Cardiovascular disease and sudden cardiac death: between genetics and genomics

This editorial refers to ‘Predicting sudden cardiac death using common genetic risk variants for coronary artery disease’†, by J.A. Hernesniemi et al., on page 1669. In 1980, polymorphic variance in the human genome was used to generate a first, physical map allowing monogenic traits to be traced to certain chromosomal regions.1 Due to the recognition of fragment length polymorphisms (microsatellite markers) with several different alleles at the same chromosomal locus, single nucleotide polymorphisms (SNP) became neglected in this instance for a long time. The obvious interindividual variability and the recognition that many cardiovascular parameters (e.g. blood pressure or ECG parameters) are continuous traits, raised the question of whether evident phenotypic differences in cardiovascular diseases and clinical outcome (e.g. in heart failure, myocardial infarction, or atrial fibrillation) have a common genetic component2 either due to small size effects3 or by multiple pathway interaction.4 To date, many investigations addressing differences in the distribution of SNP alleles in cardiovascular diseases and controls have been triggered by the increasing, but still incomplete knowledge of genomic variance after whole-genome sequencing (3 × 109 nucleotide pairs, among them 1% protein coding) (Figures 1 and 2). Per individual there are (i) around 3.3 million SNP, but within the nearly 20 000 genes only a minority can be found (>10 000 non-synonymous and >10 000 synonymous SNP);5,6 and (ii) 250–300 loss-of-function gene variants (including premature stops, splice site disruptions, and frameshifts); some might have been implicated in inherited disorders before and due to a germline mutation rate of 1 × 10–8 up to 30 de novo mutations might be expected in the next generation.6