Approved research

Mechanistic Basis for Cardiac Arrhythmias: Translating Insights from Animal Models to Human Genetics

Lay summary

AIMS: Our project proposes to leverage the unique resources of the UK Biobank to explore two interrelated scientific questions about human heart rhythm and heart rhythm disorders that have emerged from our basic science research lab. First, we believe that differences residing in regions of the human genome that control the activity of different genes in specialized heart muscle (as opposed to encoding the genes themselves) may account for a large degree of the genetic variation in human heart rhythm parameters likely heart rate and findings on EKGs, and that they may account for why some people are at increased risk for developing arrhythmias like irregular heart beat (atrial fibrillation) and slow heart beat requiring a pacemaker. Second, we have identified some genetic mutations that cause very rare forms of these disease that occur with more severity and at younger ages than in the common forms of these diseases. We want to explore whether milder mutations in these genes might explain why some people are at risk for developing the common forms of these diseases. SCIENTIFIC RATIONALE: Although some large-scale studies have tried to examine genetic underpinnings of common arrhythmias. most of these have looked at the entire genome which dilutes the statistical power to identify meaningful causal relationships. Our basic science work on the structure of DNA in the specific heart cells of interest, and our work with patients with rare arrhythmia syndromes, allows us to test narrower hypotheses with greater statistical power. The UK Biobank resource, with its combination of deep genetic data and clinical data, is ideally suited for this purpose. PROJECT DURATION: 36 months PUBLIC HEALTH IMPACT: Atrial fibrillation is the most commonly encountered clinical arrhythmia, and leads to heart failure, strokes, reduced quality of life, and in some cases mortality. Conduction system disease leads to the need for pacemakers. These are major public health issues that affect millions of patients and their families throughout the world. Our treatments for these disorders and our understanding of their causes, is limited, including our understanding of why some patients and families are at higher risk than others. Gaining a deeper knowledge of the genetic underpinnings of these disorders will potentially point the way to new treatments and, in the best case, preventive strategies that can improve the quality and length of life for patients.