{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T18:39:46Z","timestamp":1792521586562,"version":"4.5.0"},"reference-count":81,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"5","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circ: Genomic and Precision Medicine"],"published-print":{"date-parts":[[2026,10]]},"abstract":"<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, and arrhythmias. The objective of this study was to 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 and meta-analysis across 2 independent nonoverlapping, genetically homogenous data sets from the Molecular Epidemiology Resource (cases N=77, controls N=1184) 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 quantitative polymerase chain reaction 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, rs12151014 at the\n                      <jats:italic toggle=\"yes\">KCTD15 locus<\/jats:italic>\n                      was associated with doxorubicin-related arrhythmia at the genome-wide significance (minor allele frequency in Molecular Epidemiology Resource cases 0.195 versus 0.069 in controls; Tapestry cases 0.192 versus 0.079 in controls)\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      =9.01\u00d710\n                      <jats:sup>\u22129<\/jats:sup>\n                      ; odds ratio, 3.61.\n                      <jats:italic toggle=\"yes\">MMP<\/jats:italic>\n                      16 rs1094199 was associated with the broader phenotype of arrhythmia and heart failure (minor allele frequency in Molecular Epidemiology Resource cases 0.079 versus 0.019 in controls; Tapestry cases 0.038 versus 0.015)\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      =1.98\u00d710\n                      <jats:sup>\u2212<\/jats:sup>\n                      <jats:sup>8<\/jats:sup>\n                      ; odds ratio=6.15. In human cardiomyocytes,\n                      <jats:italic toggle=\"yes\">MMP16<\/jats:italic>\n                      and\n                      <jats:italic toggle=\"yes\">KCTD15<\/jats:italic>\n                      gene expression was significantly downregulated by doxorubicin, and in a zebrafish\n                      <jats:italic toggle=\"yes\">MMP16<\/jats:italic>\n                      knockout was protective of doxorubicin-induced decline in left ventricular ejection fraction.\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 toggle=\"yes\">KCTD15<\/jats:italic>\n                      and\n                      <jats:italic toggle=\"yes\">MMP16<\/jats:italic>\n                      are associated with doxorubicin-related arrhythmia and cardiac events.\n                      <jats:italic toggle=\"yes\">MMP16<\/jats:italic>\n                      is a potential cardioprotective therapeutic target.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/circgen.125.005651","type":"journal-article","created":{"date-parts":[[2026,7,29]],"date-time":"2026-07-29T09:00:10Z","timestamp":1785315610000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":0,"title":["Meta-Analysis of Genome-Wide Association Studies of Doxorubicin-Induced Arrhythmia Identifies\n                    <i>MMP16<\/i>\n                    and\n                    <i>KCTD15<\/i>\n                    as Risk Loci"],"prefix":"10.1161","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1783-4453","authenticated-orcid":true,"given":"Joseph S.","family":"Reddy","sequence":"first","affiliation":[{"name":"Department of Quantitative Health Sciences (J.S.R.), Mayo Clinic Florida, 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