The candidate has recently joined the staff at the Massachusetts General Hospital (MGH) and received an appointment at Harvard Medical School effective July 2012. Over the last four years the candidate has studied the epidemiology and genetics of atrial fibrillation (AF), achieved a Master of Public Health degree, completed cardiac electrophysiology training, and established scientifically productive relationships with hi mentors. This Career Development Award is motivated by the public health importance of AF, which affects over 3 million Americans and is increasing in incidence and prevalence worldwide. Substantial morbidity and mortality are attributable to AF, including increased risks of disabling stroke, heart failure, and death. Furthermore, AF is responsible for an estimated $26 billion in annual health care costs in the United States. A widespread heritable component underlying AF is now recognized, and common genetic variants associated with AF have been discovered. Despite advances in the understanding of AF genetics, knowledge gaps remain. Associated signals at discovered AF susceptibility loci span up to hundreds of thousands of base pairs and remain poorly characterized. Data suggest that independent susceptibility signals may exist at known loci, and may both facilitate the identification of individuals at risk for AF as well as localize functional elements involved in AF pathogenesis. Relations between AF susceptibility variants and morbidity from AF remain unexplored. Associations between AF associated variants and clinical manifestations of AF may enable efforts to apply genetic and other discoveries to patient management in an effort to prevent morbidity. The candidate seeks to address these knowledge gaps by leveraging the power and complementarity of well-phenotyped cohorts spanning hospital-referral, community-based, and clinical trials samples. Specifically, the candidate proposes to: 1) discover independent AF genetic susceptibility variants in the international CHARGE consortium;2) determine the clinical and genetic predictors of AF progression in cohorts from MGH and the Framingham Heart Study;and 3) examine relations between AF susceptibility variants and stroke in individuals with and without AF in two Thrombolysis In Myocardial Infarction Study Group trials. This K23 is designed to foster independence through advanced training in genetic epidemiology, biostatistics, and clinical trial methods. The application draws upon strengths of different cohorts and experienced mentors in a multidisciplinary fashion.
The aims will inform our understanding of the mechanisms, clinical features, and outcomes of AF, a morbid arrhythmia of substantial public health importance. In future R01 applications the candidate will be poised to test whether application of genetic knowledge can facilitate prevention of AF related morbidity, and whether genetic variants associate differentially with response to pharmacologic agents used to treat patients with AF.

Public Health Relevance

Atrial fibrillation is an increasingly common and morbid cardiac arrhythmia associated with substantial risks of disabling stroke, heart failure, and death, as well as with significant healthcare costs. It is now recognized that a widespread heritable component underlies atrial fibrillation, and common genetic variants have been discovered that associate with the arrhythmia. We seek to examine the relations between genetic variants associated with atrial fibrillation and clinical manifestations of the arrhythmia in order to asses whether applying genetic and other discoveries to patient management can reduce morbidity from atrial fibrillation.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Mentored Patient-Oriented Research Career Development Award (K23)
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Special Emphasis Panel (ZHL1-CSR-X (F1))
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Scott, Jane
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Massachusetts General Hospital
United States
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Lubitz, Steven A; Lunetta, Kathryn L; Lin, Honghuang et al. (2014) Novel genetic markers associate with atrial fibrillation risk in Europeans and Japanese. J Am Coll Cardiol 63:1200-10
Magnani, Jared W; Brody, Jennifer A; Prins, Bram P et al. (2014) Sequencing of SCN5A identifies rare and common variants associated with cardiac conduction: Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. Circ Cardiovasc Genet 7:365-73
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Tada, Hayato; Shiffman, Dov; Smith, J Gustav et al. (2014) Twelve-single nucleotide polymorphism genetic risk score identifies individuals at increased risk for future atrial fibrillation and stroke. Stroke 45:2856-62
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Lubitz, Steven A; Moser, Carlee; Sullivan, Lisa et al. (2013) Atrial fibrillation patterns and risks of subsequent stroke, heart failure, or death in the community. J Am Heart Assoc 2:e000126