Anthracycline-Related Cardiomyopathy and HP Gene Expression in Childhood Cancer Survivors

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In a study reported in JACC: CardioOncology, Singh et al found that haptoglobin (HP) gene expression was associated with risk of anthracycline-related cardiomyopathy in childhood cancer survivors.

Study Details

In the study, messenger RNA sequencing was performed on total RNA from the peripheral blood in 40 childhood cancer survivors with cardiomyopathy and 64 matched survivors without cardiomyopathy from the Children’s Oncology Group COG-ALTE03N1 study. Differentially expressed genes were identified. Analysis adjusting for sex, age at cancer diagnosis, anthracycline dose, and chest irradiation was used to evaluate associations between gene expression and between copy number variants and single-nucleotide variants and cardiomyopathy.

Key Findings

HP was identified as the top differentially expressed gene. Median HP expression was significantly higher in cases vs controls (median RNA count = 135.3 vs 70.3, P < .001). High expression was defined as RNA count of > 70 (higher than median value among controls). Survivors with high HP expression were at a significantly increased risk of cardiomyopathy (odds ratio [OR] = 6.4, 95% confidence interval [CI] = 1.4–28.6, P = .014).

Among HP genotypes (HP1-1, HP1-2, and HP2-2), the HP2-specific allele had higher transcript levels, and the G allele among single-nucleotide variants previously reported to be associated with HP gene expression (rs35283911 and rs2000999) was associated with higher HP expression. Together, the HP1-2 and HP2-2 genotypes and the G/G genotype for rs35283911 or rs2000999 posed a significantly increased risk of cardiomyopathy (OR = 3.9, 95% CI = 1.0–14.5, P = .045).

The investigators concluded, “These findings provide evidence of a novel association between [the] HP2 allele and cardiomyopathy. HP binds to free hemoglobin to form an HP-hemoglobin complex, thereby preventing oxidative damage from free heme iron, thus providing biological plausibility to the mechanistic basis of the present observation.”

Smita Bhatia, MD, MPH, of the Institute for Cancer Outcomes and Survivorship and Department of Pediatrics, University of Alabama at Birmingham, is the corresponding author for the JACC: CardioOncology article.

Disclosure: The study was supported by the National Cancer Institute, Leukemia and Lymphoma Society, and others. For full disclosures of the study authors, visit

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