The Brugada Syndrome Susceptibility Gene HEY2 Modulates Cardiac Transmural Ion Channel Patterning and Electrical Heterogeneity

Circ Res. 2017 Aug 18;121(5):537-548. doi: 10.1161/CIRCRESAHA.117.310959. Epub 2017 Jun 21.


Rationale: Genome-wide association studies previously identified an association of rs9388451 at chromosome 6q22.3 (near HEY2) 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 Hey2+/- (Hey2 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 cis-expression quantitative trait locus effects of rs9388451, which revealed an association between Brugada syndrome risk allele dosage and HEY2 expression (β=+0.159; P=0.0036). In the same transcriptomic data, we conducted genome-wide coexpression analysis for HEY2, which uncovered KCNIP2, encoding the β-subunit of the channel underlying the transient outward current (Ito), as the transcript most robustly correlating with HEY2 expression (β=+1.47; P=2×10-34). Transcript abundance of Hey2 and the Ito subunits Kcnip2 and Kcnd2, assessed by quantitative reverse transcription-polymerase chain reaction, was higher in subepicardium versus subendocardium in both left and right ventricles, with lower levels in Hey2+/- mice compared with wild type. Surface ECG measurements showed less prominent J waves in Hey2+/- 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 Vmax in subepicardium compared with subendocardium cardiomyocytes, which was paralleled by a higher Ito and a lower sodium current (INa) density in subepicardium versus subendocardium. These transmural differences were diminished in Hey2+/- mice because of changes in subepicardial cardiomyocytes.

Conclusions: This study uncovers a role of HEY2 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 HEY2-dependent alteration of ion channel expression across the cardiac ventricular wall.

Keywords: Brugada syndrome; electrophysiology; potassium channels; sodium channels; transcriptome.

MeSH terms

  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / biosynthesis*
  • Basic Helix-Loop-Helix Transcription Factors / genetics*
  • Brugada Syndrome / genetics*
  • Brugada Syndrome / metabolism*
  • Brugada Syndrome / physiopathology
  • Electrocardiography / methods
  • Female
  • Genetic Predisposition to Disease / genetics*
  • Genome-Wide Association Study / methods
  • Heart Ventricles / metabolism*
  • Heart Ventricles / physiopathology
  • Humans
  • Ion Channels / biosynthesis
  • Ion Channels / genetics
  • Male
  • Mice
  • Mice, Knockout
  • Mice, Transgenic
  • Repressor Proteins / biosynthesis*
  • Repressor Proteins / genetics*


  • Basic Helix-Loop-Helix Transcription Factors
  • HEY2 protein, human
  • Ion Channels
  • Repressor Proteins