Genome-wide association study identifies GPC5 as a novel genetic locus protective against sudden cardiac arrest

Dan E. Arking, Kyndaron Reinier, Wendy Post, Jonathan Jui, Gina Hilton, Ashley O'Connor, Ronald J. Prineas, Eric Boerwinkle, Bruce M. Psaty, Gordon F. Tomaselli, Thomas Rea, Nona Sotoodehnia, David S. Siscovick, Gregory L. Burke, Eduardo Marban, Peter M. Spooner, Aravinda Chakravarti, Sumeet S. Chugh

Research output: Contribution to journalArticle

48 Scopus citations

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. Methodology/Principal Findings: 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 ~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/Significance: 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. Copyright:

Original languageEnglish (US)
Article numbere9879
JournalPloS one
Volume5
Issue number3
DOIs
StatePublished - 2010

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

Fingerprint Dive into the research topics of 'Genome-wide association study identifies GPC5 as a novel genetic locus protective against sudden cardiac arrest'. Together they form a unique fingerprint.

  • Cite this

    Arking, D. E., Reinier, K., Post, W., Jui, J., Hilton, G., O'Connor, A., Prineas, R. J., Boerwinkle, E., Psaty, B. M., Tomaselli, G. F., Rea, T., Sotoodehnia, N., Siscovick, D. S., Burke, G. L., Marban, E., Spooner, P. M., Chakravarti, A., & Chugh, S. S. (2010). Genome-wide association study identifies GPC5 as a novel genetic locus protective against sudden cardiac arrest. PloS one, 5(3), [e9879]. https://doi.org/10.1371/journal.pone.0009879