Genome-wide association and pathway analysis of left ventricular function after anthracycline exposure in adults

Abstract

Background: Anthracyclines are important chemotherapeutic agents, but their use is limited by cardiotoxicity. Candidate gene and genome-wide studies have identified putative risk loci for overt cardiotoxicity and heart failure, but there has been no comprehensive assessment of genomic variation influencing the intermediate phenotype of anthracycline-related changes in left ventricular (LV) function. The purpose of this study was to identify genetic factors influencing changes in LV function after anthracycline chemotherapy.

Methods: We conducted a genome-wide association study (GWAS) of change in LV function after anthracycline exposure in 385 patients identified from BioVU, a resource linking DNA samples to de-identified electronic medical record data. Variants with P values less than 1×10 were independently tested for replication in a cohort of 181 anthracycline-exposed patients from a prospective clinical trial. Pathway analysis was performed to assess combined effects of multiple genetic variants.

Results: Both cohorts were middle-aged adults of predominantly European descent. Among 11 candidate loci identified in discovery GWAS, one single nucleotide polymorphism near PR domain containing 2, with ZNF domain (PRDM2), rs7542939, had a combined P value of 6.5×10 in meta-analysis. Eighteen Kyoto Encyclopedia of Gene and Genomes pathways showed strong enrichment for variants associated with the primary outcome. Identified pathways related to DNA repair, cellular metabolism, and cardiac remodeling.

Conclusion: Using genome-wide association we identified a novel candidate susceptibility locus near PRDM2. Variation in genes belonging to pathways related to DNA repair, metabolism, and cardiac remodeling may influence changes in LV function after anthracycline exposure.

Figure 1

Change in ejection fraction from baseline in discovery GWAS and replication cohorts. In each panel, total doxorubicin equivalents per square meter (mg/m²) are shown on the X-axis, and change in left ventricular ejection fraction (LVEF) on the Y-axis. A) Discovery GWAS cohort. B) Replication cohort

Figure 2

Manhattan plot of discovery GWAS of change in left ventricular ejection fraction (LVEF). Results for each variant are organized according to chromosomal position on the X-axis, with -log₁₀ (p-values) for association of genotype to change LVEF from the discovery cohort on the Y-axis. The horizontal line indicates the a priori threshold for statistical significance.