title: GWAS for discovery and replication of genetic loci associated with sudden cardiac arrest in patients with coronary artery disease.
abstract: BACKGROUND
  Epidemiologic evidence suggests a heritable component to risk for sudden cardiac arrest independent of risk for myocardial infarction. Recent candidate gene association studies for community sudden cardiac arrests have focused on a limited number of biological pathways and yielded conflicting results. We sought to identify novel gene associations for sudden cardiac arrest in patients with coronary artery disease by performing a genome-wide association study.
  
  
  METHODS
  Tagging SNPs (n = 338,328) spanning the genome were typed in a case-control study comparing 89 patients with coronary artery disease and sudden cardiac arrest due to ventricular tachycardia or ventricular fibrillation to 520 healthy controls.
  
  
  RESULTS
  Fourteen SNPs including 7 SNPs among 7 genes (ACYP2, AP1G2, ESR1, DGES2, GRIA1, KCTD1, ZNF385B) were associated with sudden cardiac arrest (all p < 1.30 × 10(-7)), following Bonferroni correction and adjustment for population substructure, age, and sex; genetic variation in ESR1 (p = 2.62 × 10(-8); Odds Ratio [OR] = 1.43, 95% confidence interval [CI]:1.277, 1.596) has previously been established as a risk factor for cardiovascular disease. In tandem, the role of 9 genes for monogenic long QT syndrome (LQT1-9) was assessed, yielding evidence of association with CACNA1C (LQT8; p = 3.09 × 10(-4); OR = 1.18, 95% CI:1.079, 1.290). We also assessed 4 recently published gene associations for sudden cardiac arrest, validating NOS1AP (p = 4.50 × 10(-2), OR = 1.15, 95% CI:1.003, 1.326), CSMD2 (p = 6.6 × 10(-3), OR = 2.27, 95% CI:1.681, 2.859), and AGTR1 (p = 3.00 × 10(-3), OR = 1.13, 95% CI:1.042, 1.215).
  
  
  CONCLUSIONS
  We demonstrate 11 gene associations for sudden cardiac arrest due to ventricular tachycardia/ventricular fibrillation in patients with coronary artery disease. Validation studies in independent cohorts and functional studies are required to confirm these associations.
authors.affiliation: Department of Physiological Nursing, Institute for Human Genetics, University of California, San Francisco, 94143, USA.
authors.forename: Bradley E
authors.initials: BE
authors.lastname: Aouizerat
authors.forename: Eric
authors.initials: E
authors.lastname: Vittinghoff
authors.forename: Stacy L
authors.initials: SL
authors.lastname: Musone
authors.forename: Ludmila
authors.initials: L
authors.lastname: Pawlikowska
authors.forename: Pui-Yan
authors.initials: PY
authors.lastname: Kwok
authors.forename: Jeffrey E
authors.initials: JE
authors.lastname: Olgin
authors.forename: Zian H
authors.initials: ZH
authors.lastname: Tseng
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D016022:Case-Control Studies; D003324:Coronary Artery Disease / Q000235:genetics* / Q000401:mortality*; D016757:Death, Sudden, Cardiac / Q000453:epidemiology*; D005260:Female; D056426:Genetic Loci / Q000235:genetics*; D055106:Genome-Wide Association Study / Q000379:methods; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D010865:Pilot Projects; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*