{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2025,12,20]],"date-time":"2025-12-20T18:03:59Z","timestamp":1766253839825,"version":"3.48.0"},"posted":{"date-parts":[[2025,12,18]]},"group-title":"Genetic and Genomic Medicine","reference-count":108,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,12,18]],"date-time":"2025-12-18T00:00:00Z","timestamp":1766016000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,12,18]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>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.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Objective<\/jats:title>\n                  <jats:p>Identify genes and genetic risk variants for doxorubicin-induced arrhythmia.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>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.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>\n                    In the meta-analysis,\n                    <jats:italic>KCTD15<\/jats:italic>\n                    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\u00d710\n                    <jats:sup>-9<\/jats:sup>\n                    , OR 3.61.\n                    <jats:italic>MMP<\/jats:italic>\n                    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\n                    <jats:sup>-8<\/jats:sup>\n                    , OR = 6.15. In human cardiomyocytes,\n                    <jats:italic>MMP16<\/jats:italic>\n                    and\n                    <jats:italic>KCTD15<\/jats:italic>\n                    gene expression was significantly down-regulated by doxorubicin and in a zebrafish\n                    <jats:italic>MMP16<\/jats:italic>\n                    knockout was protective of doxorubicin-induced decline in LVEF.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>\n                    Genetic variants at\n                    <jats:italic>KCTD15<\/jats:italic>\n                    and\n                    <jats:italic>MMP16<\/jats:italic>\n                    are associated with doxorubicin-related arrhythmia and cardiac events.\n                    <jats:italic>KCTD15<\/jats:italic>\n                    and\n                    <jats:italic>MMP16<\/jats:italic>\n                    are potential cardioprotective therapeutic targets.\n                  <\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2025.12.16.25342433","type":"posted-content","created":{"date-parts":[[2025,12,18]],"date-time":"2025-12-18T21:00:10Z","timestamp":1766091610000},"source":"Crossref","is-referenced-by-count":0,"title":["Meta-analysis of genome-wide association studies of doxorubicin-induced arrhythmia identifies\n                  <i>MMP16 and KCTD15 as risk loci<\/i>"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1783-4453","authenticated-orcid":false,"given":"Joseph 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