</italic> 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.</p></sec><sec><title>Conclusion</title><p>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.</p></sec>