Abstract 1969: Genetic Variation in SCN10a is Associated With Cardiac Conduction, Heart Block and Risk of Ventricular Fibrillation
Background Most cardiac deaths result from ventricular arrhythmia. Risk of arrhythmia is strongly influenced by genetic factors. We carried out a genome-wide association and replication study of ECG time intervals (PR, QRS and QT) amongst 17,309 people to identify novel genetic mechanisms influencing cardiac conduction and arrhythmic risk.
Methods and Results Genome-wide association was carried out using Illumina Hap300 and Hap610 BeadChips in 6,543 participants of LOLIPOP, a population cohort study, with replication in a further 10,766 LOLIPOP particpants. ECG time intervals were measured electronically using the Marquette 12SL algorithm. We identified and replicated novel association of a locus on chromosome 3 (remote from SCN5A) with PR interval (P = 3.2×10 – 43). Further testing revealed that the top-ranking SNP was independently associated with P wave duration and QRS interval (both P <10 –7), but not with QT interval or heart rate. The locus identified on chromosome 3 contains a sodium channel gene (“SCN”) not previously reported to influence cardiac conduction. We confirmed expression of SCN in the atria and ventricles of mouse and human heart, and in isolated atrial and ventricular myocytes. In SCN−/− knockout mice, PR interval was shorter compared to wild-type littermates, confirming that SCN affects cardiac conduction. We then investigated the relationship of SCN to cardiac arrhythmia. We found that genetic variants in SCN were associated with first degree, bundle branch and bifascicular heart block (all P<0.05). In a separate experiment, SCN variants were associated with with reduced risk of ventricular fibrillation amongst patients with acute myocardial infarction (P<0.05).
Conclusions We identify SCN as a novel locus influencing cardiac conduction, and risk of heart block and ventricular arrhythmia in man. Our findings provide new insight into the pathogenesis of cardiac arrhythmia.