Abstract 15509: Genomwide-Association Identifies a Novel Locus for Anthracycline Cardiotoxicity
Anthracyclines are important chemotherapeutic agents, but use can be limited by cardiotoxicity. Prior candidate gene studies have identified loci linked to toxicity. Here we used genome-wide association to test the hypothesis that common genetic variation influences the severity of cardiotoxicity after exposure to anthracyclines.
Using natural language processing, billing code queries, and manual chart review, 385 subjects with anthracycline exposure and measures of left ventricular ejection fraction (LVEF) before and after drug exposure were identified from BioVU, a Vanderbilt resource linking DNA samples to a de-identified electronic medical record. Subjects were 57.8% female and 87.5% white. The most common malignancies were non-Hodgkin’s lymphoma (28.3%), breast (20.3%), acute myelogenous leukemia (15.3%), sarcoma (10.3%), and Hodgkin’s lymphoma (7.3%). Median anthracycline dose (converted to doxorubicin equivalents) was 240 mg/m2 (IQR 180-300 mg/m2). Median change in LVEF was -6 percent (range 22 to -47) over a median follow up of 348 days (IQR 122-755). Subjects were genotyped using the Illumina Omni 1M platform. Genotypes were imputed to 1000 Genomes using IMPUTE2. Multiple linear regression was used to test for association between SNPs and change in LVEF from baseline as a continuous dependent variable, with covariates shown in Figure 1.
SNPs at 1p32.1 reached genome-wide significance (p=3.6 x 10-8, Figure 1). The top SNP confers protection from cardiotoxicity (~4 EF points/minor allele). Genes within 250 kb are C1orf87, CYP2J2, and HOOK1. Overexpression of CYP2J2 in mouse has previously been shown protective from anthracycline cardiotoxicity, and thus represents a biologically plausible candidate gene.
These findings suggest a susceptibility locus for anthracycline cardiotoxicity at 1p32.1 near CYP2J2. This association requires replication. CYP2J2 deserves further study as a modifier of anthracycline cardiotoxicity.
- © 2013 by American Heart Association, Inc.