Research ArticleHEALTH AND MEDICINE

The support of genetic evidence for cardiovascular risk induced by antineoplastic drugs

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Science Advances  14 Oct 2020:
Vol. 6, no. 42, eabb8543
DOI: 10.1126/sciadv.abb8543
  • Fig. 1 The pipeline overview for the data collection, processing, and analysis in this study.

    (A) The DirCEs of CVD-associated genes mediated by risk allele were obtained through fine-mapping using collected GWAS summary statistics, VEP annotation, and functional prediction. The drug-target and associated mechanisms were obtained and mapped using DGIdb. According to different strategies, including concordance mapping and comprehensive evaluations, the genetic evidence of drug-induced cardiovascular toxicity were predicted and demonstrated. MOA, mechanism of action. (B) The number of the GWAS data across the CVD complications. (C) The clinical state and target statistics of antineoplastic drugs. (D) The pipeline of DirCE prediction for CVD-associated genes. By integrating GWAS summary information, eQTL effect size, and variant functional predictions, we estimated the causal allele effect and its DirCE for CVD-associated genes.

  • Fig. 2 The predication of causal allele mediated DirCE for CVDs-associated genes.

    (A) The number of causal loci and CRVs among investigated CVDs. (B) The types of casual allele effect of CRVs and estimated DirCEs. (C) The number of DirCEs for CRV gene among CVDs (left); the number of CVD genes with valid DirCE (right).

  • Fig. 3 Antineoplastic-induced cardiovascular risk predicted by direct gene matching and network random walk.

    (A) The number of oncological drugs among CVDs. The y axis represents the number of drugs. The color and size of the circle mean the number of CRV gene evidence and associated genes for each CVD. Hypertension (1592 CRV genes and 9 genes), atrial fibrillation (421 CRV genes and 4 genes), coronary artery disease (315 CRV genes and 7 genes), other arterial diseases (12 CRV genes and 1 gene), and myocardial infarction (29 CRV genes and 2 genes). (B) The types of causal allele effect of CRVs among predicted drug-induced CVDs in the direct gene matching method. (C) The schematic diagram of possible genetic evidence and mechanism for the tosedostat-induced hypertension risk in the direct gene matching strategy. (D) The number of the genetic evidence for each CVD-drug pair by direct gene matching. (E) The number of the CRV-path evidence for each CVD-drug pair by network propagation. (F) The schematic diagram of possible genetic evidence and mechanism for bexarotene-induced coronary artery disease risk.

  • Fig. 4 In vitro experimental validation of the effect of alitretinoin and bexarotene on the GoF of Angptl4.

    (A) Angptl4 gene expression measured by RT-qPCR in differentiated 3T3-L1 adipocytes. Angptl4 mRNA levels were normalized by β-actin. Differentiated 3T3-L1 adipocytes were incubated for 24 hours in the presence of DMSO (control), alitretinoin (10 μM), bexarotene (0.2 μM), or UVI3003 (10 μM). Data represent mean ± SEM. **P < 0.01 and ***P < 0.001 (unpaired two-tailed t test); n = 8 to 10 for all groups. (B to E) Differentiated 3T3-L1 adipocytes were stimulated with DMSO (control), alitretinoin (10 μM), bexarotene (0.2 μM), or UVI3003 (10 μM) for 48 hours, and then Angptl4 protein expression was determined by Western blotting (B) and immunofluorescence (C); relative TG level (D) and heparin-releasable LPL activity (E) were measured by TG assay and LPL assay kit. Scale bar, 50 μm; data represent mean ± SEM. *P < 0.05 and **P < 0.01 versus control (unpaired two-tailed t test); n = 4 to 6. (F) RNA expression was analyzed by RT-PCR for the knockdown efficiency of Angptl4 siRNA (si-Angptl4) on Angptl4 expression in differentiated 3T3-L1 adipocytes. The nonspecific siRNA (Scramble) used as control. Data represent mean ± SEM. *P < 0.05 versus control (unpaired two-tailed t test); n = 3 to 4. (G to I) Effects of DMSO (control), alitretinoin (10 μM), or bexarotene (0.2 μM) on the expression of Angptl4 protein expression (G), relative TG level (H), and heparin-releasable LPL activity (I) in the absence of Scramble or si-Angptl4. Data represent mean ± SEM. *P < 0.05 versus control (unpaired two-tailed t test); n = 4 to 6.

  • Fig. 5 Evaluation of cardiovascular toxicity prediction.

    (A) The evaluation through an independent literature-based association analysis. (B) The evaluation according to the recorded adverse drug reactions. (C) The genetic evidence and possible mechanism for anthracycline-induced hypertension risk. (D) The genetic evidence and possible mechanism for ponatinib and BCR-ABL1 tyrosine kinase inhibitor (TKI)–induced coronary artery disease risk.

Supplementary Materials

  • Supplementary Materials

    The support of genetic evidence for cardiovascular risk induced by antineoplastic drugs

    Hui Cui, Shengkai Zuo, Zipeng Liu, Huanhuan Liu, Jianhua Wang, Tianyi You, Zhanye Zheng, Yao Zhou, Xinyi Qian, Hongcheng Yao, Lu Xie, Tong Liu, Pak Chung Sham, Ying Yu, Mulin Jun Li

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