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

Heinrich Wieneke, Jesper Hastrup Svendsen, Jeffrey Lande, Sebastian Spencker, Juan Gabriel Martinez, Bernhard Strohmer, Lauri Toivonen, Hervé Le Marec, F Javier Garcia-Fernandez, Domenico Corrado, Adriana Huertas-Vazquez, Audrey Uy-Evanado, Carmen Rusinaru, Kyndaron Reinier, Csaba Foldesi, Wieslaw Hulak, Sumeet S Chugh, Winfried Siffert, Heinrich Wieneke, Jesper Hastrup Svendsen, Jeffrey Lande, Sebastian Spencker, Juan Gabriel Martinez, Bernhard Strohmer, Lauri Toivonen, Hervé Le Marec, F Javier Garcia-Fernandez, Domenico Corrado, Adriana Huertas-Vazquez, Audrey Uy-Evanado, Carmen Rusinaru, Kyndaron Reinier, Csaba Foldesi, Wieslaw Hulak, Sumeet S Chugh, Winfried Siffert

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.

© 2016 The Authors and Medtronic. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.

Figures

Figure 1
Figure 1
Study overview. ARVC indicates… ; ICD, implantable cardioverter‐defibrillator; VT, ventricular tachyarrhythmias
Figure 2
Figure 2
Kaplan‐Meier estimates of time to first VT episodes for c.393C>T (A) and c.2273C>T (B) separately. Hazard ratio (HR) and P‐value are shown as derived from a Cox regression model including genotype as ordinal variable, counting the number of T alleles. (C), Kaplan‐Meier estimates of time to first VT episodes for combined effects of c.393C>T/c.2273C>T. Hazard ratio (HR) and P‐value are shown as derived from a Cox regression model including genotype as ordinal variable, counting the number of T alleles.

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