4 - Genetics, genomics and proteomics in sudden cardiac death

Summary

Introduction

Sudden cardiac death (SCD) is an enigma: despite an overall decrease in cardiac mortality, SCD rates appear to be rising along with the concomitant increase in prevalence of coronary disease and heart failure. Even with decades of research, the underlying cellular mechanisms and stimulus/triggers are not well understood. This chapter addresses the application of large scale “omic” strategies to this critical clinical problem. First, is a discussion of the steps currently underway using genetic strategies to characterize several inherited arrhythmogenic diseases. The final two sections focus on two newer strategies, the technologies of genomics and proteomics.

Genetics, genomics and proteomics are complementary technologies. Figure 4.1 shows the flow from genes to proteins and emphasizes the increasing complexity at each step. Genetics strategies concentrate on identifying and characterizing a small number of candidate genes, informed by our understanding of the relevant biology, and are largely focused on analyzing sequence variants.Genomics looks more globally, with new approaches using unbiased whole-genome scans to examine both sequence variants and other genomic alterations, such as copy number polymorphism. Analysis of expressed genes, mRNA, is performed using the technologies of transcriptomics. Finally, the expressed proteins are studied using proteomics. This includes potential mutations (seen as amino acid changes) as well as post-translational modification (such as glycosylation or phosphorylation). It is only through the combined application of these technologies that we will be able to elucidate the underlying mechanisms of SCD, with the ultimate goal of both predicting individual risk and improving therapeutic intervention.