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

作者全名："Qi, Fenglin; Yang, Lunzhe; Chang, Guanglei; Wang, Xiangbin; Tao, Guanghong; Xiao, Hua"

作者地址："[Qi, Fenglin; Chang, Guanglei; Tao, Guanghong; Xiao, Hua] Chongqing Med Univ, Affiliated Hosp 1, Dept Cardiol, Chongqing, Peoples R China; [Yang, Lunzhe] Southern Med Univ, Guangdong Prov Peoples Hosp, Guangdong Acad Med Sci, Dept Neurosurg, Guangzhou, Peoples R China; [Wang, Xiangbin] Guangdong Pharmaceut Univ, Sch Life Sci & Biopharmaceut, Guangzhou, Peoples R China"

通信作者："Xiao, H (通讯作者)，Chongqing Med Univ, Affiliated Hosp 1, Dept Cardiol, Chongqing, Peoples R China."

来源：FRONTIERS IN PHARMACOLOGY

ESI学科分类：PHARMACOLOGY & TOXICOLOGY

WOS号：WOS:001294162600001

JCR分区：Q1

影响因子：5.6

年份：2024

卷号：15

期号：　

开始页：　

结束页：　

文献类型：Article

关键词：atrial fibrillation; breast cancer; mendelian randomization; drug target; cardio-oncology

摘要："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 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.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."

基金机构："Natural Science Foundation of Chongqing Municipality [CSTB2023NSCQ-MSX0491, cstc2020jcyj-msxmX0863]"

基金资助正文："All authors thank The Cardiovascular Disease Knowledge Portal (CVDKP). Atrial fibrillation GWAS data were obtained from CVDKP. All authors thank the Breast Cancer Association Coalition (BCAC) for providing breast cancer GWAS data (total, ER+, ER-). All authors thank the Genotype-Tissue Expression project (GTEx) Version eight and the eQTLGen consortium for our study's eQTL dataset of blood and atrial appendage tissue. All authors thank the Lee Laboratory of Statistical Genetics and Data Science for providing phenotypic data for this study. All authors thank GeneCards, Drug-Gene Interaction Database (DGIdb), and Connectivity map information platforms for providing information about drug targets, druggable genes, or drug-gene interactions. BCAC was established in 2005 as an international consortium to study genetic susceptibility to breast cancer. It is supported by Cancer Research United Kingdom (C1287/A16563), the European Community's Seventh Framework Programme Grant Agreement 223175 (HEALTH-F2-2009-223175) (COGS), and the European Union's Horizon 2020 Research and Innovation Programme Grant Agreements 633784 (B-CAST) and 634935 (BRIDGES)."