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

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

Author information

1
From the Department of Clinical and Experimental Cardiology, Heart Center, Academic Medical Center, Amsterdam, The Netherlands (C.C.V., S.P., R.T., E.M.L., I.M., L.B., A.A.M.W., R.C., A.O.V., C.A.R., C.R.B.); Department of Medicine, Cardiovascular Genetics Center, Montreal Heart Institute, Canada (R.T.); Université de Montréal, Canada (R.T.); Department of Medical Biology, Academic Medical Center, Amsterdam, The Netherlands (B.d.J., R.W., B.J.B., A.O.V.); INSERM, CNRS, Université de Nantes, L'institut du Thorax, Nantes, France (J.B.); Princess Al-Jawhara Al-Brahim Centre of Excellence in Research of Hereditary Disorders, Jeddah, Saudi Arabia (A.A.M.W.); and Electrophysiology and Heart Modeling Institute LIRYC, Université de Bordeaux, France (R.C.).
2
From the Department of Clinical and Experimental Cardiology, Heart Center, Academic Medical Center, Amsterdam, The Netherlands (C.C.V., S.P., R.T., E.M.L., I.M., L.B., A.A.M.W., R.C., A.O.V., C.A.R., C.R.B.); Department of Medicine, Cardiovascular Genetics Center, Montreal Heart Institute, Canada (R.T.); Université de Montréal, Canada (R.T.); Department of Medical Biology, Academic Medical Center, Amsterdam, The Netherlands (B.d.J., R.W., B.J.B., A.O.V.); INSERM, CNRS, Université de Nantes, L'institut du Thorax, Nantes, France (J.B.); Princess Al-Jawhara Al-Brahim Centre of Excellence in Research of Hereditary Disorders, Jeddah, Saudi Arabia (A.A.M.W.); and Electrophysiology and Heart Modeling Institute LIRYC, Université de Bordeaux, France (R.C.). c.r.bezzina@amc.uva.nl.

Abstract

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

PMID:
28637782
DOI:
10.1161/CIRCRESAHA.117.310959
[Indexed for MEDLINE]

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