title: From GWAS to function: genetic variation in sodium channel gene enhancer influences electrical patterning.
abstract: The electrical activity of the heart depends on the correct interplay between key transcription factors and cis-regulatory elements, which together regulate the proper heterogeneous expression of genes encoding for ion channels and other proteins. Genome-wide association studies of ECG parameters implicated genetic variants in the genes for these factors and ion channels modulating conduction and depolarization. Here, we review recent insights into the regulation of localized expression of ion channel genes and the mechanism by which a single-nucleotide polymorphism (SNP) associated with alterations in cardiac conduction patterns in humans affects the transcriptional regulation of the sodium channel genes, SCN5A and SCN10A. The identification of regulatory elements of electrical activity genes helps to explain the impact of genetic variants in non-coding regulatory DNA sequences on regulation of cardiac conduction and the predisposition for cardiac arrhythmias.
authors.affiliation: Department of Anatomy, Embryology and Physiology, Heart Failure Research Center, Academic Medical Center, University of Amsterdam, Meibergdreef 15, 1105 AZ, Amsterdam, the Netherlands.
authors.forename: Malou
authors.initials: M
authors.lastname: van den Boogaard
authors.affiliation: Department of Anatomy, Embryology and Physiology, Heart Failure Research Center, Academic Medical Center, University of Amsterdam, Meibergdreef 15, 1105 AZ, Amsterdam, the Netherlands.
authors.forename: Phil
authors.initials: P
authors.lastname: Barnett
authors.affiliation: Department of Anatomy, Embryology and Physiology, Heart Failure Research Center, Academic Medical Center, University of Amsterdam, Meibergdreef 15, 1105 AZ, Amsterdam, the Netherlands. Electronic address: v.m.christoffels@amc.uva.nl.
authors.forename: Vincent M
authors.initials: VM
authors.lastname: Christoffels
mesh_terms: D001145:Arrhythmias, Cardiac / Q000235:genetics*; D006801:Humans; D062554:NAV1.5 Voltage-Gated Sodium Channel / Q000235:genetics*; D062559:NAV1.8 Voltage-Gated Sodium Channel / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*
chemical_list: D062554:NAV1.5 Voltage-Gated Sodium Channel; D062559:NAV1.8 Voltage-Gated Sodium Channel; C568317:SCN10A protein, human; C568320:SCN5A protein, human