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.

Autor: Wieneke H; Department of Cardiology, Contilia Heart and Vessel Centre, St. Marien-Hospital Mülheim, Mülheim, Germany heinrich.wieneke@t-online.de., Svendsen JH; Department of Cardiology, Rigshospitalet, Copenhagen, Denmark., Lande J; Medtronic plc, Mounds View, MN., Spencker S; Department of Cardiology, DRK Kliniken Berlin I Köpenick, Berlin, Germany., Martinez JG; Department of Cardiology, Hospital General Universitario de Alicante, Spain., Strohmer B; Department of Cardiology, Salzburger Landeskliniken, Paracelsus Private Medical University, Salzburg, Austria., Toivonen L; Department of Cardiovascular Research, Meilahden Sairaala, Helsinki, Finland., Le Marec H; Department of Cardiology and Vascular Medicine, Hospital Guillaume et René Laennec, Nantes, France., Garcia-Fernandez FJ; Electrophysiology Department, Hospital Universitario de Burgos, Burgos, Spain., Corrado D; Department of Cardiac, Thoracic, and Vascular Sciences, Medical School, University of Padua, Padua, Italy., Huertas-Vazquez A; Cedars Sinai Medical Center, Los Angeles, CA., Uy-Evanado A; Cedars Sinai Medical Center, Los Angeles, CA., Rusinaru C; Cedars Sinai Medical Center, Los Angeles, CA., Reinier K; Cedars Sinai Medical Center, Los Angeles, CA., Foldesi C; Gottsegen National Institute of Cardiology, Budapest, Hungary., Hulak W; Samodzielny Publiczny Szpital Wojewódzki Gorzowie Wielkopolski, Gorzow, Poland., Chugh SS; Cedars Sinai Medical Center, Los Angeles, CA., Siffert W; Institute of Pharmacogenetics, University Hospital Essen, Essen, Germany.
Jazyk: angličtina
Zdroj: Journal of the American Heart Association [J Am Heart Assoc] 2016 Nov 28; Vol. 5 (12). Date of Electronic Publication: 2016 Nov 28.
DOI: 10.1161/JAHA.116.003905
Abstrakt: Background: Population-based studies suggest that genetic factors contribute to sudden cardiac death (SCD).
Methods and Results: 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.
Conclusions: 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.
Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00478933.
(© 2016 The Authors and Medtronic. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.)
Databáze: MEDLINE
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