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

Wells QS, Veatch OJ, Fessel JP, Joon AY, Levinson RT, Mosley JD, Held EP, Lindsay CS, Shaffer CM, Weeke PE, Glazer AM, Bersell KR, Van Driest SL, Karnes JH, Blair MA, Lagrone LW, Su YR, Bowton EA, Feng Z, Ky B, Lenihan DJ, Fisch MJ, Denny JC, Roden DM
Pharmacogenet Genomics. 2017 27 (7): 247-254

PMID: 28542097 · PMCID: PMC5502740 · DOI:10.1097/FPC.0000000000000284

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.

MeSH Terms (13)

Adult Anthracyclines Cohort Studies Demography Female Genome-Wide Association Study Humans Male Middle Aged Reproducibility of Results Signal Transduction Stroke Volume Ventricular Function, Left

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