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


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.





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Publication Info

Hildebrandt, Michelle AT, Monica Reyes, Xifeng Wu, Xia Pu, Kara A Thompson, Jianzhong Ma, Andrew P Landstrom, Alanna C Morrison, et al. (2017). Hypertension Susceptibility Loci are Associated with Anthracycline-related Cardiotoxicity in Long-term Childhood Cancer Survivors. Scientific reports, 7(1). p. 9698. 10.1038/s41598-017-09517-2 Retrieved from https://hdl.handle.net/10161/20303.

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Andrew Paul Landstrom

Associate Professor of Pediatrics

Dr. Landstrom is a physician scientist who specializes in the care of children and young adults with arrhythmias, heritable cardiovascular diseases, and sudden unexplained death syndromes. As a clinician, he is trained in pediatric cardiology with a focus on arrhythmias and genetic diseases of the heart.  He specializes in caring for patients with heritable arrhythmia (channelopathies) such as long QT syndrome, Brugada syndrome, catecholaminergic polymorphic ventricular tachycardia, and short QT syndrome.  He also specializes in the evaluation of children following a cardiac arrest or after the sudden and unexplained death of a family member.  He has expertise in cardiovascular genetics and uses it to identify individuals in a family who may be at risk of a disease, even if all clinical testing is negative.  As a scientist, he is trained in genetics and cell biology.  He runs a research lab exploring the genetic and molecular causes of arrhythmias, sudden unexplained death syndromes, and heart muscle disease (cardiomyopathies).  He utilizes patient-derived induced pluripotent stem cells and genetic mouse models to identify the mechanisms of cardiovascular genetic disease with the goal of developing novel therapies.

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