Genome-Wide Association Study Identifies GPC5 as a Novel Genetic Locus Protective against Sudden Cardiac Arrest

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.

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“…Thus, evidence is mounting for the GPC5 gene being a genuine susceptibility factor for MS. Recently, polymorphisms within this gene have been associated with sudden cardiac arrest 22 or lung cancer in non-smokers, 23 and variants in the adjacent GPC6 gene have also been associated with primary sclerosing cholangitis. 24 Both genes span around 3 Mb in 13q32, a chromosomal region where genomic amplification has been reported in different types of tumors.…”

Multisite haplotype on cattle chromosome 3 is associated with quantitative trait locus effects on lactation traits

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Risk Stratification for Sudden Cardiac Death

“…Unbiased scans of the human genome have provided proof of concept and potentially important insights into novel mechanisms involved in the development of CAD and acute myocardial infarction, [53][54][55] ECG surrogates, 56,57 and SCD itself. 16,58,59 The limitation to clinical applicability of these observations to date is the relatively small effect sizes of the associations identified. However, amplification of effect size by identification of enriched phenotype subgroups as well as from interactions between multiple genetic variants and clinical markers remains a realistic goal for the future, based on the hypothesis that altered gene and gene product expression-especially of genes that modify the substrate or act as triggers of malignant ventricular arrhythmias-is likely to be associated with SCD.…”