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Transcriptome-wide association study uncovers the role of essential genes in anthracycline-induced cardiotoxicity

Erika N Scott1,2, Galen E B Wright1,2, Britt I Drögemöller2,3

  • 1Faculty of Medicine, Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada.

NPJ Genomic Medicine
|May 22, 2021
PubMed

Insights

Decreased GDF5 gene expression is linked to anthracycline-induced cardiotoxicity (ACT), a severe chemotherapy side effect. This finding, confirmed in independent studies, suggests GDF5 plays a role in protecting heart cells from chemotherapy damage.

Area of Science:

  • Genetics
  • Cardiology
  • Pharmacology

Background:

  • Anthracyclines are vital chemotherapy drugs, but their use is limited by cardiotoxicity (ACT).
  • Previous genome-wide association studies (GWAS) identified genetic links to ACT, but require further investigation.
  • Understanding genetic predispositions to ACT is crucial for improving cancer patient outcomes.

Purpose of the Study:

  • To identify gene expression associations with anthracycline-induced cardiotoxicity (ACT) using transcriptome-wide association study (TWAS).
  • To validate the role of identified genes in ACT development and cardiac myocyte response to anthracyclines.

Main Methods:

  • Conducted a transcriptome-wide association study (TWAS) utilizing prior GWAS summary statistics from 280 patients.
  • Replicated key findings in an independent cohort of 845 patients.
  • Performed gene set enrichment and pathway analyses on TWAS data.
  • Assessed the impact of GDF5 gene silencing on human cardiac myocyte viability under anthracycline treatment.

Main Results:

  • Identified a significant association between decreased GDF5 gene expression and ACT (P = 1.70 × 10⁻⁵), replicated in an independent cohort (P = 3.54 × 10⁻³).
  • GDF5-silenced human cardiac myocytes exhibited reduced viability upon anthracycline exposure.
  • TWAS data highlighted the importance of survival, cardioprotection, anthracycline response, ribosomal, spliceosomal, and cardiomyopathy pathways in ACT development.

Conclusions:

  • Decreased GDF5 expression is a significant genetic factor associated with anthracycline-induced cardiotoxicity.
  • GDF5 plays a protective role in cardiac myocytes against anthracycline-induced damage.
  • Genetic pathways related to cellular survival, ribosome function, and cardiomyopathy are implicated in ACT pathogenesis.

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