Common Variant Near HEY2 Has a Protective Effect on Ventricular Fibrillation Occurrence in Brugada Syndrome by Regulating the Repolarization Current

Abstract

B rugada syndrome (BrS) is characterized by right precordial ST elevation, susceptibility to ventricular arrhythmias, and sudden cardiac death.1,2 Because the SCN5A gene, which codes for cardiac voltage-gated sodium channels, was reported to be a causative gene of BrS, 3 many other susceptibility genes have been identified. 4 Among them, the SCN5A gene accounts for the vast majority of cases.In 2009, Kapplinger et al 5 reported that 300 distinct SCN5A mutations were detected in 438 (21%) of 2111 unrelated, clinically diagnosed patients with BrS, with the mutation detection yield ranging from 11% to 28% across the 9 testing centers. Mutations in calcium channel genes, including CACNA1C (Cav1.2, BrS3), CACNB2b (Cav b2b, BrS4), and CACNA2D1 (Cav a2δ1, BrS9), have been found in ≈12%© 2016 American Heart Association, Inc. ; odds ratio, 1.7, respectively). Interestingly, the HEY2 risk allele C was less frequent in BrS patients with ventricular fibrillation than in those without (59% versus 74%; P=4.1×10 ). The HEY2 mRNA expression level in the right ventricular specimens from patients with BrS (n=20) was significantly lower in patients with CC genotype than the other genotypes (P=0.04). Additionally, during 63±28 months follow-up periods after implantable cardioverter defibrillator implantation (n=90), Kaplan-Meier event-free survival curves revealed that the cumulative rate of ventricular fibrillation events was significantly lower in cases with HEY2 CC genotype (P=0.04). Conclusions-Our findings suggest that HEY2 CC genotype may be a favorable prognostic marker for BrS, protectively acting to prevent ventricular fibrillation presumably by regulating the repolarization current. (Circ Arrhythm Electrophysiol. 2016;9:e003436. Circ Arrhythm Electrophysiol

Syncope in patients with inherited arrhythmias

“…In a recent genome-wide association study, three single-nucleotide polymorphisms, SCN10A, SCN5A, and HEY 2, were reported to be associated with BrS [37] . We confirmed the results through a separate study and could demonstrate that the HEY2 single-nucleotide polymorphism (SNP) could be a useful prognostic marker for BrS [38] .…”

H558R, a common SCN5A polymorphism, modifies the clinical phenotype of Brugada syndrome by modulating DNA methylation of SCN5A promoters

“…The total RNA and genome DNA were isolated from the right atrial sections using an All Prep DNA/RNA/miRNA universal kit (QIAGEN). Quantitative reverse transcription PCR of the SCN5A mRNA was performed by QX200 Droplet Digital PCR (dd-PCR) system (Bio-Rad, Hercules, CA, USA) as described previously, using GAPDH as a reference gene [ 11 , 12 ].…”

The Brugada Syndrome: A Rare Arrhythmia Disorder with Complex Inheritance

“…Another source of progress regarding risk stratification among BrS patients could go through the identification of specific ECG indices associated with higher risk of (fatal) arrhythmia. Genetic variants at the SCN5A , HEY2 , and SCN10A loci have been associated with arrhythmia occurrence in independent studies ( 47 , 102 , 103 ). Integrating such effects toward establishing a global genetic model for BrS is the next step before including genetic testing into the clinical management of BrS.…”

“…These data uncovered the role of Hey2 in the cardiac electrical function and more specifically in the pathogenesis of BrS. Among its role on BrS phenotype, common variant in this gene could also presented with a protective role from ventricular fibrillation in BrS patients by regulating the repolarization current ( 102 ).…”