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Genetics of Cardiotoxic Drug Response

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? DESCRIPTION (provided by applicant): This is the application for the K23 Mentored Patient-oriented Research Career Development Award for Dr. Michael Rosenberg, a cardiac electrophysiologist at Massachusetts General Hospital, Boston. Dr. Rosenberg is seeking to become an independent clinical investigator in genetics of cardiac arrhythmias. This award will provide Dr. Rosenberg with support necessary to acquire the following research skills: 1) Understanding of human genetic variation and its relationship to complex and Mendelian traits, 2) Clinical study design and implementation; and 3) Tools of large-??scale data management, statistical analysis, and interpretation. Drug-??induced QT-??interval prolongation, and resultant lethal arrhythmia torsade de pointes (TdP), is the number one clinical toxicity leading to removal of medications from the market. Most concerning, this toxicity can occur with medications prescribed for noncardiac conditions, such as allergic rhinitis and depression. For patients with cardiac conditions that require use of antiarrhythmic medications, such as dofetilide, the U.S. Food and Drug Administration mandates a period of hospitalization to monitor for excess QT prolongation during initiation. Better risk stratification is clearly needed for drug-??induced QT prolongation. The possibility that genetics might be used to identify susceptible individuals presents a unique opportunity for direct clinical application from ongoing population studies. The electrocardiographic QT interval is heritable, and has a graded relationship to arrhythmias and sudden cardiac death in the general population. Recently, 68 common genetic variants in 35 genes were predictive of variability in QT duration. Prior studies had shown that the top quintile of a QT genetic score predicted a 10-??15ms difference in QT interval. This duration is longer than the QT prolongation that forced some non-??cardiac medications from the market. However, the demonstration that genetic risk can predict drug-??induced QT prolongation remains elusive. Dr. Rosenberg's research will focus on the use of a polygenic risk score derived from these 68 common variants associated with QT interval to predict drug-??induced QT prolongation in healthy young individuals selected by genotype (Aim 1), in 'real-??world populations' mined using electronic health records (Aim 2), in high-??risk patients being administered anti-??arrhythmics associated with QT prolongation (Aim 3), and in survivors of torsade de pointes lethal arrhythmias (Aim 4). Through completion of these aims, Dr. Rosenberg will establish the role of genetic testing in predicting drug-??induced QT prolongation. The activities proposed in this Career Development Award application will provide Dr. Rosenberg with outstanding training in preparation for an independent research career in genetic epidemiology, and at the same time, bring important new insights into common cardiovascular disease.
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