title: Polymorphisms in the GNAS Gene as Predictors of Ventricular Tachyarrhythmias and Sudden Cardiac Death: Results From the DISCOVERY Trial and Oregon Sudden Unexpected Death Study.
abstract: Population-based studies suggest that genetic factors contribute to sudden cardiac death (SCD).
  
  
  
  In the first part of the present study (Diagnostic Data Influence on Disease Management and Relation of Genetic Polymorphisms to Ventricular Tachy-arrhythmia in ICD Patients [DISCOVERY] trial) Cox regression was done to determine if 7 single-nucleotide polymorphisms (SNPs) in 3 genes coding G-protein subunits (GNB3, GNAQ, GNAS) were associated with ventricular tachyarrhythmia (VT) in 1145 patients receiving an implantable cardioverter-defibrillator (ICD). In the second part of the study, SNPs significantly associated with VT were further investigated in 1335 subjects from the Oregon SUDS, a community-based study analyzing causes of SCD. In the DISCOVERY trial, genotypes of 2 SNPs in the GNAS gene were nominally significant in the prospective screening and significantly associated with VT when viewed as recessive traits in post hoc analyses (TT vs CC/CT in c.393C>T: HR 1.42 [CI 1.11-1.80], P=0.005; TT vs CC/CT in c.2273C>T: HR 1.57 [CI 1.18-2.09], P=0.002). TT genotype in either SNP was associated with a HR of 1.58 (CI 1.26-1.99) (P=0.0001). In the Oregon SUDS cohort significant evidence for association with SCD was observed for GNAS c.393C>T under the additive (P=0.039, OR=1.21 [CI 1.05-1.45]) and recessive (P=0.01, OR=1.52 [CI 1.10-2.13]) genetic models.
  
  
  
  GNAS harbors 2 SNPs that were associated with an increased risk for VT in ICD patients, of which 1 was successfully replicated in a community-based population of SCD cases. To the best of our knowledge, this is the first example of a gene variant identified by ICD VT monitoring as a surrogate parameter for SCD and also confirmed in the general population.
  
  
  
  URL: http://www.clinicaltrials.gov. Unique identifier: NCT00478933.
authors.affiliation: Department of Cardiology, Contilia Heart and Vessel Centre, St. Marien-Hospital Mülheim, Mülheim, Germany heinrich.wieneke@t-online.de.
authors.forename: Heinrich
authors.initials: H
authors.lastname: Wieneke
authors.affiliation: Department of Cardiology, Rigshospitalet, Copenhagen, Denmark.
authors.forename: Jesper Hastrup
authors.initials: JH
authors.lastname: Svendsen
authors.affiliation: Medtronic plc, Mounds View, MN.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Lande
authors.affiliation: Department of Cardiology, DRK Kliniken Berlin I Köpenick, Berlin, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Spencker
authors.affiliation: Department of Cardiology, Hospital General Universitario de Alicante, Spain.
authors.forename: Juan Gabriel
authors.initials: JG
authors.lastname: Martinez
authors.affiliation: Department of Cardiology, Salzburger Landeskliniken, Paracelsus Private Medical University, Salzburg, Austria.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Strohmer
authors.affiliation: Department of Cardiovascular Research, Meilahden Sairaala, Helsinki, Finland.
authors.forename: Lauri
authors.initials: L
authors.lastname: Toivonen
authors.affiliation: Department of Cardiology and Vascular Medicine, Hospital Guillaume et René Laennec, Nantes, France.
authors.forename: Hervé
authors.initials: H
authors.lastname: Le Marec
authors.affiliation: Electrophysiology Department, Hospital Universitario de Burgos, Burgos, Spain.
authors.forename: F Javier
authors.initials: FJ
authors.lastname: Garcia-Fernandez
authors.affiliation: Department of Cardiac, Thoracic, and Vascular Sciences, Medical School, University of Padua, Padua, Italy.
authors.forename: Domenico
authors.initials: D
authors.lastname: Corrado
authors.affiliation: Cedars Sinai Medical Center, Los Angeles, CA.
authors.forename: Adriana
authors.initials: A
authors.lastname: Huertas-Vazquez
authors.affiliation: Cedars Sinai Medical Center, Los Angeles, CA.
authors.forename: Audrey
authors.initials: A
authors.lastname: Uy-Evanado
authors.affiliation: Cedars Sinai Medical Center, Los Angeles, CA.
authors.forename: Carmen
authors.initials: C
authors.lastname: Rusinaru
authors.affiliation: Cedars Sinai Medical Center, Los Angeles, CA.
authors.forename: Kyndaron
authors.initials: K
authors.lastname: Reinier
authors.affiliation: Gottsegen National Institute of Cardiology, Budapest, Hungary.
authors.forename: Csaba
authors.initials: C
authors.lastname: Foldesi
authors.affiliation: Samodzielny Publiczny Szpital Wojewódzki Gorzowie Wielkopolski, Gorzow, Poland.
authors.forename: Wieslaw
authors.initials: W
authors.lastname: Hulak
authors.affiliation: Cedars Sinai Medical Center, Los Angeles, CA.
authors.forename: Sumeet S
authors.initials: SS
authors.lastname: Chugh
authors.affiliation: Institute of Pharmacogenetics, University Hospital Essen, Essen, Germany.
authors.forename: Winfried
authors.initials: W
authors.lastname: Siffert
mesh_terms: D000368:Aged; D002864:Chromogranins / Q000235:genetics*; D015331:Cohort Studies; D016757:Death, Sudden, Cardiac / Q000209:etiology*; D017147:Defibrillators, Implantable; D005260:Female; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000235:genetics*; D006333:Heart Failure / Q000150:complications / Q000503:physiopathology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D016016:Proportional Hazards Models; D017180:Tachycardia, Ventricular / Q000209:etiology / Q000235:genetics* / Q000628:therapy; D014693:Ventricular Fibrillation / Q000209:etiology / Q000235:genetics* / Q000628:therapy
chemical_list: D002864:Chromogranins; C406732:GNAS protein, human; D019205:GTP-Binding Protein alpha Subunits, Gs
keywords: G proteins; arrhythmia; implantable cardioverter‐defibrillator; single nucleotide polymorphism; sudden cardiac death; ventricular tachycardia arrhythmia