The Brugada Syndrome Susceptibility Gene HEY2 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 HEY2) with Brugada syndrome (BrS). 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 heterozygous knockout mice (Hey2+/-) to dissect the underpinnings of the 6q22.31 association with BrS.
Methods and Results: We queried expression quantitative trait locus (eQTL) data acquired in 190 human left ventricular (LV) samples from the Genotype-Tissue Expression (GTEx) consortium for cis-eQTL effects of rs9388451 which revealed an association between BrS risk allele dosage and HEY2 expression (β=+0.159; P=0.0036). In the same transcriptomic data, we conducted genome-wide co-expression 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=2X10-34). Transcript abundance of HEY2 and the Ito subunits Kcnip2 and Kcnd2, assessed by qRT-PCR, was higher in subepicardium (epi) vs. subendocardium (endo) in both left (LV) and right (RV) ventricles, with lower levels in HEY2 heterozygous knockout (Hey2+/-) mice compared to wildtype (WT). Surface ECG measurements showed less prominent J-waves in Hey2+/- mice compared to WT. In WT mice, patch-clamp electrophysiological studies on cardiac myocytes from RV demonstrated a shorter AP duration and a lower Vmax in epi compared to endo cardiac myocytes, which was paralleled by a higher Ito and a lower INa density in epi vs. endo. These transmural differences were diminished in Hey2+/- mice due to changes in subepicardial cardiac myocytes.
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 BrS through a HEY2-dependent alteration of ion channel expression across the cardiac ventricular wall.
- Received March 9, 2017.
- Revision received June 14, 2017.
- Accepted June 19, 2017.