Genomics of Sudden Cardiac Death in the General Population – SCD-GEN

Sudden cardiac death (SCD) accounts for 5 to 10% of overall mortality. The resuscitation rate remains below 5 %, therefore an early identification of high risk subjects is necessary.(1-6) SCD poses a major challenge for public health in industrialized countries. We and others have shown that genetic factors are likely to contribute to the occurrence of SCD in the general population.(7,8) SCD in adults is mainly due to ventricular fibrillation occurring as an immediate complication of acute coronary syndrome. SCD in the context of acute ischemia has a strong but yet unspecified heritable component. (8) The aim of SCD-Gene is to identify susceptibility genes contributing to SCD risk by comparing SCD cases to survivors of myocardial infarction (MI) with no evidence of ventricular arrhythmia as well as a population based cohort. Instead of including patients hospitalized in intensive care units (ICU), the SCD-Gene project is reflecting as much as possible the population at large. The project will rely on 1.500 SCD cases which occurred in every day situations (at home, at work, in the street, etc.) This proposal is based on a large and well designed epidemiological study on out of hospital sudden cardiac death in France. CARTAGENE will be the largest genetic database of out of hospital SCD worldwide. Instead of testing selected known candidate genes (such as derived from previous evidence in rare monogenic disorders or pathophysiological hypotheses), state of the art genotyping technology allows for a genome wide association study (GWAS) to identify Single Nucleotide Polymorphisms (SNPs) associated with an increased risk of SCD without any a priori hypothesis. This approach requires a substantial number of patients and the constitution of a consortium associating various expertises, including epidemiologists, geneticists, statisticians, cardiologists, (and a complex logistics network between national resuscitation council, emergency medical services, fire fighters etc.). The epidemiological study (inclusion of more than 1.500 SCD cases and DNA extraction) is already funded and the recruitment is under way in several major cities in France. The control group of 2.000 MI cases already exists and a DNA resource has been constituted (FAST MI study). This proposal is aimed to fund the follow-up genotyping of an already completed pilot study performed in Munich (GWAS in n= 500 cases
and n=500 MI controls completed in March 2009). The consortium is now applying for funding the GWAS of 1 000 additional SCD cases.
We have pioneered studies on common genetic variants modulating quantitative traits of the surface ECG in the general population.(9-11) Quantitative traits such as QT interval and QRS duration have been linked to SCD. A prolonged QT interval increases the risk of sudden cardiac death (SCD) between 1,5- and 5-fold, depending on underlying cardiac conditions.(11) As a proof of concept, recently NOS1AP a common variant modulating the QT interval in the general population could be associated with SCD in a US population based study.(12) As our secondary objective, we aim to systematically investigate such common variants modulating myocardial electrical properties for their potential association with SCD in the CARTAGENE population.
The identification of common genetic variants associated with SCD in the general population will help to discover novel mechanisms and research directions for a better understanding of the physiopathology of SCD.(13,14) We strongly expect that the results could also help building at mean term diagnostic tools and/or tests for a personal assessment of the level of risk for SCD, allowing an early identification of subjects at high risk for SCD.