Sudden death due to ventricular fibrillation kills 250,000-500,000 Americans each year and up to 5,000.000 American have a history of atrial fibrillation, which is associated with stroke, heart failure, and increase mortality. There is substantial inter-individual variability in response ti ion channel blocker, B-blocker, and warfarin, drugs widely used in the therapy of arrhythmias; some patients display beneficial effects, while others exhibit lack of efficacy or even life- threatening adverse effects. The hypothesis to be tested here is that allelic variants in candidate genes- implicated by an emerging understanding of molecular physiology and pharmacology-contribute to such variable drug responses. Work in our laboratories and elsewhere has identified allelic variants, and their functional consequences, in candidate genes, including drug metabolizing enzymes, ion channel proteins, and components of intracellular signaling systems. We have 4 Specific Aims: (1) to expand polymorphism discovery, focusing on new candidate genes; to determine frequencies of common polymorphisms in defined ethnic groups; and to ealuate variant protein function in vito; (2) to assess the role of allelic variants in modulating atrial and ventricular fibrillation and their response to drugs; (3) to determine the value of pre-prescription genotyping for QT prolonging antiarrhythmics and for warfarin; and (4) to use acute challenge with ibutilide and atenolol in sib-pairs to identify familial component(s) in drug responses (QT and heart rate change), and to determine the role of candidate and gene-gene interactions in modulating those responses. The studies will be supported by expertise in clinical pharmacology, clinical and basic electrophysiology, genetic epidemiology, bioinformatics, and polymorphism discovery and allele typing. This research will rigorously test the concept that advances in genetic science and molecular pharmacology can be combined to improve drug therapy. The outcomes will be not only improved drug therapy of arrhythmias, but also further development of appropriate methods to exploit genomic science to enhance drug therapy in general.
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