Elsevier

Heart Rhythm

Volume 17, Issue 12, December 2020, Pages 2145-2153
Heart Rhythm

Clinical
Genetic
Common and rare susceptibility genetic variants predisposing to Brugada syndrome in Thailand

https://doi.org/10.1016/j.hrthm.2020.06.027Get rights and content

Background

Mutations in SCN5A are rarely found in Thai patients with Brugada syndrome (BrS). Recent evidence suggested that common genetic variations may underlie BrS in a complex inheritance model.

Objective

The purpose of this study was to find common and rare/low-frequency genetic variants predisposing to BrS in persons in Thailand.

Methods

We conducted a genome-wide association study (GWAS) to explore the association of common variants in 154 Thai BrS cases and 432 controls. We sequenced SCN5A in 131 cases and 205 controls. Variants were classified according to current guidelines, and case-control association testing was performed for rare and low-frequency variants.

Results

Two loci were significantly associated with BrS. The first was near SCN5A/SCN10A (lead marker rs10428132; odds ratio [OR] 2.4; P = 3 × 10–10). Conditional analysis identified a novel independent signal in the same locus (rs6767797; OR 2.3; P = 2.7 × 10–10). The second locus was near HEY2 (lead marker rs3734634; OR 2.5; P = 7 × 10–9). Rare (minor allele frequency [MAF] <0.0001) coding variants in SCN5A were found in 8 of the 131 cases (6.1% in cases vs 2.0% in controls; P = .046; OR 3.3; 95% confident interval [CI] 1.0–11.1), but an enrichment of low-frequency (MAF<0.001 and >0.0001) variants also was observed in cases, with 1 variant (SCN5A: p.Arg965Cys) detected in 4.6% of Thai BrS patients vs 0.5% in controls (P = 0.015; OR 9.8; 95% CI 1.2–82.3).

Conclusion

The genetic basis of BrS in Thailand includes a wide spectrum of variant frequencies and effect sizes. As previously shown in European and Japanese populations, common variants near SCN5A and HEY2 are associated with BrS in the Thai population, confirming the transethnic transferability of these 2 major BrS loci.

Introduction

The Brugada syndrome (BrS), first described by Brugada and Brugada1 in 1992, is considered a leading cause of sudden cardiac death in young men worldwide.2 The prevalence of BrS is highest in Asia, with estimates as high as 0.5–1 per 1000 in Southeast Asia.3 In Thailand, BrS is the most common cause of sudden unexplained nocturnal death syndrome, particularly in the northeastern part of the country.4

In 1998, Chen et al5 reported disease-causing variants in SCN5A (which encodes the cardiac sodium channel NaV1.5) in 3 small families with BrS and initially suggested that BrS was a monogenic disorder. However, most patients with BrS do not carry pathogenic variants in BrS-associated genes. In addition, several families in which some individuals affected by BrS did not carry the familial SCN5A pathogenic variant (phenotype-positive, genotype-negative cases) have been described.6 These observations led to the hypothesis that the genetic basis of BrS was more complex, such that disease susceptibility was determined by the accumulation of genetic variants of diverse allele frequencies and effect sizes (oligogenic or polygenic inheritance). This hypothesis led to a genome-wide association study (GWAS), which found an association between common variants at the SCN5A-SCN10A locus and a locus close to HEY2 with BrS susceptibility in individuals of European and Japanese ancestry.7 The aim of this study was to explore the genetic basis of BrS in the Thai population, for both common variants (through a GWAS) and rare/low-frequency variants (through sequencing of SCN5A).

Section snippets

Study population

The study population was drawn from a consortium comprising 7 institutions in Thailand. Inclusion criteria were self-reported ethnic Thai patients diagnosed with BrS according to the 2013 Heart Rhythm Society/European Heart Rhythm Association/Asia Pacific Heart Rhythm Society Expert Consensus Statement.3 Blood samples were collected for DNA extraction and genotyping. Electrocardiograms (ECGs) showing type I Brugada pattern were read by treating physicians and confirmed by a cardiac

SCN5A rare and low-frequency variants

Rare (gnomAD exomes FAF <0.0001) protein-altering variants in SCN5A were detected in 8 of 131 BrS cases (6.1%) and were enriched over both Thai controls (4/205 [2.0%]; P = .046; odds ratio [OR] 3.3; 95% confident interval [CI] 1.0–11.1) and gnomAD East Asian samples (192/8945 [2.15%]; P = 8.3 × 10–3; OR 3.0; 95% CI 1.4–6.1). All variants detected in both cases and controls were missense variants: 3 transmembrane and 5 interdomain linker variants were found in the cases, and 3 interdomain linker

Discussion

Sudden cardiac death in young patients with structurally normal heart is often a result of an inherited cardiac disorder. With the assumption that BrS was a monogenic disorder and using a candidate gene approach, Chen et al5 demonstrated that pathogenic variants in SCN5A contributed to the development of BrS in 3 small families. Multiple studies subsequently reported putative pathogenic variants in at least 21 different genes.3,11 However, a recent study disputed most of these genes, except for

Study Limitation

Due to the lack of published segregation or functional data, all of our rare SCN5A variants (gnomAD exomes FAF < 0.0001) were classified as variants of unknown significance. Although we demonstrated enrichment of these rare variants compared to the control group, we were unable to determine the functional effect of each variant and thus elected not to include them in the PRS nor survival analyses.

Conclusion

Through GWAS in Thai BrS cases vs ancestry-matched controls, we demonstrated that, as for individuals of European and Japanese descent, common variants at the SCN5A-SCN10A and HEY2 loci are associated with susceptibility to BrS in Thai individuals. Through GWAS we also extended the known common susceptibility variants at the SCN5A-SCN10A locus by the identification of a novel common susceptibility variant. Finally, in contrast to the European population, the incidence of rare pathogenic SCN5A

Acknowledgments

We thank Mischa Clerk at the Amsterdam UMC for his support. We thank Prof. Vorasuk Shotelersuk and the Center of Excellence in Medical Genomics, Faculty of Medicine, Chulalongkorn University, for providing the Thai population genetic data and the high-performance computer to manage and store the genomics data in Thailand.

References (20)

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Funding sources: This work is supported by a grant from the National Research Council of Thailand (2558-114, 1/2561, 3/2562: Dr Nademanee, Principal Investigator; Dr Khongphatthanayothin, Co-Principal Investigator). Dr Nademanee received grant in aid from Bumrungrad Hospital, Bangkok, Thailand. Dr Khongphatthanayothin received support from the Thailand Research Fund (RSA5980077). Dr Poovorawan was supported by the National Science and Technology Development Agency (P-15-5004), the Center of Excellence in Clinical Virology, Chulalongkorn University, and King Chulalongkorn Memorial Hospital. Drs Bezzina and Wilde acknowledge the support from the Dutch Heart Foundation, Netherlands, (CVON 2018-30 Predict 2) and the Netherlands Organization for Scientific Research (VICI Fellowship 016.150.610 to Dr Bezzina). Dr Tadros received support from the Canadian Heart Rhythm Society’s George Mines Award, the European Society of Cardiology research award, and the Philippa and Marvin Carsley Cardiology Chair; and is currently a clinical research scholar of the Fonds de Recherche du Québec–Santé. Dr Glinge was supported by the European Society of Cardiology research award. Dr Tjong received support from the Dutch Heart Foundation (E. Dekker Grant 2014T053). ClinicalTrials.gov Identifier: NCT04232787.

Disclosures: The authors have no conflicts of interests to disclose.

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