Genetics of QT Response to Moxifloxacin

I. Background and Significance A. Historical Background and Scientific Basis The most common cause of withdrawal or restriction of drugs that are already on the market is prolongation of the QT interval, and the consequent, potentially fatal, arrhythmia, torsade de pointes1. First described in the 1960s with quinidine therapy2, torsade de pointes occurs most commonly with antiarrhythmics3, although sudden cardiac death risk is increased 270% with use of a non-cardiac QT-prolonging medication4.

The QT interval of the electrocardiogram reflects ventricular myocardial repolarization, and abnormalities in the duration of the QT interval are the most common indicator of abnormal repolarization. Although a number of hypotheses exist for how abnormal repolarization, and specifically QT prolongation, results in ventricular arrhythmias, the most consistent finding appears to be that during prolonged depolarization sodium channels recover from inactivation and reactivate, causing what are termed early afterdepolarizations. When combined with heterogeneity in repolarization as well, these early afterdepolarizations create a favorable myocardial substrate for reentry, resulting in propagation of intramyocardial reentry waves and torsade de pointes5.

Drug-induced QT prolongation is the number one barrier for new therapeutic agents making it to market. While a number of medications, environmental factors, and genetic factors have been associated with QT prolongation, our ability to predict on an individual basis who will develop QT prolongation, not to mention torsade de pointes, is limited.

A personalized genetic approach to toxicity prevention would be important because cardiotoxic drug response is not specific to a single class of drugs; risk prediction for arrhythmogenicity can be applied across medications used in a variety of conditions. Narrowly, this research can enable drugs with currently marginal risk/benefit profiles to be brought to market, sparing those at-risk and providing access to new therapies for those who are not. From a public health perspective, it will reduce potentially fatal toxicity and thus improve human health through identification of particular at-risk individuals.

B. Previous Studies In a meta-analysis of three prospective cohorts--Cardiovascular Health Study, the Framingham Heart Study, and the Rotterdam Study--in 13,685 white people of European descent as part of the QTGEN consortium, Newton-Cheh and colleagues identified common variant associations (p < 5x10-8) at five loci previously associated with QT interval: NOS1AP, KCNQ1, KCNE1, KCNH2, and SCN5A, as well as new associations in 5 other loci previously unrecognized to influence myocardial repolarization10. At these 10 loci, 14 independent variants explained 5.4 - 6.5% of the variation of the QT interval, which was more than is explained by sex or age, the strongest non-genetic clinical factors10. A QT genotype score based on these variants was associated with a 9.7 - 12.4ms longer QTc in the top quintile compared with the bottom quintile in the meta-analysis samples, which included heterogeneous age, risk factor and drug exposure profiles10-12. These effects were consistent in individuals of both European and African American ancestry. This QT score was independently validated in a Finnish population sample in which complete medication ascertainment enabled excluding those on QT-altering therapy, and in which the QT score was associated with a 15.6ms QT interval difference between the top and bottom quintiles13.