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J Am Heart Assoc. 2016 Nov 28;5(12). pii: e003905.

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.

Author information

1
Department of Cardiology, Contilia Heart and Vessel Centre, St. Marien-Hospital Mülheim, Mülheim, Germany heinrich.wieneke@t-online.de.
2
Department of Cardiology, Rigshospitalet, Copenhagen, Denmark.
3
Medtronic plc, Mounds View, MN.
4
Department of Cardiology, DRK Kliniken Berlin I Köpenick, Berlin, Germany.
5
Department of Cardiology, Hospital General Universitario de Alicante, Spain.
6
Department of Cardiology, Salzburger Landeskliniken, Paracelsus Private Medical University, Salzburg, Austria.
7
Department of Cardiovascular Research, Meilahden Sairaala, Helsinki, Finland.
8
Department of Cardiology and Vascular Medicine, Hospital Guillaume et René Laennec, Nantes, France.
9
Electrophysiology Department, Hospital Universitario de Burgos, Burgos, Spain.
10
Department of Cardiac, Thoracic, and Vascular Sciences, Medical School, University of Padua, Padua, Italy.
11
Cedars Sinai Medical Center, Los Angeles, CA.
12
Gottsegen National Institute of Cardiology, Budapest, Hungary.
13
Samodzielny Publiczny Szpital Wojewódzki Gorzowie Wielkopolski, Gorzow, Poland.
14
Institute of Pharmacogenetics, University Hospital Essen, Essen, Germany.

Abstract

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.

KEYWORDS:

G proteins; arrhythmia; implantable cardioverter‐defibrillator; single nucleotide polymorphism; sudden cardiac death; ventricular tachycardia arrhythmia

PMID:
27895044
PMCID:
PMC5210425
DOI:
10.1161/JAHA.116.003905
[Indexed for MEDLINE]
Free PMC Article

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