Hypertension Susceptibility Loci are Associated with Anthracycline-related Cardiotoxicity in Long-term Childhood Cancer Survivors.

Published online

Journal Article

Anthracycline-based chemotherapy is associated with dose-dependent, irreversible damage to the heart. Childhood cancer survivors with hypertension after anthracycline exposure are at increased risk of cardiotoxicity, leading to the hypothesis that genetic susceptibility loci for hypertension may serve as predictors for development of late cardiotoxicity. Therefore, we determined the association between 12 GWAS-identified hypertension-susceptibility loci and cardiotoxicity in a cohort of long-term childhood cancer survivors (N = 108) who received anthracyclines and were screened for cardiac function via echocardiograms. Hypertension-susceptibility alleles of PLCE1:rs9327264 and ATP2B1:rs17249754 were significantly associated with cardiotoxicity risk conferring a protective effect with a 64% (95% CI: 0.18-0.76, P = 0.0068) and 74% (95% CI: 0.07-0.96, P = 0.040) reduction in risk, respectively. In RNAseq experiments of human induced pluripotent stem cell (iPSC) derived cardiomyocytes treated with doxorubicin, both PLCE1 and ATP2B1 displayed anthracycline-dependent gene expression profiles. In silico functional assessment further supported this relationship - rs9327264 in PLCE1 (P = 0.0080) and ATP2B1 expression (P = 0.0079) were both significantly associated with daunorubicin IC50 values in a panel of lymphoblastoid cell lines. Our findings demonstrate that the hypertension-susceptibility variants in PLCE1 and ATP2B1 confer a protective effect on risk of developing anthracycline-related cardiotoxicity, and functional analyses suggest that these genes are influenced by exposure to anthracyclines.

Full Text

Duke Authors

Cited Authors

  • Hildebrandt, MAT; Reyes, M; Wu, X; Pu, X; Thompson, KA; Ma, J; Landstrom, AP; Morrison, AC; Ater, JL

Published Date

  • August 29, 2017

Published In

Volume / Issue

  • 7 / 1

Start / End Page

  • 9698 -

PubMed ID

  • 28851949

Pubmed Central ID

  • 28851949

Electronic International Standard Serial Number (EISSN)

  • 2045-2322

Digital Object Identifier (DOI)

  • 10.1038/s41598-017-09517-2

Language

  • eng

Conference Location

  • England