{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T05:02:06Z","timestamp":1790744526310,"version":"4.1.0"},"reference-count":52,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"9","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["JAHA"],"published-print":{"date-parts":[[2016,9]]},"abstract":"\n Background<\/jats:title>\n \n Mutations in the coding sequence of\n \n SCN<\/jats:styled-content>\n 5A\n <\/jats:italic>\n , which encodes the cardiac Na\n +<\/jats:sup>\n channel \u03b1 subunit, have been associated with inherited susceptibility to various arrhythmias. Variable expression of\n \n SCN<\/jats:styled-content>\n 5A\n <\/jats:italic>\n is a possible mechanism responsible for this pleiotropic effect; however, it is unknown whether variants in the promoter and regulatory regions of\n \n SCN<\/jats:styled-content>\n 5A\n <\/jats:italic>\n also modulate the risk of arrhythmias.\n <\/jats:p>\n <\/jats:sec>\n \n Methods and Results<\/jats:title>\n \n We resequenced the core promoter region of\n \n SCN<\/jats:styled-content>\n 5A\n <\/jats:italic>\n and the regulatory regions of\n \n SCN<\/jats:styled-content>\n 5A\n <\/jats:italic>\n 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\n \n SCN<\/jats:styled-content>\n 5A\n <\/jats:italic>\n 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\u00a0higher in patients with arrhythmias than in controls. In the alignment with chromatin immunoprecipitation sequencing\u00a0data, 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\u00a0characterized, and each displayed decreased promoter activity compared with the wild\u2010type sequences. We also identified rare variants in the regulatory region that were associated with atrial fibrillation, and the variant decreased promoter activity.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions<\/jats:title>\n \n Variants in the core promoter region and the transcription regulatory region of\n \n SCN<\/jats:styled-content>\n 5A\n <\/jats:italic>\n were identified in multiple arrhythmia phenotypes, consistent with the idea that altered\n \n SCN<\/jats:styled-content>\n 5A\n <\/jats:italic>\n transcription levels modulate susceptibility to arrhythmias.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1161\/jaha.116.003644","type":"journal-article","created":{"date-parts":[[2016,9,14]],"date-time":"2016-09-14T01:39:23Z","timestamp":1473817163000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":29,"title":["Variants in the\n SCN5A<\/i>\n Promoter Associated With Various Arrhythmia Phenotypes"],"prefix":"10.1161","volume":"5","author":[{"given":"Nobue","family":"Yagihara","sequence":"first","affiliation":[{"name":"Department of Cardiovascular Biology and Medicine, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroshi","family":"Watanabe","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Biology and Medicine, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan"},{"name":"Departments of Medicine and Pharmacology, Vanderbilt University School of Medicine, Nashville, TN"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Phil","family":"Barnett","sequence":"additional","affiliation":[{"name":"Department of Anatomy, Embryology and Physiology, Academic Medical Center, Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laetitia","family":"Duboscq\u2010Bidot","sequence":"additional","affiliation":[{"name":"Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale (INSERM) Unit\u00e9 Mixte de Recherche (UMR) 1087, L'Institut du Thorax, Nantes, France"},{"name":"Centre National de la Recherche Scientifique (CNRS) UMR 6291, Nantes, France"},{"name":"Universit\u00e9 de Nantes, France"},{"name":"Centre Hospitalier Universitaire (CHU) Nantes, Nantes, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Atack C.","family":"Thomas","sequence":"additional","affiliation":[{"name":"Departments of Medicine and Pharmacology, Vanderbilt University School of Medicine, Nashville, TN"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ping","family":"Yang","sequence":"additional","affiliation":[{"name":"Departments of Medicine and Pharmacology, Vanderbilt University School of Medicine, Nashville, 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