Pharmacogenomics of Ventricular Conduction in Multi-Ethnic Populations Amanda Seyerle Dissertation Committee: Christy Avery (chair) Kari North Eric Whitsel Til Stürmer Craig Lee 1 TABLE OF CONTENTS Page LIST OF TABLES ...................................................................................................................................... v LIST OF FIGURES ..................................................................................................................................... vi LIST OF ABBREVIATIONS ..................................................................................................................... vii LIST OF GENE NAMES ............................................................................................................................ ix 1. Overview .............................................................................................................................................. 1 2. Specific Aims ....................................................................................................................................... 3 3. Background and Significance ............................................................................................................ 4 A. Ventricular Conduction ......................................................................................................................... 4 A.1. Electrical Conduction of the Heart ................................................................................................ 4 A.1.1. Sodium Channels................................................................................................................... 6 A.1.2. Calcium Channels ................................................................................................................. 7 A.1.3. Potassium Channels .............................................................................................................. 8 A.2. Ventricular Conduction on the Electrocardiogram ....................................................................... 9 A.2.1. QT Interval ............................................................................................................................ 9 A.2.1.1. Heart Rate Correction Formulas for QT Interval ........................................................ 10 A.2.2. QRS Complex ...................................................................................................................... 12 A.2.3. JT Interval ........................................................................................................................... 12 B. QT Interval Prolongation .................................................................................................................... 13 B.1. Risk Factors ................................................................................................................................ 14 B.1.1. Acquired Clinical Conditions .............................................................................................. 14 B.1.2. Congenital Conditions ........................................................................................................ 14 B.1.3. Electrolyte Imbalances ........................................................................................................ 15 B.2. Drug-Induced QT Prolongation .................................................................................................. 16 B.2.1. QT-Prolonging Medications ............................................................................................... 16 B.2.1.1 Cardiac Medications ................................................................................................... 16 B.2.1.2 Non-Cardiac Medications ........................................................................................... 17 B.2.2. Prevalence of QT-Prolonging Medication Use ................................................................... 18 B.2.3. Clinical Considerations ...................................................................................................... 19 B.2.4. Mechanisms ......................................................................................................................... 19 B.3. Categorical Versus Continuous Measures of QT Prolongation .................................................. 20 B.4. Potential Clinical Outcomes of Prolonged QT............................................................................ 21 B.4.1. Arrhythmias ......................................................................................................................... 21 B.4.2. Coronary Heart Disease ..................................................................................................... 22 B.4.3. Chronic Heart Failure ........................................................................................................ 24 B.4.4. Stroke .................................................................................................................................. 24 B.4.5. Mortality ............................................................................................................................. 25 ii C. QT Interval Genetics ........................................................................................................................... 27 C.1. Heritability .................................................................................................................................. 27 C.2. Early Studies ............................................................................................................................... 28 C.2.1. Congenital Long and Short QT Syndrome .......................................................................... 28 C.2.2. Family/Twin Studies ............................................................................................................ 30 C.2.3. Candidate Gene Studies ...................................................................................................... 30 C.3. Genome-Wide Association Studies ............................................................................................ 31 C.3.1. Ion Channel Genes .............................................................................................................. 33 C.3.2. Novel Associations .............................................................................................................. 33 C.3.3. Replication in Multi-Ethnic Populations ............................................................................ 34 C.4. Gene-Environment Studies ......................................................................................................... 35 D. Thiazide Diuretics ............................................................................................................................... 35 D.1. Pharmacologic Characteristics .................................................................................................... 36 D.2. Indications of Use ....................................................................................................................... 37 D.2.1. Contraindications................................................................................................................ 38 D.3. Prevalence ................................................................................................................................... 38 D.4. Thiazide-Induced QT Prolongation ............................................................................................ 39 D.4.1. Pharmacoepidemiology ...................................................................................................... 39 D.4.2. Proposed Mechanisms ........................................................................................................ 41 E. Pharmacogenomics ............................................................................................................................. 42 E.1. Pharmacogenomics of QT-Prolonging Drugs ............................................................................. 42 E.2. Pharmacogenomics of Thiazide Diuretics .................................................................................. 44 E.2.1. Thiazide Diuretics and QT Prolongation ............................................................................ 45 F. Bias in Pharmacoepidemiologic and Pharmacogenomic Studies ....................................................... 45 G. Multi-Ethnic Populations .................................................................................................................... 47 H. Public Health Significance .................................................................................................................. 48 4. Research Plan .................................................................................................................................... 50 A. Overview ............................................................................................................................................. 50 B. Specific Aim 1 .................................................................................................................................... 50 B.1. Simulation Overview .................................................................................................................. 50 B.2. Simulation Parameters and Values ............................................................................................. 51 B.2.1. Covariates ..........................................................................................................................