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


RESULTS
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
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.
Arking
Dan E
DE
Center for Complex Diseases Genomics, McKusick-Nathans Institute of Genetic Medicine, the Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
Reinier
Kyndaron
K
Post
Wendy
W
Jui
Jonathan
J
Hilton
Gina
G
O'Connor
Ashley
A
Prineas
Ronald J
RJ
Boerwinkle
Eric
E
Psaty
Bruce M
BM
Tomaselli
Gordon F
GF
Rea
Thomas
T
Sotoodehnia
Nona
N
Siscovick
David S
DS
Burke
Gregory L
GL
Marban
Eduardo
E
Spooner
Peter M
PM
Chakravarti
Aravinda
A
Chugh
Sumeet S
SS
D000368:Aged; D000483:Alleles; D016022:Case-Control Studies; D015331:Cohort Studies; D016757:Death, Sudden, Cardiac / Q000517:prevention & control*; D005006:Ethnicity; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D053673:Glypicans / Q000235:genetics*; D006331:Heart Diseases / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D008957:Models, Genetic; D020411:Oligonucleotide Array Sequence Analysis; D009922:Oregon; D020641:Polymorphism, Single Nucleotide
C106228:GPC5 protein, human; D053673:Glypicans