Variants in the SCN5A Promoter Associated With Various Arrhythmia Phenotypes.
Mutations in the coding sequence of SCN5A, which encodes the cardiac Na(+) channel α subunit, have been associated with inherited susceptibility to various arrhythmias. Variable expression of SCN5A is a possible mechanism responsible for this pleiotropic effect; however, it is unknown whether variants in the promoter and regulatory regions of SCN5A also modulate the risk of arrhythmias.



We resequenced the core promoter region of SCN5A and the regulatory regions of SCN5A transcription in 1298 patients with arrhythmia phenotypes (atrial fibrillation, n=444; sinus node dysfunction, n=49; conduction disease, n=133; Brugada syndrome, n=583; and idiopathic ventricular fibrillation, n=89). We identified 26 novel rare variants in the SCN5A promoter in 29 patients affected by various arrhythmias (atrial fibrillation, n=6; sinus node dysfunction, n=1; conduction disease, n=3; Brugada syndrome, n=14; idiopathic ventricular fibrillation, n=5). The frequency of rare variants was higher in patients with arrhythmias than in controls. In the alignment with chromatin immunoprecipitation sequencing data, the majority of variants were located at regions bound by transcription factors. Using a luciferase reporter assay, 6 variants (Brugada syndrome, n=3; idiopathic ventricular fibrillation, n=2; conduction disease, n=1) were functionally characterized, and each displayed decreased promoter activity compared with the wild-type sequences. We also identified rare variants in the regulatory region that were associated with atrial fibrillation, and the variant decreased promoter activity.



Variants in the core promoter region and the transcription regulatory region of SCN5A were identified in multiple arrhythmia phenotypes, consistent with the idea that altered SCN5A transcription levels modulate susceptibility to arrhythmias.
Department of Cardiovascular Biology and Medicine, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.
Nobue
N
Yagihara
Department of Cardiovascular Biology and Medicine, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan Departments of Medicine and Pharmacology, Vanderbilt University School of Medicine, Nashville, TN.
Hiroshi
H
Watanabe
Department of Anatomy, Embryology and Physiology, Academic Medical Center, Amsterdam, The Netherlands.
Phil
P
Barnett
Institut National de la Santé et de la Recherche Médicale (INSERM) Unité Mixte de Recherche (UMR) 1087, L'Institut du Thorax, Nantes, France Centre National de la Recherche Scientifique (CNRS) UMR 6291, Nantes, France Université de Nantes, France Centre Hospitalier Universitaire (CHU) Nantes, Nantes, France.
Laetitia
L
Duboscq-Bidot
Departments of Medicine and Pharmacology, Vanderbilt University School of Medicine, Nashville, TN.
Atack C
AC
Thomas
Departments of Medicine and Pharmacology, Vanderbilt University School of Medicine, Nashville, TN.
Ping
P
Yang
Department of Cardiovascular and Respiratory Medicine, Shiga University of Medical Science, Shiga, Japan.
Seiko
S
Ohno
Department of Cardiovascular Biology and Medicine, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.
Kanae
K
Hasegawa
Department of Molecular Genetics, Brain Research Institute, Niigata University, Niigata, Japan.
Ryozo
R
Kuwano
Institut National de la Santé et de la Recherche Médicale (INSERM) Unité Mixte de Recherche (UMR) 1087, L'Institut du Thorax, Nantes, France Centre National de la Recherche Scientifique (CNRS) UMR 6291, Nantes, France Université de Nantes, France Centre Hospitalier Universitaire (CHU) Nantes, Nantes, France.
Stéphanie
S
Chatel
Institut National de la Santé et de la Recherche Médicale (INSERM) Unité Mixte de Recherche (UMR) 1087, L'Institut du Thorax, Nantes, France Centre National de la Recherche Scientifique (CNRS) UMR 6291, Nantes, France Université de Nantes, France Centre Hospitalier Universitaire (CHU) Nantes, Nantes, France.
Richard
R
Redon
Institut National de la Santé et de la Recherche Médicale (INSERM) Unité Mixte de Recherche (UMR) 1087, L'Institut du Thorax, Nantes, France Centre National de la Recherche Scientifique (CNRS) UMR 6291, Nantes, France Université de Nantes, France Centre Hospitalier Universitaire (CHU) Nantes, Nantes, France.
Jean-Jacques
JJ
Schott
Institut National de la Santé et de la Recherche Médicale (INSERM) Unité Mixte de Recherche (UMR) 1087, L'Institut du Thorax, Nantes, France Centre National de la Recherche Scientifique (CNRS) UMR 6291, Nantes, France Université de Nantes, France Centre Hospitalier Universitaire (CHU) Nantes, Nantes, France.
Vincent
V
Probst
Department of Clinical and Experimental Cardiology, Academic Medical Center, Amsterdam, The Netherlands.
Tamara T
TT
Koopmann
Department of Clinical and Experimental Cardiology, Academic Medical Center, Amsterdam, The Netherlands.
Connie R
CR
Bezzina
Department of Clinical and Experimental Cardiology, Academic Medical Center, Amsterdam, The Netherlands Princess Al-Jawhara Al-Brahim Centre of Excellence in Research of Hereditary Disorders, Jeddah, Kingdom of Saudi Arabia.
Arthur A M
AA
Wilde
Division of Frontier Medical Science, Department of Cardiovascular Medicine, Programs for Biomedical Research, Graduate School of Biomedical Science, Hiroshima University, Hiroshima, Japan.
Yukiko
Y
Nakano
Division of Arrhythmia and Electrophysiology, Department of Cardiovascular Medicine, National Cerebral and Cardiovascular Center, Suita, Japan.
Takeshi
T
Aiba
Division of Arrhythmia and Electrophysiology, Department of Cardiovascular Medicine, National Cerebral and Cardiovascular Center, Suita, Japan.
Yoshihiro
Y
Miyamoto
Division of Arrhythmia and Electrophysiology, Department of Cardiovascular Medicine, National Cerebral and Cardiovascular Center, Suita, Japan.
Shiro
S
Kamakura
Departments of Medicine and Pharmacology, Vanderbilt University School of Medicine, Nashville, TN University of Illinois at Chicago, IL.
Dawood
D
Darbar
Departments of Medicine and Pharmacology, Vanderbilt University School of Medicine, Nashville, TN.
Brian S
BS
Donahue
Department of Medical Science Mathematics, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan Laboratory for Medical Science Mathematics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
Daichi
D
Shigemizu
Department of Human Genetics and Disease Diversity, Tokyo Medical and Dental University, Tokyo, Japan.
Toshihiro
T
Tanaka
Department of Medical Science Mathematics, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan Laboratory for Medical Science Mathematics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
Tatsuhiko
T
Tsunoda
Department of Cardiovascular Biology and Medicine, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.
Masayoshi
M
Suda
Department of Cardiovascular Biology and Medicine, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.
Akinori
A
Sato
Department of Cardiovascular Biology and Medicine, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.
Tohru
T
Minamino
Division of Orthopedic Surgery, Brain Research Institute, Niigata University, Niigata, Japan Center for the Inter-organ Communication Research, Brain Research Institute, Niigata University, Niigata, Japan.
Naoto
N
Endo
Division of Arrhythmia and Electrophysiology, Department of Cardiovascular Medicine, National Cerebral and Cardiovascular Center, Suita, Japan Department of Cardiovascular Medicine, Nippon Medical School, Tokyo, Japan.
Wataru
W
Shimizu
Department of Cardiovascular and Respiratory Medicine, Shiga University of Medical Science, Shiga, Japan.
Minoru
M
Horie
Departments of Medicine and Pharmacology, Vanderbilt University School of Medicine, Nashville, TN.
Dan M
DM
Roden
Department of Molecular Physiology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan makitan@nagasaki-u.ac.jp.
Naomasa
N
Makita
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001145:Arrhythmias, Cardiac / Q000235:genetics; D001281:Atrial Fibrillation / Q000235:genetics*; D053840:Brugada Syndrome / Q000235:genetics*; D000075224:Cardiac Conduction System Disease / Q000235:genetics*; D002648:Child; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D062554:NAV1.5 Voltage-Gated Sodium Channel / Q000235:genetics*; D010641:Phenotype; D011401:Promoter Regions, Genetic / Q000235:genetics; D012804:Sick Sinus Syndrome / Q000235:genetics*; D014693:Ventricular Fibrillation / Q000235:genetics*; D055815:Young Adult
D062554:NAV1.5 Voltage-Gated Sodium Channel; C568320:SCN5A protein, human
arrhythmias; genetics; ion channels; sodium channels; transcription