A Genome-Wide Association Study in Patients Experiencing Drug-Induced Long-QT Syndrome and/or Torsades de Pointes; A Collaboration Between the NIH Pharmacogenomics Research Network and the RIKEN Yokohama Institute Center for Genomic Medicine

The goal of this study was to identify genetic risk factors for drug-induced prolongation of the QT interval (diLQT) and the ventricular arrhythmia torsades de pointes (TdP). We conducted a genome-wide association study (GWAS) focusing on subjects with a history of long QT and/or TdP after taking medication. Controls for this study were individuals with a history of cardiac arrhythmias who had begun treatment with potentially QT-prolonging antiarrhythmics. An additional control group of normal volunteers were given ibutilide, a drug with documented proarrhythmic properties. All study participants were recruited and treated/evaluated at Vanderbilt University Medical Center. This study was conducted by the Pharmacogenomics of Arrhythmia Therapy subgroup of the Pharmacogenetics Research Network, a nationwide collaboration of scientists studying the genetic contributions to drug response variability. Genotyping was performed by the RIKEN research institute in Japan using the Illumina 610 Quad Beadchip platform.]]>
Inclusion criteria for Cases: Cases were defined as those subjects ≥18 years of age at the time of an incident of drug-induced LQTS and/or TdP who had one of the following: An uncorrected QT interval ≥600 msec while on drug that decreased to <480 msec following withdrawal of drug; A change in uncorrected QT interval of at least 100 msec (either from the pre-exposure to the during-exposure ECG or from the during-exposure to the post-exposure ECG) with an uncorrected QT interval >480 msec while on drug; or An episode of ECG-documented TdP with a subsequent ECG with no evidence of TdP following withdrawal of drug. Exclusion criteria for Cases: Potassium level ≤3 mmol at onset of event (1 mEq = 1 mmol); Subarachnoid hemorrhage at onset of event; Cardiac bypass <24 hours before onset of event; Hospital admission diagnosis of hypothermia at time of event; Diagnosed with congenital LQTS prior to onset of event; Currently leukopenic (WBC<1000 cells/mL); Has had a non-autologous bone marrow transplant at anytime in the past Inclusion criteria for Control Group A: 18 years of age or older; New start on QT-prolonging antiarrhythmic drug(s); and Hasn't received a blood transfusion in the past 4 months Inclusion criteria for Control Group B: Healthy subjects between the ages of 18 and 40; Not on any regular medication; Non-smoker; and Normal ECG ]]>