TY - JOUR
T1 - Polymorphisms in the GNAS Gene as Predictors of Ventricular Tachyarrhythmias and Sudden Cardiac Death
T2 - Results From the DISCOVERY Trial and Oregon Sudden Unexpected Death Study
AU - Wieneke, Heinrich
AU - Svendsen, Jesper Hastrup
AU - Lande, Jeffrey
AU - Spencker, Sebastian
AU - Martinez, Juan Gabriel
AU - Strohmer, Bernhard
AU - Toivonen, Lauri
AU - Le Marec, Hervé
AU - Garcia-Fernandez, F Javier
AU - Corrado, Domenico
AU - Huertas-Vazquez, Adriana
AU - Uy-Evanado, Audrey
AU - Rusinaru, Carmen
AU - Reinier, Kyndaron
AU - Foldesi, Csaba
AU - Hulak, Wieslaw
AU - Chugh, Sumeet S
AU - Siffert, Winfried
N1 - © 2016 The Authors and Medtronic. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.
PY - 2016/11/28
Y1 - 2016/11/28
N2 - 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.
AB - 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.
U2 - 10.1161/JAHA.116.003905
DO - 10.1161/JAHA.116.003905
M3 - Journal article
C2 - 27895044
SN - 2047-9980
VL - 5
SP - e003905
JO - Journal of the American Heart Association
JF - Journal of the American Heart Association
IS - 12
ER -