ANR WIRES: Flavien Charpentier (2023-2027)

Flavien Charpentier is the scientific leader the ANR funded project : Post-GWAS explorations in Brugada syndrome: new wires to phenotypes

• Clinical coordinator: Jean Baptiste Gourraud (partner 4; CIC Thorax, Centre de Référence sur les Arythmies Cardiaques Héréditaires, l'institut du thorax, CHU de Nantes)
• Partner 2: Nathalie Arquier (Théories et approches de la complexité génomique, INSERM UMR 1090, Aix Marseille Université)
• Partner 3: Saïd Moussaoui (Laboratoire des Sciences du Numérique de Nantes (LS2N), CNRS UMR 6004, Ecole Centrale de Nantes)

Abstract

The Brugada Syndrome (BrS), implicated in over 20% of sudden cardiac death (SCD) cases without structural heart disease, lacks reliable diagnostic methods due to the labile nature of its electrocardiographic pattern. Currently, there is no available pharmacological treatment. Implanting defibrillators is the primary therapy for the patients at high risk for SCD. In this context, identifying the patients who would benefit most from defibrillator implantation is crucial.  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 genomic studies performed by team I revealed 21 common risk alleles in non-coding regions influencing BrS. Chromatin conformation analysis identified 56 genes interacting with these regulatory regions, with 10 risk alleles linked to transcription factors. These discoveries altered our understanding of BrS at the molecular level.
 

Objectives

The WIRES project aims to enhance BrS diagnosis and prediction of SCD risk by determining the functional associations of identified risk alleles. It combines expertise in biology, signal processing, and medicine to: (1) identify genes among the 56 interacting with regulatory regions using high-throughput functional screening in the Drosophila model (partners 1 & 2);  (2) investigate the transcriptional and functional impact of risk alleles near genes encoding transcription factors on human induced pluripotent stem cell-derived cardiomyocytes (Nathalie Gaborit, partner 1); (3) develop an algorithm for automatic detection of BrS-specific electrocardiographic patterns, which will enhance BrS diagnosis (partners 1, 3 & 4). WIRES represents the initial phase of a comprehensive project integrating clinical, functional, and genotype data to provide clinicians with improved tools for SCD risk prediction in BrS patients.