TY - JOUR T1 - Genome-wide association study identifies GPC5 as a novel genetic locus protective against sudden cardiac arrest. JF - PLoS One Y1 - 2010 A1 - Arking, Dan E A1 - Reinier, Kyndaron A1 - Post, Wendy A1 - Jui, Jonathan A1 - Hilton, Gina A1 - O'Connor, Ashley A1 - Prineas, Ronald J A1 - Boerwinkle, Eric A1 - Psaty, Bruce M A1 - Tomaselli, Gordon F A1 - Rea, Thomas A1 - Sotoodehnia, Nona A1 - Siscovick, David S A1 - Burke, Gregory L A1 - Marbán, Eduardo A1 - Spooner, Peter M A1 - Chakravarti, Aravinda A1 - Chugh, Sumeet S KW - Aged KW - Alleles KW - Case-Control Studies KW - Cohort Studies KW - Death, Sudden, Cardiac KW - Ethnic Groups KW - Female KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Glypicans KW - Heart Diseases KW - Humans KW - Male KW - Middle Aged KW - Models, Genetic KW - Oligonucleotide Array Sequence Analysis KW - Oregon KW - Polymorphism, Single Nucleotide AB -

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 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/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.

VL - 5 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20360844?dopt=Abstract ER -