The purpose of this award is to enable the Principle Investigator, Dr. Nona Sotoodehnia, to develop into an independent clinical scientist in the field of molecular epidemiology of cardiovascular diseases with a special focus on sudden cardiac death (SCD). The training plan includes two concomitant activities: didactic coursework with a pursuit of a master s degree in genetic epidemiology, and a comprehensive 5-year program of research investigating the association of SCD with candidate genes in the renin-angiotensin (RAS) and sympathetic nervous systems (SNS). The scientific goals of this research proposal are as follows: 1) to identify genetic markers in the RAS and SNS associated with SCD, 2) to determine the association of these genetic factors with intermediate phenotypes that predispose to SCD (e.g. left ventricular mass and heart rate), and 3) to investigate the influence of specific environmental, pharmacologic, and other genetic factors on the above genetic associations. To the best of our knowledge, this will be the first study to systematically investigate genetic risk factors for SCD in the general population. In collaboration with investigators from the NHLBI-funded UW Program for Genomic Applications, we will first determine common haplotype structure for the five candidate genes using complete sequence information. We will then identify a few informative single nucleotide polymorphisms in each gene that capture the common haplotypes for further genotyping of the study participants. The genetic investigations using haplotype analysis will then be performed in two studies that allow rigorous identification of the SCD phenotype: the Cardiovascular Health Study (CHS), a biracial cohort of 5,888 men and women over age 65, and the Seattle Cardiac Arrest Blood Study (CABS), a case-control study of SCD in the community. Using CHS information on clinical characteristics, subclinical disease, and medications use, we will also investigate association of genotype with intermediate phenotypes and explore gene-environment and drug-gene interactions. By the conclusion of this award, the Principle Investigator will have achieved a solid foundation in traditional epidemiologic methods as well as attained cutting-edge human genome epidemiology analytic skills, which will enable her to contribute as an independent investigator to the fields of cardiovascular and genetic epidemiology.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Clinical Investigator Award (CIA) (K08)
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Special Emphasis Panel (ZHL1-CSR-M (M1))
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Silsbee, Lorraine M
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University of Washington
Internal Medicine/Medicine
Schools of Medicine
United States
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Ilkhanoff, Leonard; Arking, Dan E; Lemaitre, Rozenn N et al. (2014) A common SCN5A variant is associated with PR interval and atrial fibrillation among African Americans. J Cardiovasc Electrophysiol 25:1150-7
Sotoodehnia, Nona; Li, Guo; Johnson, Catherine O et al. (2009) Genetic variation in angiotensin-converting enzyme-related pathways associated with sudden cardiac arrest risk. Heart Rhythm 6:1306-14
Sotoodehnia, Nona; Siscovick, David S; Vatta, Matteo et al. (2006) Beta2-adrenergic receptor genetic variants and risk of sudden cardiac death. Circulation 113:1842-8