Meta-analysis of genome-wide association studies of doxorubicin-induced arrhythmia identifies MMP16 and KCTD15 as risk loci

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ABSTRACT Background Anthracyclines are a widely used and effective class of chemotherapy. However, a major limitation for their use is cardiotoxicity, manifesting as systolic dysfunction, congestive heart failure (HF) and arrhythmias. Objective Identify genes and genetic risk variants for doxorubicin-induced arrhythmia. Methods We performed genome-wide association studies (GWAS) and meta-analysis across two independent non-overlapping, genetically homogenous datasets from the Molecular Epidemiology Resource (MER, cases N=77, controls, N=1,184) and Tapestry, (cases N=13, controls, N=172). Doxorubicin-related arrhythmia was the primary cardiac outcome followed by investigation of a broader phenotype of cardiac events. Effects of doxorubicin on top associated genes were assessed by qPCR on RNA extracted from human cardiomyocytes following treatment with doxorubicin and by echocardiography in a zebrafish model of doxorubicin-induced cardiomyopathy. Results In the meta-analysis, KCTD15 rs12151014 was associated with doxorubicin-related arrhythmia at the genome-wide significance, (MAF in MER cases 0.195 vs 0.069 in controls; Tapestry cases 0.192 vs 0.079 in controls) p=9.01×10 -9 , OR 3.61. MMP 16 rs1094199, was associated with the broader phenotype of arrhythmia and/or HF (MAF in MER cases 0.08 vs 0.01 in controls; Tapestry cases 0.038 vs 0.015) p = 1.98 x 10 -8 , OR = 6.15. In human cardiomyocytes, MMP16 and KCTD15 gene expression was significantly down-regulated by doxorubicin and in a zebrafish MMP16 knockout was protective of doxorubicin-induced decline in LVEF. Conclusions Genetic variants at KCTD15 and MMP16 are associated with doxorubicin-related arrhythmia and cardiac events. KCTD15 and MMP16 are potential cardioprotective therapeutic targets.

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