Haptoglobin Gene Expression and Anthracycline-Related Cardiomyopathy in Childhood Cancer Survivors: A COG-ALTE03N1 Report.

Background: Anthracycline-related cardiomyopathy is a leading cause of premature death in childhood cancer survivors. The high interindividual variability in risk suggests the need to understand the underlying pathogenesis.
Objectives: The authors interrogated differentially expressed genes (DEGs) to identify genetic variants serving regulatory functions or genetic variants not easily identified when using genomewide array platforms. Using leads from DEGs, candidate copy number variants (CNVs) and single-nucleotide variants (SNVs) were genotyped.
Methods: Messenger RNA sequencing was performed on total RNA from peripheral blood of 40 survivors with cardiomyopathy (cases) and 64 matched survivors without cardiomyopathy (control subjects). Conditional logistic regression analysis adjusting for sex, age at cancer diagnosis, anthracycline dose, and chest radiation was used to assess the associations between gene expression and cardiomyopathy and between CNVs and SNVs and cardiomyopathy.
Results: Haptoglobin ( HP ) was identified as the top DEG. Participants with higher HP gene expression had 6-fold greater odds of developing cardiomyopathy (OR: 6.4; 95% CI: 1.4-28.6). The HP2 -specific allele among the HP genotypes (HP1-1, HP1-2, and HP2-2) had higher transcript levels, as did the G allele among SNVs previously reported to be associated with HP gene expression (rs35283911 and rs2000999). The HP1-2 and HP2-2 genotypes combined with the G/G genotype for rs35283911 and/or rs2000999 placed the survivors at 4-fold greater risk (OR: 3.9; 95% CI: 1.0-14.5) for developing cardiomyopathy.
Conclusions: These findings provide evidence of a novel association between 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.
Competing Interests: This research is supported by the National Cancer Institute (R35CA220502; principal investigator [PI], S. Bhatia), Leukemia and Lymphoma Society (6563-19; PI, S. Bhatia), and the V Foundation (DT2019-010; PI, S. Bhatia). The Children’s Oncology Group study (COG-ALTE03N1 [NCT00082745]; PI, S. Bhatia) reported here is supported by the National Clinical Trials Network Operations Center Grant (U10CA180886; PI, D.S. Hawkins), the National Clinical Trials Network Statistics & Data Center Grant (U10CA180899; PI, Alonzo), the Children’s Oncology Group Chair’s Grant (U10CA098543; PI, Adamson), the Children’s Oncology Group Statistics & Data Center Grant (U10CA098413; PI, Anderson), the National Cancer Institute Community Oncology Research Program Grant (UG1CA189955; PI, Pollock), and the Community Clinical Oncology Program Grant (U10CA095861; PI, Pollock), and the St. Baldrick’s Foundation through an unrestricted grant. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The authors have reported that they have no relationships relevant to the contents of this paper to disclose.
(© 2023 The Authors.)