Scott Erika N, Wright Galen E B, Drögemöller Britt I, Hasbullah Jafar S, Gunaretnam Erandika P, Miao Fudan, Bhavsar Amit P, Shen Fei, Schneider Bryan P, Carleton Bruce C, Ross Colin J D
Faculty of Medicine, Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada.
British Columbia Children's Hospital Research Institute, Vancouver, BC, Canada.
NPJ Genom Med. 2021 May 21;6(1):35. doi: 10.1038/s41525-021-00199-4.
Anthracyclines are highly effective chemotherapeutic agents; however, their clinical utility is limited by severe anthracycline-induced cardiotoxicity (ACT). Genome-wide association studies (GWAS) have uncovered several genetic variants associated with ACT, but the impact of these findings requires further elucidation. We conducted a transcriptome-wide association study (TWAS) using our previous GWAS summary statistics (n = 280 patients) to identify gene expression-related associations with ACT. We identified a genetic association between decreased expression of GDF5 and ACT (Z-score = -4.30, P = 1.70 × 10), which was replicated in an independent cohort (n = 845 patients, P = 3.54 × 10). Additionally, cell viability of GDF5-silenced human cardiac myocytes was significantly decreased in response to anthracycline treatment. Subsequent gene set enrichment and pathway analyses of the TWAS data revealed that genes essential for survival, cardioprotection and response to anthracyclines, as well as genes involved in ribosomal, spliceosomal and cardiomyopathy pathways are important for the development of ACT.
蒽环类药物是高效的化疗药物；然而，它们的临床应用受到严重的蒽环类药物诱导的心脏毒性（ACT）的限制。全基因组关联研究（GWAS）已经发现了几种与ACT相关的基因变异，但这些发现的影响需要进一步阐明。我们使用我们之前的GWAS汇总统计数据（n = 280例患者）进行了全转录组关联研究（TWAS），以确定与ACT相关的基因表达关联。我们发现GDF5表达降低与ACT之间存在遗传关联（Z分数 = -4.30，P = 1.70×10），这在一个独立队列（n = 845例患者，P = 3.54×10）中得到了重复验证。此外，在蒽环类药物治疗后，GDF5沉默的人心脏心肌细胞的细胞活力显著降低。随后对TWAS数据进行的基因集富集和通路分析表明，对于存活、心脏保护和对蒽环类药物的反应至关重要的基因，以及参与核糖体、剪接体和心肌病通路的基因，对于ACT的发生发展都很重要。
