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

Research output: Contribution to journalJournal articleResearchpeer-review

  • Heinrich Wieneke
  • Svendsen, Jesper Hastrup
  • 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

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, acommunity-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.

Original languageEnglish
Article numbere003905
JournalJournal of the American Heart Association
Issue number12
Number of pages35
Publication statusPublished - 2016
Externally publishedYes

    Research areas

  • Arrhythmia, G proteins, Implantable cardioverter-defibrillator, Single nucleotide polymorphism, Sudden cardiac death, Ventricular tachycardia arrhythmia

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