title: An enhancer polymorphism at the cardiomyocyte intercalated disc protein NOS1AP locus is a major regulator of the QT interval.
abstract: QT interval variation is assumed to arise from variation in repolarization as evidenced from rare Na- and K-channel mutations in Mendelian QT prolongation syndromes. However, in the general population, common noncoding variants at a chromosome 1q locus are the most common genetic regulators of QT interval variation. In this study, we use multiple human genetic, molecular genetic, and cellular assays to identify a functional variant underlying trait association: a noncoding polymorphism (rs7539120) that maps within an enhancer of NOS1AP and affects cardiac function by increasing NOS1AP transcript expression. We further localized NOS1AP to cardiomyocyte intercalated discs (IDs) and demonstrate that overexpression of NOS1AP in cardiomyocytes leads to altered cellular electrophysiology. We advance the hypothesis that NOS1AP affects cardiac electrical conductance and coupling and thereby regulates the QT interval through propagation defects. As further evidence of an important role for propagation variation affecting QT interval in humans, we show that common polymorphisms mapping near a specific set of 170 genes encoding ID proteins are significantly enriched for association with the QT interval, as compared to genome-wide markers. These results suggest that focused studies of proteins within the cardiomyocyte ID are likely to provide insights into QT prolongation and its associated disorders.
authors.affiliation: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Ashish
authors.initials: A
authors.lastname: Kapoor
authors.affiliation: Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Rajesh B
authors.initials: RB
authors.lastname: Sekar
authors.affiliation: National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA.
authors.forename: Nancy F
authors.initials: NF
authors.lastname: Hansen
authors.affiliation: Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Karen
authors.initials: K
authors.lastname: Fox-Talbot
authors.affiliation: Penn Cardiovascular Institute, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Morley
authors.affiliation: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Vasyl
authors.initials: V
authors.lastname: Pihur
authors.affiliation: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Sumantra
authors.initials: S
authors.lastname: Chatterjee
authors.affiliation: Penn Cardiovascular Institute, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Brandimarto
authors.affiliation: Department of Cardiovascular Medicine, Cleveland Clinic Foundation, Cleveland, OH 44195, USA.
authors.forename: Christine S
authors.initials: CS
authors.lastname: Moravec
authors.affiliation: University Medical Center Utrecht, Utrecht, 3584 CX, the Netherlands.
authors.forename: Sara L
authors.initials: SL
authors.lastname: Pulit
authors.affiliation: Institute of Bioinformatics and Systems Biology, Helmholtz Zentrum Munchen, Neuherberg 85764, Germany; Isar Medizin Zentrum, Sonnenstr, 24-26, 80331 Munchen, Germany.
authors.forename: Arne
authors.initials: A
authors.lastname: Pfeufer
authors.affiliation: National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA.
authors.forename: Jim
authors.initials: J
authors.lastname: Mullikin
authors.affiliation: Illumina United Kingdom, Little Chesterford, Essex, CB10 1XL, UK.
authors.forename: Mark
authors.initials: M
authors.lastname: Ross
authors.affiliation: National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA.
authors.forename: Eric D
authors.initials: ED
authors.lastname: Green
authors.affiliation: Illumina United Kingdom, Little Chesterford, Essex, CB10 1XL, UK.
authors.forename: David
authors.initials: D
authors.lastname: Bentley
authors.affiliation: Center for Human Genetic Research, Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA 02114, USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Newton-Cheh
authors.affiliation: Division of Epidemiology, Human Genetics and Environmental Sciences, University of Texas Health Science Center, Houston, TX 77030, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Boerwinkle
authors.affiliation: Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Gordon F
authors.initials: GF
authors.lastname: Tomaselli
authors.affiliation: Penn Cardiovascular Institute, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Cappola
authors.affiliation: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Dan E
authors.initials: DE
authors.lastname: Arking
authors.affiliation: Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Marc K
authors.initials: MK
authors.lastname: Halushka
authors.affiliation: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Electronic address: aravinda@jhmi.edu.
authors.forename: Aravinda
authors.initials: A
authors.lastname: Chakravarti
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000818:Animals; D015331:Cohort Studies; D004562:Electrocardiography; D005786:Gene Expression Regulation; D055106:Genome-Wide Association Study; D005838:Genotype; D057809:HEK293 Cells; D006801:Humans; D016086:Lentivirus / Q000235:genetics; D008133:Long QT Syndrome / Q000235:genetics*; D051379:Mice; D032383:Myocytes, Cardiac / Q000378:metabolism*; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci; D015027:Zebrafish / Q000196:embryology / Q000235:genetics
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C488081:NOS1AP protein, human