Abstract
BackgroundExisting 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.Methodology/Principal FindingsWe 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 ∼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<5×10−8). 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/SignificanceA 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.
Highlights
Sudden cardiac arrest (SCA) claims 250,000–300,000 lives in the US and 4–5 million around the world, on an annual basis [1]
SUDS genome-wide association studies (GWAS) were both predominantly male (72.9% vs. 68.6%, p = 0.25), while case subjects were younger than controls (59.4612.3 vs. 63.269.9 yrs, p,0.0001); 75% of cases and 90% of controls were age 50 or older (p,0.0001)
All subjects included in the Oregon-SUDS GWAS were white, based on inclusion criteria
Summary
Sudden cardiac arrest (SCA) claims 250,000–300,000 lives in the US and 4–5 million around the world, on an annual basis [1]. Risk stratification for SCA is an area of active investigation, but available techniques do not identify the vast majority of subjects at risk [3]. Further advancements in this field await the discovery of novel mechanisms related to ventricular arrhythmogenesis. We successfully used a GWAS to identify novel determinants of the QT interval These variants in NOS1AP were subsequently tested and found to be associated with risk for SCA in the general population [9]. 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
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