Insight into genes predisposing to sudden cardiac death
09 / 2000 - 09 / 2004
Background: Sudden cardiac death (SCD) is a heterogenic phenotype, influenced by multiple pathologies. It is responsible for approximately 50% of the mortality from cardiovascular disease. It is the most common and in at least 25% of coronary artery disease patients it is the first manifestation of the disease. In population based studies as well as in cohort studies a family history of SCD has been shown to be an independent predictor for subsequent SCD. Several genes may be involved, among them genes involved in electrical activity, plaque stability and thrombogeneity. The final common pathway, however, is electrical instability and therefore genes involved in cardiac excitability and conduction emerge as immediate candidate genes. Furthermore, using twin methodology in normal young subjects, one of our collaborators on this project (A. Busjahn) has shown that cardiac ion channel gene loci, indeed, constitute quantitative trait loci (QTLs) that influence electrocardiographic (ECG) features in the general population. Hypothesis: Cardiac ion channel genes contain sequence variations (polymorphisms) associated with functionally relevant variants that influence ECG features in the general population and predispose individuals/families with coronary artery disease (CAD) to sudden death. Study objectives / methods / expected results: In the course of our research on inherited arrhythmias, we have identified several polymorphisms in cardiac ion channel genes (amino acid substitutions and splice site variations) which could potentially impact on ECG parameters. These polymorphisms will be assessed for association directly in a combined linkage and association sib-pair analysis for quantitative traits on a panel of normal monozygotic and dizygotic twin subjects. In addition, the eventual presence of pertinent polymorphisms will be screened in patients who survived a cardiac arrest episode [databases Isala klinieken Zwolle, AMC, Amsterdam, AZM, Maastricht and the patient population of the Amsterdamse Arrest Trials]. Its prevalence will be compared with a gender and age matched control group. Methods to be employed are standard techniques of genotype analysis which are all running in our laboratory. With this study we intend to identify genetic markers predisposing for SCD. Identification of markers within the genes that predispose to SCD will be of benefit, in future risk stratification, to patients and/or families with CAD and may, with timely treatment, prevent SCD in these patients.