Network investigators have been leaders in identifying and characterizing key genes involved in normal and abnormal cardiac electrophysiology. The study of variants in these genes has progressed from rare monogenic disease to the current Network focus on common polymorphisms and their role in influencing responses to exogenous stressors as causes of SCD in the general population.

Participating investigators have an established record of collaborative research, and establishing the Network will expand thee collaborations, foster new ones, and move the field forward by pooling populations and other resources and allowing genomic analyses on a scale that individual centers could not undertake. The network includes a spectrum of expertise required to execute the proposed studies: basic science, molecular genetics, genome science, translational and clinical science, information technology, and genetic epidemiology.

Our objectives are:

• to accrue clinical data and DNA samples in well-characterized human populations with a spectrum of SCD risk;
• to analyze genomic determinants of SCD risk in these populations, focusing on arrhythmia pathway and whole genome approaches;
• to use clinical, animal, and in vitro approaches to understand mechanisms whereby established and new markers influence SCD risk;
• to create a Leducq SCD Network fellowship program that will offer training and exchange program to talented young investigators prepared to make a career commitment to genetic cardiovascular research.

Our specific aims for the 2005-2010 are:

• to identify common DNA variants that influence SCD risk at baseline and during exposure to stressors such as drugs or acute myocardial ischemia. To approach this goal, the clinical characteristics and frequencies of polymorphisms in candidate arrhythmia pathways and across the genome will be assessed in 5 populations of patients with a spectrum of SCD risk;
• to understand the mechanisms whereby genetic variants lead to electrical instability in the heart. The goal is to identify not only disease markers but also to gain mechanistic insights that will serve as a starting point for development of new specific therapies. .