Post-GWAS explorations in Brugada syndrome: new wires to phenotypes – WIRES

The Brugada Syndrome (BrS) is an inherited arrhythmic disease suspected to be responsible for >20% of cases of sudden cardiac death (SCD) in patients without structural heart disease. It is also suspected to be involved in 4-12% of SCD in the general population. Clinical diagnosis is based on a specific electrocardiographic (ECG) pattern, i.e., a ST-segment elevation and T wave inversion in the right precordial leads (type-1 ECG pattern). However, this pattern is labile and often unveiled only after provocative drug tests. There is thus a need to develop new methods to improve BrS patient diagnosis. Currently, the only efficient therapy to prevent severe arrhythmias and SCD in BrS patients is to implant a defibrillator, which leads to 30% risk of complications at 10-year follow-up. In this context, identifying the patients at higher risk of SCD who would benefit the most of a defibrillator implantation is primordial. However, there is a lack of relevant parameters for risk stratification, not only at the clinical level, but also at the biological level, due to a lack of understanding of BrS molecular mechanisms.
Recent scientific discoveries have totally changed our perception of the molecular bases BrS, opening new perspectives in translational research to solve those clinical issues. Indeed, genome-wide association studies allowed us to identify 21 common risk alleles located in non-coding regions with a strong polygenic influence on BrS. Most of these risk alleles reside in non-coding regions of the genome and may alter gene regulatory elements. Indeed, chromatin conformation analysis points to 56 genes interacting with these regulatory regions. Interestingly, 10 of the 21 risk alleles overlap or are located near 8 genes encoding transcription factors (TF) known to impact cardiac development, supporting the hypothesis that BrS might partly result from cardiac developmental defects.
In this context, WIRES aims to determine how the recently identified risk alleles are functionally associated with BrS and to develop new tools to improve BrS diagnosis. These objectives involve complementary approaches in clinical and basic research with high added value to achieve the ultimate goal of generating effective tools for BrS diagnosis and SCD risk prediction.
WIRES combines expertise in biology (the research lab of l'institut du thorax - Inserm UMR1087/CNRS UMR6291; the lab Théories et approches de la complexité génomique - Inserm UMR1090), signal processing (Laboratoire des Sciences du Numérique de Nantes - CNRS UMR6004) and medicine (Reference Centre for hereditary cardiac arrhythmias, Nantes University Hospital) in order to:
1. Determine which of the 56 genes interacting with the identified gene regulatory regions are involved in cardiac physiology using high-throughput functional screening in the Drosophila model;
2. Determine whether the risk alleles located near the genes encoding TFs have transcriptional and functional impact on differentiation and function of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). In addition, hiPSC-CMs will be used to assess the functional impact of the risk alleles located near the genes identified in Drosophila as having the most significant cardiac impact.
3. Develop a novel algorithm to detect ST-segment elevation and/or subtler J-wave patterns for automatic detection of type-1 ECGs, which will improve BrS diagnosis and enable to evaluate the actual incidence of BrS in the general population, starting with the Constances cohort, which remains globally unknown.
WIRES is the first brick in a larger ambitious project that aims at integrating clinical, functional and genotype data on both rare and common genetic variants to provide the clinicians with new tools and markers for improving SCD risk prediction among BrS patients.