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

ABSTRACT: 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^-5). Subsequently, single-nucleotide polymorphisms (SNPs) that reached the established GWAS threshold (P<5×10^-8) 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) ? 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 PDGFR? 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 PDGFR?. 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.

SUBMITTER: Li Y

PROVIDER: S-EPMC7751338 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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

Li Yilan Y Wang Weijie W Gao Rong R Xu Xueming X Zhang Yao Y

Oncology letters 20201206 2

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 invest ...[more]

PMID: 33376527

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Project description:Thiazide diuretics are among the most commonly prescribed antihypertensives. However, <50% of thiazide-treated patients achieve blood pressure (BP) control. Herein, we used different omics (genomics and transcriptomics) to identify novel biomarkers of thiazide diuretics BP response.Genome-wide analysis included 228 white hypertensives with BP determined at baseline and after 9 weeks of hydrochlorothiazide. Single-nucleotide polymorphisms with P <5×10-5 were prioritized according to their biological function, using RegulomeDB, haploreg, and Genome-Wide Annotation of Variants. The results from the prioritization approach revealed rs10995 as the most likely functional single-nucleotide polymorphism, among single-nucleotide polymorphisms tested, that has been associated with hydrochlorothiazide BP response. The rs10995 G-allele was associated with better BP response to hydrochlorothiazide versus noncarriers (? systolic BP/? diastolic BP: -12.3/-8.2 versus -6.8/-3.5 mm?Hg, respectively, ? systolic BP P=3×10-4, ? diastolic BP P=5×10-5). This association was replicated in independent participants treated with chlorthalidone. In addition, rs10995 G-allele was associated with increased mRNA expression of VASP (vasodilator-stimulated phosphoprotein). Moreover, baseline expression of the VASP mRNA was significantly higher in 25 good responders to hydrochlorothiazide compared with 25 poor responders (P=0.01). This finding was replicated in independent participants treated with chlorthalidone (P=0.04). Last, allelic-specific expression analysis revealed a significant but modest imbalance with rs10995 and rs10156, a single-nucleotide polymorphism in high linkage disequilibrium (r2=0.7) with rs10995, which both could contribute to the observed genetic effects by affecting VASP mRNA expression.This study highlights the strength of using different omics to identify novel biomarkers of drug response and suggests VASP as a potential determinant of thiazide diuretics BP response.URL: http://www.clinicaltrials.gov. Unique identifiers: NCT00246519 and NCT01203852.

Project description:BACKGROUND: Analyses of DNA sequences from cultivated microorganisms have revealed genome-wide, taxa-specific nucleotide compositional characteristics, referred to as genome signatures. These signatures have far-reaching implications for understanding genome evolution and potential application in classification of metagenomic sequence fragments. However, little is known regarding the distribution of genome signatures in natural microbial communities or the extent to which environmental factors shape them. RESULTS: We analyzed metagenomic sequence data from two acidophilic biofilm communities, including composite genomes reconstructed for nine archaea, three bacteria, and numerous associated viruses, as well as thousands of unassigned fragments from strain variants and low-abundance organisms. Genome signatures, in the form of tetranucleotide frequencies analyzed by emergent self-organizing maps, segregated sequences from all known populations sharing < 50 to 60% average amino acid identity and revealed previously unknown genomic clusters corresponding to low-abundance organisms and a putative plasmid. Signatures were pervasive genome-wide. Clusters were resolved because intra-genome differences resulting from translational selection or protein adaptation to the intracellular (pH approximately 5) versus extracellular (pH approximately 1) environment were small relative to inter-genome differences. We found that these genome signatures stem from multiple influences but are primarily manifested through codon composition, which we propose is the result of genome-specific mutational biases. CONCLUSIONS: An important conclusion is that shared environmental pressures and interactions among coevolving organisms do not obscure genome signatures in acid mine drainage communities. Thus, genome signatures can be used to assign sequence fragments to populations, an essential prerequisite if metagenomics is to provide ecological and biochemical insights into the functioning of microbial communities.

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

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

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