Genome‑wide prioritization reveals novel gene signatures associated with cardiotoxic effects of tyrosine kinase inhibitors

Figures

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  Figure 1.. Experimental strategy. 1, TKIs raise the risk of HF. 2, All known TKI-targeting genes were extracted from the DGIdb. 3, DGIdb revealed 90 genes interacting with TKIs. 4, GWAS was performed between all common SNPs in chromosomal regions representing 90 genes and HF. 5, A total of 549 SNPs of 60 genes displayed significance for both TKI and HF risk. 6, These genes were candidate risk genes for cardiotoxicity. 7, It can be hypothesized that TKI-induced genes associated with cardiotoxicity may be involved in adverse drug reactions. TKI, tyrosine kinase inhibitor; DGIdb, Drug Gene Interaction Database; SNP, single nucleotide polymorphism; HF, heart failure; GWAS, genome-wide association study.

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  Figure 2.. Aggregated Manhattan plot of the 549 SNPs from the GWAS results for association with cardiotoxicity and tyrosine kinase inhibitors targets. The red line indicates the level of genome-wide significance (P=5×10−8). Highlighted points represent SNPs of RegulomeDB with annotation score ≤3, and rs191188930 was highly significant. SNP, single nucleotide polymorphism; GWAS, genome-wide association studies.

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  Figure 3.. Number of SNPs (n=345) in each RegulomeDB score. ND, no data; SNP, single nucleotide polymorphism.

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  Figure 4.. Gene expression levels of PDGFRα from GTEx using the University of California Santa Cruz Genome Browser. PDGFR, platelet-derived growth factor receptor; GTEx, Genotype-Tissue Expression; RPKM, reads per kilobase million.

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  Figure 5.. Protein-protein interaction network of PDGFRα using the Search Tool for the Retrieval of Interacting Genes/Proteins database. PDGFR, platelet-derived growth factor receptor.

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  Figure 6.. Pharmacodynamic effects of sunitinib treatment and genetically associated signals. All SNPs and their functional implications are based on cardiotoxicity risk alleles. The rs numbers indicate the lead SNPs and their hypothesized function. T-shaped lines indicate inhibition, parallel green lines indicate an unknown effect and red arrows indicate induction. Dotted lines indicate a potential intermediate functional link. Potential associations were reported for EGFR with myocardial infarction, congestive heart failure, hypertrophic cardiomyopathy and myocarditis. PDGFA was strongly associated with cardiac fibrosis and atrial fibrosis. PDGFRα was strongly associated with cardiac fibrosis, Loeffler endocarditis, heart sarcoma and OHD. The function of SNPs has not been reported. EGFR, epidermal growth factor receptor; PDGFA, platelet-derived growth factor subunit A; PDGFRα, platelet-derived growth factor receptor α; OHD, organic heart disease.