心房颤动（AF）和乳腺癌对人类健康构成重大风险。房颤和乳腺癌同时发生的原因尚不清楚，导致治疗方法复杂。孟德尔随机化 (MR) 分析旨在提供支持 AF 和乳腺癌之间因果关系的遗传证据，并调查与这两种情况相关的常见药物基因。我们使用两个 MR 样本依次探索心房颤动和乳腺癌之间的因果关系，以及房颤与乳腺癌治疗药物之间的比较，并通过共定位分析验证了结果的稳定性。我们利用连接图数据库来推断药物对疾病的作用方向。最后，我们探索了在 AF 和乳腺癌中发挥作用的可药物基因，并进行了全表型 MR 分析，以分析药物靶标的潜在副作用。我们发现了 15 种乳腺癌治疗药物，显着支持 AF 和乳腺癌之间的因果关系通过在血液和/或心耳组织中表达而产生癌症。其中，多西他赛激活ANXA5、氟维司群抑制EIF5A和他莫昔芬抑制GNA12会增加房颤风险，而吉西他滨和长春瑞滨抑制ANXA5以及紫杉醇抑制PCGF6会降低房颤风险。环磷酰胺抑制 MSH6 和 SF3B1，以及阿霉素抑制 SMAD4 和 PSMD2 以及激活 ASAH1 和 MLST8，可以对 AF 的发生产生双向影响。 XBP1可以作为AF和乳腺癌的常见药物基因，并且针对该靶点的治疗没有潜在的副作用。这项研究没有发现AF和乳腺癌之间的直接疾病因果关系，但确定了15个乳腺癌的40个靶基因研究人员对与 AF 相关的癌症治疗药物进行了研究，明确了 8 种乳腺癌治疗药物对 AF 的作用方向，最终确定了 AF 和乳腺癌的一个共同药物靶点。版权所有 © 2024 Qi、Yang、Chang、Wang、Tao、Xiao。

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.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.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 ANXA5 by Docetaxel, inhibition of EIF5A by Fulvestrant, and inhibition of GNA12 by Tamoxifen increased the risk of AF, while inhibition of ANXA5 by Gemcitabine and Vinorebine and inhibition of PCGF6 by Paclitaxel reduced the risk of AF. Inhibition of MSH6 and SF3B1 by Cyclophosphamide, as well as inhibition of SMAD4 and PSMD2 and activation of ASAH1 and MLST8 by Doxorubicin can have bidirectional effects on AF occurrence. XBP1 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.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.Copyright © 2024 Qi, Yang, Chang, Wang, Tao and Xiao.