A Systems Biology Approach to Decipher Genetic Variants in a Canine Model of Sudden Cardiac Death

Sudden cardiac death (SCD) represents a major public health challenge, accounting for approximately 25% of all cardiac deaths. It refers to an unexpected death from ventricular arrhythmia, occurring in individuals with preexisting cardiovascular disorders as well as in individuals not previously diagnosed with heart disease. The identification of genetic variants that increase susceptibility to SCD is fundamental to improve risk stratification and understanding of molecular pathophysiology. In this study, to investigate the molecular mechanisms underlying SCD, a canine model, recapitulating what may happen to patients with a prior myocardial infarction, was used to accomplish a genome-wide association study comparing dogs resulting susceptible or resistant to ventricular fibrillation during submaximal exercise. The identified variants were explored by means of a systems biology approach, which maps human orthologues of mutated genes into a network encompassing co-expression and physical interactions. The paths connecting mutated genes highlighted a subnetwork enriched for genes involved in regulation of cardiac function.