GSTM3 variant is a novel genetic modifier in Brugada syndrome, a disease with risk of sudden cardiac death
Jyh-Ming Jimmy Juang,
Anna Binda,
Shyh-Jye Lee,
Juey-Jen Hwang,
Wen-Jone Chen,
Yen-Bin Liu,
Lian-Yu Lin,
Chih-Chieh Yu,
Li-Ting Ho,
Hui-Chun Huang,
Ching-Yu Julius Chen,
Tzu-Pin Lu,
Liang-Chuan Lai,
Shih-Fan Sherri Yeh,
Ling-Ping Lai,
Eric Y. Chuang,
Ilaria Rivolta,
Charles Antzelevitch
Affiliations
Jyh-Ming Jimmy Juang
Cardiovascular Center and Division of Cardiology, Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan
Anna Binda
University of Milano Bicocca School of Medicine and Surgery, Via Cadore, 48, 20900 Monza (MB), Italy
Shyh-Jye Lee
Department of Life Science, National Taiwan University, Taipei, Taiwan
Juey-Jen Hwang
Cardiovascular Center and Division of Cardiology, Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan
Wen-Jone Chen
Cardiovascular Center and Division of Cardiology, Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan
Yen-Bin Liu
Cardiovascular Center and Division of Cardiology, Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan
Lian-Yu Lin
Cardiovascular Center and Division of Cardiology, Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan
Chih-Chieh Yu
Cardiovascular Center and Division of Cardiology, Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan
Li-Ting Ho
Cardiovascular Center and Division of Cardiology, Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan
Hui-Chun Huang
Cardiovascular Center and Division of Cardiology, Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan
Ching-Yu Julius Chen
Cardiovascular Center and Division of Cardiology, Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan
Tzu-Pin Lu
Institute of Epidemiology and Preventive Medicine, National Taiwan University, Taipei, Taiwan; Department of Public Health, National Taiwan University, Taipei, Taiwan; Corresponding author at: Institute of Epidemiology and Preventive Medicine, National Taiwan University, Taipei, Taiwan.
Liang-Chuan Lai
Graduate Institute of Physiology, National Taiwan University, Taipei, Taiwan
Shih-Fan Sherri Yeh
Department of Environmental and Occupational Medicine, National Taiwan University Hospital, Hsin-Chu branch and National Taiwan University College of Medicine, Taipei, Taiwan
Ling-Ping Lai
Cardiovascular Center and Division of Cardiology, Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan
Eric Y. Chuang
Graduate Institute of Biomedical Electronics and Bioinformatics, National Taiwan University, Taipei, Taiwan
Ilaria Rivolta
University of Milano Bicocca School of Medicine and Surgery, Via Cadore, 48, 20900 Monza (MB), Italy
Charles Antzelevitch
Lankenau Institute for Medical Research and Lankenau Heart Institute, Wynnewood, PA and Sidney Kimmel Medical College of Thomas Jefferson University, Philadelphia, PA, USA; Corresponding author.
Background: Brugada syndrome (BrS) is a rare inherited disease causing sudden cardiac death (SCD). Copy number variants (CNVs) can contribute to disease susceptibility, but their role in Brugada syndrome (BrS) is unknown. We aimed to identify a CNV associated with BrS and elucidated its clinical implications. Methods: We enrolled 335 unrelated BrS patients from 2000 to 2018 in the Taiwanese population. Microarray and exome sequencing were used for discovery phase whereas Sanger sequencing was used for the validation phase. HEK cells and zebrafish were used to characterize the function of the CNV variant. Findings: A copy number deletion of GSTM3 (chr1:109737011-109737301, hg38) containing the eighth exon and the transcription stop codon was observed in 23.9% of BrS patients versus 0.8% of 15,829 controls in Taiwan Biobank (P < 0.001), and 0% in gnomAD. Co-segregation analysis showed that the co-segregation rate was 20%. Patch clamp experiments showed that in an oxidative stress environment, GSTM3 down-regulation leads to a significant decrease of cardiac sodium channel current amplitude. Ventricular arrhythmia incidence was significantly greater in gstm3 knockout zebrafish at baseline and after flecainide, but was reduced after quinidine, consistent with clinical observations. BrS patients carrying the GSTM3 deletion had higher rates of sudden cardiac arrest and syncope compared to those without (OR: 3.18 (1.77–5.74), P<0.001; OR: 1.76 (1.02–3.05), P = 0.04, respectively). Interpretation: This GSTM3 deletion is frequently observed in BrS patients and is associated with reduced INa, pointing to this as a novel potential genetic modifier/risk predictor for the development of the electrocardiographic and arrhythmic manifestations of BrS. Funding: This work was supported by the Ministry of Science and Technology (107-2314-B-002-261-MY3 to J.M.J. Juang), and by grants HL47678, HL138103 and HL152201 from the National Institutes of Health to CA.
