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Risk Stratification for Sudden Cardiac Death

Periodic Reporting for period 1 - RISTRAD (Risk Stratification for Sudden Cardiac Death)

Reporting period: 2015-05-01 to 2017-04-30

Sudden cardiac death (SCD) is a leading cause of total and cardiovascular mortality with about 400 000 death per year in Western Europe. Ventricular fibrillation (VF) is the most common arrhythmia causing SCD. However as of today, the large gap in our knowledge concerning the determinants of VF at the genetic and molecular level hinders developing preventive strategies. In young individuals, SCD occurs primarily in the setting of rare cardiac disorders generally considered as Mendelian diseases. Among these are the primary electrical disorders associating lethal arrhythmias such as VF. These disorders are highly amenable to genetic studies since they manifest clinically with specific features on the electrocardiogram. They constitute then a powerful vector of genes and pathways discoveries allowing breakthroughs in the development of risk stratification and preventive strategies. As a model of a primary rhythm disorder, Brugada syndrome (BrS) may be considered as 'sensitized model' for SCD and be relevant to the broad problem of SCD in the setting of common cardiac pathologies.
The aim of RISTRAD was to propose a translational study, combining genome wide association studies in the largest biobank of patients with cardiac arrhythmia ever collected, genotype-phenotype studies for clinical relevance/use and functional characterization for novel genes uncovered. The overarching aim of the study was identifying novel genetic factors associated with rare cardiac arrhythmia disorders and impacts much broader in the field by highlighting mechanisms underlying VF/SCD.In a previous genome wide association study (GWAS) led on 312 BrS cases only and we uncovered a large effect on the development of the disease by the accumulation within the genome of common genetic variants. The cumulative effect of the 3 loci on disease susceptibility was unexpectedly large with an odds ratio of 21.5 in the presence of more than 4 risk alleles versus less than 2.
RISTRAD extended this GWAS to 2153 European cases of which 871 came from Nantes referral center. This massive extension considerably increased the power of the study. Another collaboration with a Japanese consortium gathering over 700 BrS samples is ongoing to complete/replicate our results.
The GWAS results, comparing the genetic background of 2153 BrS samples to 9821 samples from the general population identified 13 independent loci (reaching at least the genome-wide significant pvalue (p<5×10-8)): 8 are located in the SCN5A/SCN10A locus (from which 2 were already identified by the pilot study) demonstrating the predominance and pivotal role of SCN5A locus in the BrS physiopathology. Previous studies demonstrated that non-coding regions of this locus and more specifically variants within enhancer or promoter regions impact on the SCN5A expression level.
More interestingly, through this GWAS and its pan-genomic screening, we uncovered association of genes with the Brugada syndrome unrelated so far to the cardiac electrical activity. The preliminary analysis uncovered 5 loci harboring genes presenting a strong implication into the cardiac development. Among them only HEY2 was identified by the pilot study. (see Figure attached)
This constitutes a major breakthrough into the comprehension of the development of the Brugada syndrome considered so far as a pure electrical disorder. The implication of these 5 cardiac transcription factors may imply a complex regulation of the ion channels and their protein partner expressions but may also indicate that potential developmental and structural components may be implicated into development of primary electrical disorders. Investigation of the expression level and functional impact is ongoing (WP3).
Importantly, aside from the molecular markers increasing drastically the susceptibility to the disease, preliminary analysis suggest that a specific locus might be predictive for severe arrhythmia outcome and might be of interest for clinical management and specifically for defibrillator implantation.
Impact on the scientific community:
The results of this GWAS open entire new fields of research such as the understanding of the precise direct or indirect role of the cardiac transcription factors on the cardiac electrical activity regulation. More specifically, the exploration of the mechanisms linking these transcription factors to the electrical activity required further experiments as well as mechanisms deciphering how the common variations uncovered by RISTRAD modulate the Brugada Syndrome risk susceptibility.

Impact of RISTRAD on the researcher career:
RISTRAD indisputably accelerates the development of Julien Barc’s network in particular by international collaborations with worldwide group leader in genetics of arrhythmia. Furthermore this major breakthrough in the genetics of the cardiac arrhythmias will be shared to scientific community during the following national and international congresses and will represent for Julien Barc an occasion to present his independent research and extend his international visibility in view of future collaboration and network participation. As an illustration, collaboration with Prof. Naomasa Makita allowed Dr Barc to work on the clinical and molecular description of a new syndromic arrhythmia disorder: Progressive Atrial Conduction Defects Associated With Bone Malformation Caused by a Connexin 45 Mutation, recently accepted for publication in JACC (IF:19.9)
Aside from the progress into the physiopathology comprehension of the cardiac arrhythmia, the new model uncovered by RISTRAD will represent a step forward for Dr Barc’s career and specifically constitutes the basement for proposing an ambitious grant application such as an ERC starting grant. The unexpected implication of cardiac transcription factors raises the intriguing involvement of epigenetic mechanisms modulating genes expression and impacting on rare arrhythmia phenotypes.


Socio-economic impact and the wider societal implications of the project
Most of the SCD happen in individuals with none known cardiopathy leading extremely difficult prevention. On the other hand, since the risk stratification of arrhythmia events is poorly established, prevention is often restricted to ICD implantation leading to inappropriate implantation, inappropriate shocks, infectious and a consequent cost for the society. The results of RISTRAD may conduct to develop a personalized and precise medicine with the determining of the number of risk alleles carried and the associated risk score within each individual and propose an adapted care management and therapy.


Education:
The personalized medicine required to change the medical teaching, specifically train the future clinicians to the new technologies and approaches. Since last year, the University of Nantes proposes 12 classes focused on precision medicine and targeted therapy in which Julien Barc is in charged with the Prof. Le Marec of the personalized medicine applicate to arrhythmia disorders and where the results of RISTRAD will be presented. s (http://www.edbiologiesante.fr)
In the context of an international school on the structure and function of ion channels Julien Barc presented an update of RISTRAD with the objective to describe the new technologies and approaches employed to discover the molecular mechanisms of the inherited arrhythmia syndromes. (https://www.bioeng.ru/en/event/isonic17)
Manhattan plot - RISTRAD