Genome-wide association and pathway analysis of left ventricular function after anthracycline exposure in adults. Issue 7 (July 2017)

• Record Type: Journal Article
• Authors: Wells, Quinn S.; Veatch, Olivia J.; Fessel, Joshua P.; Joon, Aron Y.; Levinson, Rebecca T.; Mosley, Jonathan D.; Held, Elizabeth P.; Lindsay, Chase S.; Shaffer, Christian M.; Weeke, Peter E.; Glazer, Andrew M.; Bersell, Kevin R.; Van Driest, Sara L.; Karnes, Jason H.; Blair, Marcia A.; Lagrone, Lore W.; Su, Yan R.; Bowton, Erica A.; Feng, Ziding; Ky, Bonnie; Lenihan, Daniel J.; Fisch, Michael J.; Denny, Joshua C.; Roden, Dan M.
• Is Part Of: Pharmaocogenetics and genomics. Volume 27:Issue 7(2017:Jul.)
• Publication Date: 2017-07
• Subjects: anthracycline -- cardiotoxicity -- genome-wide association study -- pathway analysis; Pharmacogenetics -- Periodicals; Pharmacogenomics -- Periodicals; Genetic toxicology -- Periodicals; Biomedical genetics -- Periodicals; 615.7
• DOI: 10.1097/FPC.0000000000000284
• Languages: English
• ISSNs: 1744-6872

Abstract

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 −5 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 −7 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. Abstract : Supplemental Digital Content is available in the text.