Atrial Fibrillation Susceptibility Due to Genetic Variation at Chromosome 4q25

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 DESCRIPTION (provided by applicant): Candidate: Dr. Shoemaker is a cardiac electrophysiologist with an advanced degree in patient-oriented research (Master of Science in Clinical Investigation). He joined faculty as a physician-scientist in July 2014 with plans to pursue a career studying the pharmacogenomics of cardiac arrhythmias. Dr. Shoemaker's shortterm goal is to understand the electrophysiologic (EP) mechanisms by which common genetic variants lead to atrial fibrillation (AF) and modulate clinical response to AF therapies. During the five years of this career development award, he plans to strengthen his understanding of clinical pharmacology and drug science, genetics, methods for quantitative trait analysis, and clinical trial design. Dr. Shoemaker's long-term goal is to establish a researc program focused on the development of personalized and pharmacogenomics-based approaches to AF therapy. The goal of his career development plan and complementary research proposal is to develop the skills and generate preliminary data to successfully compete for independent funding through R01 grant mechanisms. Environment: As both the coordinating center of the NIH's Clinical and Translational Science Award (CTSA) program, and lead site for the Pharmacogenomics of Arrhythmia Therapy (PAT) node of the Pharmacogenomics Research Network (PGRN), Vanderbilt University is ideally suited to provide Dr. Shoemaker cross-training in clinical investigation and pharmacogenomics research methods. He has a well established mentorship team with combined expertise in the genetics of arrhythmias, pharmacogenomics, and clinical trial design and implementation. Dr. Dawood Darbar is a clinical electrophysiologist and established physician-scientist with national leadership recognition in the human genetics of AF, and Director of the Vanderbilt Arrhythmia Service. Dr. C. Michael Stein is a clinical trialist with expertise in cardiovascular pharmacogenomics and previously Assistant Dean for Clinical and Translational Research Scientist Development. Dr. Roden is Assistant Vice Chancellor for Personalized Medicine and serves as Principal Investigator for several large federally-funded projects focused on implementation of pharmacogenomics including the PAT node of the PGRN. All three mentors are committed to Dr. Shoemaker's career development and have a track record of successfully mentoring young investigators. Research: We propose two Specific Aims that seek to define the EP mechanism(s) by which common genetic variants at the chromosome 4q25 locus contribute to AF susceptibility and modulate response to AF therapies. Phenotyping will be performed using standardized collection of intracardiac EP measurements in patients with AF undergoing ablation. The Specific Aims focus on single nucleotide polymorphisms (SNPs) at chromosome 4q25 that were identified by GWAS to be strongly associated with AF. They are suspected to be transcriptional regulators of a nearby gene, PITX2 (paired-like homeodomain transcription factor 2), which in transgenic mice has been found to regulate development of the pulmonary vein (PV) myocardial sleeve - a critical structure in AF pathogenesis, and result in pro-arrhythmic changes in atrial electrophysiology through adverse electrical and structural remodeling. While we have demonstrated that AF risk alleles at 4q25 predict an impaired clinical response to treatment with AF ablation and modulate response to antiarrhythmic drugs (AADs), the underlying mechanism(s) for these observations remains unknown. In Specific Aim 1, we seek to further our understanding of the effect of 4q25 risk allele carriers on PV myocardial sleeve size and changes in atrial refractoriness. These findings will not only advance our understanding of how 4q25 risk allele carriers respond to isolation of the PV myocardial sleeves (ablation) but also to specific AAD therapies, which mediate their effect by slowing either atrial repolarization or conduction velocity. In Specific Aim 2 we focus specifically on AF ablation by testing the hypothesis that 4q25 risk allele carriers who undergo AF ablation are more likely to have recurrence of atrial tachyarrhythias due to non-PV mediated AF sources. This finding would inform trials testing personalized AF ablation strategies based on 4q25 genotype. These Aims are designed to provide preliminary data for Dr. Shoemaker to propose future clinical trials investigating both personalization of AF ablation therapy and a pharmacogenomics-based approach to AAD therapy for this common and morbid condition.