Dataset Information

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

ABSTRACT: 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.

SUBMITTER: Hildebrandt MAT

PROVIDER: S-EPMC5575079 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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

Hildebrandt Michelle A T MAT Reyes Monica M Wu Xifeng X Pu Xia X Thompson Kara A KA Ma Jianzhong J Landstrom Andrew P AP Morrison Alanna C AC Ater Joann L JL

Scientific reports 20170829 1

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-ter ...[more]

PMID: 28851949

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Project description:BACKGROUND:Anthracycline-related heart failure is a leading cause of morbidity in survivors of adult-onset lymphoma. There is a paucity of information on screening for late-occurring preclinical disease, which, in turn, has limited guidelines for early detection and intervention. The objectives of this study were to examine the prevalence and risk of cardiac dysfunction, as measured by echocardiography (abnormal left ventricular systolic/diastolic function or strain), in lymphoma survivors who received treatment with anthracyclines and to evaluate the diagnostic yield of blood biomarkers in the asymptomatic setting. METHODS:Lymphoma survivors who underwent hematopoietic cell transplantation (HCT) (n = 78) or received conventional therapy (non-HCT; n = 77) were compared with each other and with a group of matched controls (n = 51); the study was limited to lymphoma survivors who were >5 years from diagnosis. RESULTS:At a median follow-up of 9.4 years after diagnosis, 1 in 5 (20.6 %) lymphoma survivors had cardiac dysfunction; the odds of having cardiac dysfunction were 6.6-fold greater (odds ratio [OR], 6.6; P = .01) among lymphoma survivors compared with matched controls. There was a dose-dependent risk of cardiac dysfunction according to the cumulative anthracycline dose (controls [referent group], 1-249 mg/m2 [OR, 4.7; P = .05], and ≥250 mg/m2 [OR, 7.6; P < .01]), but there was no difference in the prevalence of cardiac dysfunction between conventionally treated and HCT survivors. The diagnostic accuracy of cardiac blood biomarkers in the asymptomatic setting was quite poor. CONCLUSIONS:In these long-term survivors, there was a high rate of cardiac dysfunction that was independent of HCT status. The growing number of lymphoma survivors makes it imperative to identify reliable and cost-effective strategies to decrease the burden of heart failure in this population. Cancer 2018;124:850-7. © 2017 American Cancer Society.

Dataset Information

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

Publications

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

Similar Datasets

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