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Published on: June 7, 2018
Genome-wide association and pathway analysis of left ventricular function after anthracycline exposure in adults
Quinn S Wells1, Olivia J Veatch, Joshua P Fessel
1aDepartment of Medicine bVanderbilt Translational and Clinical Cardiovascular Research Group cDepartment of Neurology dDepartment of Pediatrics eInstitute for Clinical and Translational Research fDepartment of Biomedical Informatics, Vanderbilt University, Nashville, Tennessee gDepartment of General Oncology hDepartment of Biostatistics, University of Texas MD Anderson Cancer Center, Houston, Texas iDepartment of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA jDepartment of Cardiology, The Heart Centre, Rigshospitalet, University of Copenhagen, Denmark.
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.
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