TY - JOUR
T1 - Genome-wide association study identifies GPC5 as a novel genetic locus protective against sudden cardiac arrest
AU - Arking, Dan E.
AU - Reinier, Kyndaron
AU - Post, Wendy
AU - Jui, Jonathan
AU - Hilton, Gina
AU - O'Connor, Ashley
AU - Prineas, Ronald J.
AU - Boerwinkle, Eric
AU - Psaty, Bruce M.
AU - Tomaselli, Gordon F.
AU - Rea, Thomas
AU - Sotoodehnia, Nona
AU - Siscovick, David S.
AU - Burke, Gregory L.
AU - Marban, Eduardo
AU - Spooner, Peter M.
AU - Chakravarti, Aravinda
AU - Chugh, Sumeet S.
PY - 2010
Y1 - 2010
N2 - 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:
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 ~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:
UR - http://www.scopus.com/inward/record.url?scp=77952636003&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=77952636003&partnerID=8YFLogxK
U2 - 10.1371/journal.pone.0009879
DO - 10.1371/journal.pone.0009879
M3 - Article
C2 - 20360844
AN - SCOPUS:77952636003
SN - 1932-6203
VL - 5
JO - PLoS One
JF - PLoS One
IS - 3
M1 - e9879
ER -