The Brugada Syndrome Susceptibility Gene Modulates Cardiac Transmural Ion Channel Patterning and Electrical Heterogeneity.

Rationale: Genome-wide association studies previously identified an association of rs9388451 at chromosome 6q22.3 (near ) with Brugada syndrome. The causal gene and underlying mechanism remain unresolved.

Objective: We used an integrative approach entailing transcriptomic studies in human hearts and electrophysiological studies in ( heterozygous knockout) mice to dissect the underpinnings of the 6q22.31 association with Brugada syndrome.

Methods And Results: We queried expression quantitative trait locus data acquired in 190 human left ventricular samples from the genotype-tissue expression consortium for -expression quantitative trait locus effects of rs9388451, which revealed an association between Brugada syndrome risk allele dosage and expression (β=+0.159; =0.0036). In the same transcriptomic data, we conducted genome-wide coexpression analysis for , which uncovered , encoding the β-subunit of the channel underlying the transient outward current (), as the transcript most robustly correlating with expression (β=+1.47; =2×10). Transcript abundance of and the subunits and , assessed by quantitative reverse transcription-polymerase chain reaction, was higher in subepicardium versus subendocardium in both left and right ventricles, with lower levels in mice compared with wild type. Surface ECG measurements showed less prominent J waves in mice compared with wild-type. In wild-type mice, patch-clamp electrophysiological studies on cardiomyocytes from right ventricle demonstrated a shorter action potential duration and a lower V in subepicardium compared with subendocardium cardiomyocytes, which was paralleled by a higher and a lower sodium current () density in subepicardium versus subendocardium. These transmural differences were diminished in mice because of changes in subepicardial cardiomyocytes.

Conclusions: This study uncovers a role of in the normal transmural electrophysiological gradient in the ventricle and provides compelling evidence that genetic variation at 6q22.31 (rs9388451) is associated with Brugada syndrome through a -dependent alteration of ion channel expression across the cardiac ventricular wall.