Transcriptional control of ion channel genes in arrhythmogenesis

The coordinated contraction of the heart relies on proper functioning of ion channels that generate the cardiac electrical impulse. Inappropriate regulation of these ion channels can result in a wide variety of cardiac arrhythmias. Mutations in the genetic code of genes encoding cardiac ion channels are an important cause of cardiac arrhythmias. Increasing evidence shows that genetic variation in noncoding regulatory regions can disturb important biological processes, thereby adding to the complexity of heritable diseases. This thesis explores the role of noncoding regulatory elements and the effects of genetic variants therein on cardiac ion channel gene expression and function. Using current state-of-the-art techniques we identified several regulatory elements in the vicinity of ion channel genes. We show that loss of these regulatory elements results in reduced expression of ion channel genes, which consequently affects cardiac conduction. Furthermore, we provide evidence that genetic variants herein affect ion channel gene expression in humans. These insights will help to stratify the risk of arrhythmia and will provide clues towards developing novel therapeutic strategies that can bring personalized medicine closer to clinical application.