Li Yilan, Wang Weijie, Gao Rong, Xu Xueming, Zhang Yao
Department of Cardiology, The 2nd Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150000, P.R. China.
Key Laboratory of Myocardial Ischemia, Ministry of Education, Harbin Medical University, Harbin, Heilongjiang 150000, P.R. China.
Oncol Lett. 2021 Feb;21(2):94. doi: 10.3892/ol.2020.12355. Epub 2020 Dec 6.
Tyrosine kinase inhibitors (TKIs) are characterized as multi-targeted anticancer agents that lack specificity, leading to cardiovascular adverse effects. To date, there are no reliable means to predict the cardiotoxicity of TKIs under development. The present study assessed the usual variants of genes to determine the molecular targets of TKIs associated with heart failure (HF). Gene or gene products affected by TKIs were assessed using the Drug Gene Interaction Database. These genes were investigated in genome-wide association studies (GWAS) datasets associated with HF at a genome-wide significant level (P<1×10). Subsequently, single-nucleotide polymorphisms (SNPs) that reached the established GWAS threshold (P<5×10) were investigated for genome-wide significance. Based on a threshold score of 3, nine gene loci yielded associations according to their biological function using RegulomeDB. Finally, comprehensive functional analysis of SNPs was performed using bioinformatics databases to identify potential drug targets. Using rSNPBase, rs7115242, rs143160639 and rs870064 were found to interfere with proximal transcription regulation, while rs7115242, rs143160639 and rs117153772 were involved in distal regulation, and most SNPs participated in post-transcriptional RNA binding protein-mediated regulation. rs191188930 on platelet-derived growth factor receptor (PDGFR) α was associated with numerous TKI drugs, including sunitinib, pazopanib, sorafenib, dasatinib and nilotinib. Using RegulomeDB and HaploReg v4.1, rs191188930 was predicted to be located in enhancer histone markers. PhenoScanner GWAS analysis revealed that rs191188930 was associated with other diseases or phenotypes, in addition to HF. Genotype-Tissue Expression analysis indicated that the PDGFRα gene had the highest median expression in 'Cells-Transformed fibroblasts', and the Search Tool for the Retrieval of Interacting Genes/Proteins revealed the protein-protein interaction network of PDGFRα. The present findings demonstrated the overlap of TKI-induced genes and those mediating HF risk, suggesting molecular mechanisms potentially responsible for TKI-induced HF risk. Additionally, the present genetic study may be helpful to further investigate off-target drug effects.
酪氨酸激酶抑制剂（TKIs）是一类缺乏特异性的多靶点抗癌药物，会导致心血管不良反应。迄今为止，尚无可靠方法预测正在研发的TKIs的心脏毒性。本研究评估了常见基因变异，以确定与心力衰竭（HF）相关的TKIs分子靶点。利用药物基因相互作用数据库评估受TKIs影响的基因或基因产物。在全基因组显著水平（P<1×10）下，在与HF相关的全基因组关联研究（GWAS）数据集中对这些基因进行研究。随后，对达到既定GWAS阈值（P<5×10）的单核苷酸多态性（SNP）进行全基因组显著性研究。基于3的阈值分数，使用RegulomeDB根据九个基因座的生物学功能得出关联。最后，利用生物信息学数据库对SNP进行综合功能分析，以确定潜在的药物靶点。使用rSNPBase发现，rs7115242、rs143160639和rs870064干扰近端转录调控，而rs7115242、rs143160639和rs117153772参与远端调控，且大多数SNP参与转录后RNA结合蛋白介导的调控。血小板衍生生长因子受体（PDGFR）α上的rs191188930与多种TKI药物相关，包括舒尼替尼、帕唑帕尼、索拉非尼、达沙替尼和尼洛替尼。使用RegulomeDB和HaploReg v4.1预测rs191188930位于增强子组蛋白标记中。PhenoScanner GWAS分析显示，除HF外，rs191188930还与其他疾病或表型相关。基因型-组织表达分析表明，PDGFRα基因在“细胞-转化成纤维细胞”中的中位表达最高，而检索相互作用基因/蛋白质的搜索工具揭示了PDGFRα的蛋白质-蛋白质相互作用网络。本研究结果表明TKIs诱导的基因与介导HF风险的基因存在重叠，提示了可能导致TKIs诱导HF风险的分子机制。此外，本基因研究可能有助于进一步研究药物的脱靶效应。
