title: Genome-wide association study identifies GPC5 as a novel genetic locus protective against sudden cardiac arrest.
abstract: BACKGROUND
  Existing studies indicate a significant genetic component for sudden cardiac arrest (SCA) and genome-wide association studies (GWAS) provide an unbiased approach for identification of novel genes. We performed a GWAS to identify genetic determinants of SCA.
  
  
  RESULTS
  We used a case-control design within the ongoing Oregon Sudden Unexpected Death Study (Oregon-SUDS). Cases (n = 424) were SCAs with coronary artery disease (CAD) among residents of Portland, OR (2002-07, population approximately 1,000,000) and controls (n = 226) were residents with CAD, but no history of SCA. All subjects were of White-European ancestry and GWAS was performed using Affymetrix 500K/5.0 and 6.0 arrays. High signal markers were genotyped in SCA cases (n = 521) identified from the Atherosclerosis Risk in Communities Study (ARIC) and the Cardiovascular Health Study (CHS) (combined n = 19,611). No SNPs reached genome-wide significance (p<5x10(-8)). SNPs at 6 loci were prioritized for follow-up primarily based on significance of p<10(-4) and proximity to a known gene (CSMD2, GPR37L1, LIN9, B4GALNT3, GPC5, and ZNF592). The minor allele of GPC5 (GLYPICAN 5, rs3864180) was associated with a lower risk of SCA in Oregon-SUDS, an effect that was also observed in ARIC/CHS whites (p<0.05) and blacks (p<0.04). In a combined Cox proportional hazards model analysis that adjusted for race, the minor allele exhibited a hazard ratio of 0.85 (95% CI 0.74 to 0.98; p<0.01).
  
  
  CONCLUSIONS
  A novel genetic locus for SCA, GPC5, was identified from Oregon-SUDS and successfully validated in the ARIC and CHS cohorts. Three other members of the Glypican family have been previously implicated in human disease, including cardiac conditions. The mechanism of this specific association requires further study.
authors.affiliation: Center for Complex Diseases Genomics, McKusick-Nathans Institute of Genetic Medicine, the Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: Dan E
authors.initials: DE
authors.lastname: Arking
authors.forename: Kyndaron
authors.initials: K
authors.lastname: Reinier
authors.forename: Wendy
authors.initials: W
authors.lastname: Post
authors.forename: Jonathan
authors.initials: J
authors.lastname: Jui
authors.forename: Gina
authors.initials: G
authors.lastname: Hilton
authors.forename: Ashley
authors.initials: A
authors.lastname: O'Connor
authors.forename: Ronald J
authors.initials: RJ
authors.lastname: Prineas
authors.forename: Eric
authors.initials: E
authors.lastname: Boerwinkle
authors.forename: Bruce M
authors.initials: BM
authors.lastname: Psaty
authors.forename: Gordon F
authors.initials: GF
authors.lastname: Tomaselli
authors.forename: Thomas
authors.initials: T
authors.lastname: Rea
authors.forename: Nona
authors.initials: N
authors.lastname: Sotoodehnia
authors.forename: David S
authors.initials: DS
authors.lastname: Siscovick
authors.forename: Gregory L
authors.initials: GL
authors.lastname: Burke
authors.forename: Eduardo
authors.initials: E
authors.lastname: Marban
authors.forename: Peter M
authors.initials: PM
authors.lastname: Spooner
authors.forename: Aravinda
authors.initials: A
authors.lastname: Chakravarti
authors.forename: Sumeet S
authors.initials: SS
authors.lastname: Chugh
mesh_terms: D000368:Aged; D000483:Alleles; D016022:Case-Control Studies; D015331:Cohort Studies; D016757:Death, Sudden, Cardiac / Q000517:prevention & control*; D005006:Ethnicity; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D053673:Glypicans / Q000235:genetics*; D006331:Heart Diseases / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D008957:Models, Genetic; D020411:Oligonucleotide Array Sequence Analysis; D009922:Oregon; D020641:Polymorphism, Single Nucleotide
chemical_list: C106228:GPC5 protein, human; D053673:Glypicans