Yukiko Nakano1, Hidenori Ochi2, Yuko Onohara2, Masaaki Toshishige2, Takehito Tokuyama2, Hiroya Matsumura2, Hiroshi Kawazoe2, Shunsuke Tomomori2, Akinori Sairaku2, Yoshikazu Watanabe2, Hiroki Ikenaga2, Chikaaki Motoda2, Kazuyoshi Suenari2, Yasufumi Hayashida2, Daiki Miki2, Nozomu Oda2, Shinji Kishimoto2, Noboru Oda2, Yukihiko Yoshida2, Satoshi Tashiro2, Kazuaki Chayama2, Yasuki Kihara2. 1. From the Department of Cardiovascular Medicine, Hiroshima University Graduate School of Biomedical & Health Sciences, Hiroshima, Japan (A.S., C.M., H.I., H.K., H.M., K.S., M.T., Noboru Oda, Nozomu Oda, S. Tomomori, S.K., T.T., Y. O., Y.K., Y.N., Y.W.); Laboratory for Digestive Diseases, Center for Integrative Medical Sciences, RIKEN, Hiroshima, Japan (D.M., H.O., K.C., Y.N.); Division of Frontier Medical Science, Department of Gastroenterology and Metabolism, Programs for Biomedical Research Graduate School of Biomedical Science (H.O., K.C., Y.H.), and Department of Cellular Biology, Research Institute for Radiation Biology and Medicine (S. Tashiro), Hiroshima University, Hiroshima, Japan; and Division of Cardiology, Nagoya Daini Red Cross Hospital, Nagoya, Japan (Y.Y.) nakanoy@hiroshima-u.ac.jp. 2. From the Department of Cardiovascular Medicine, Hiroshima University Graduate School of Biomedical & Health Sciences, Hiroshima, Japan (A.S., C.M., H.I., H.K., H.M., K.S., M.T., Noboru Oda, Nozomu Oda, S. Tomomori, S.K., T.T., Y. O., Y.K., Y.N., Y.W.); Laboratory for Digestive Diseases, Center for Integrative Medical Sciences, RIKEN, Hiroshima, Japan (D.M., H.O., K.C., Y.N.); Division of Frontier Medical Science, Department of Gastroenterology and Metabolism, Programs for Biomedical Research Graduate School of Biomedical Science (H.O., K.C., Y.H.), and Department of Cellular Biology, Research Institute for Radiation Biology and Medicine (S. Tashiro), Hiroshima University, Hiroshima, Japan; and Division of Cardiology, Nagoya Daini Red Cross Hospital, Nagoya, Japan (Y.Y.).
Abstract
BACKGROUND: Risk stratification of Brugada syndrome (BrS) remains controversial and the majority of patients with BrS have no genetic explanation. We investigated relationships between genotypes of 3 single-nucleotide polymorphisms reported in a recent genome-wide association study and BrS phenotypes. METHODS AND RESULTS: SCN10A (rs10428132), SCN5A (rs11708996), and downstream from HEY2 (rs9388451) single-nucleotide polymorphisms were genotyped and compared between 95 Japanese patients with BrS and 1978 controls. Relationships between the single-nucleotide polymorphisms and clinical characteristics, 12-lead ECG findings, signal-averaged ECG findings, and electrophysiological parameters were also examined in patients with BrS. Both rs10428132 and rs9388451 were significantly associated with BrS (P=2.7×10(-14); odds ratio, 3.0; P=9.2×10(-4); 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(-2); odds ratio, 0.5). A significant linear correlation was found between HEY2 genotypes and QTc interval (CC: 422±27 ms; CT: 408±21 ms; and TT: 381±27 ms; P= 4.0×10(-4)). 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.
BACKGROUND: Risk stratification of Brugada syndrome (BrS) remains controversial and the majority of patients with BrS have no genetic explanation. We investigated relationships between genotypes of 3 single-nucleotide polymorphisms reported in a recent genome-wide association study and BrS phenotypes. METHODS AND RESULTS:SCN10A (rs10428132), SCN5A (rs11708996), and downstream from HEY2 (rs9388451) single-nucleotide polymorphisms were genotyped and compared between 95 Japanese patients with BrS and 1978 controls. Relationships between the single-nucleotide polymorphisms and clinical characteristics, 12-lead ECG findings, signal-averaged ECG findings, and electrophysiological parameters were also examined in patients with BrS. Both rs10428132 and rs9388451 were significantly associated with BrS (P=2.7×10(-14); odds ratio, 3.0; P=9.2×10(-4); 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(-2); odds ratio, 0.5). A significant linear correlation was found between HEY2 genotypes and QTc interval (CC: 422±27 ms; CT: 408±21 ms; and TT: 381±27 ms; P= 4.0×10(-4)). 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.
Authors: Mel Lina Pinsach-Abuin; Bernat Del Olmo; Adrian Pérez-Agustin; Jesus Mates; Catarina Allegue; Anna Iglesias; Qi Ma; Daria Merkurjev; Sergiy Konovalov; Jing Zhang; Farah Sheikh; Amalio Telenti; Josep Brugada; Ramon Brugada; Melissa Gymrek; Julia di Iulio; Ivan Garcia-Bassets; Sara Pagans Journal: Cell Rep Med Date: 2021-04-20
Authors: Jean-Baptiste Gourraud; Julien Barc; Aurélie Thollet; Solena Le Scouarnec; Hervé Le Marec; Jean-Jacques Schott; Richard Redon; Vincent Probst Journal: Front Cardiovasc Med Date: 2016-04-25