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

47 Citations (Scopus)

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 - Dec 1 2010
Externally publishedYes

Fingerprint

cardiac arrest
Genetic Loci
Genome-Wide Association Study
Sudden Cardiac Death
Genes
loci
Sudden Death
atherosclerosis
Atherosclerosis
Health
death
Single Nucleotide Polymorphism
Coronary Artery Disease
Hazards
Glypicans
Alleles
alleles
cohort studies
Proportional Hazards Models
human diseases

ASJC Scopus subject areas

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

Cite this

Arking, D. E., Reinier, K., Post, W., Jui, J., Hilton, G., O'Connor, 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

Genome-wide association study identifies GPC5 as a novel genetic locus protective against sudden cardiac arrest. / Arking, Dan E.; Reinier, Kyndaron; Post, Wendy; Jui, Jonathan; Hilton, Gina; O'Connor, Ashley; Prineas, Ronald J.; Boerwinkle, Eric; Psaty, Bruce M.; Tomaselli, Gordon F.; Rea, Thomas; Sotoodehnia, Nona; Siscovick, David S.; Burke, Gregory L.; Marban, Eduardo; Spooner, Peter M.; Chakravarti, Aravinda; Chugh, Sumeet S.

In: PLoS One, Vol. 5, No. 3, e9879, 01.12.2010.

Research output: Contribution to journalArticle

Arking, DE, Reinier, K, Post, W, Jui, J, Hilton, G, O'Connor, A, Prineas, RJ, Boerwinkle, E, Psaty, BM, Tomaselli, GF, Rea, T, Sotoodehnia, N, Siscovick, DS, Burke, GL, Marban, E, Spooner, PM, Chakravarti, A & Chugh, SS 2010, 'Genome-wide association study identifies GPC5 as a novel genetic locus protective against sudden cardiac arrest', PLoS One, vol. 5, no. 3, e9879. https://doi.org/10.1371/journal.pone.0009879
Arking, Dan E. ; Reinier, Kyndaron ; Post, Wendy ; Jui, Jonathan ; Hilton, Gina ; O'Connor, Ashley ; Prineas, Ronald J. ; Boerwinkle, Eric ; Psaty, Bruce M. ; Tomaselli, Gordon F. ; Rea, Thomas ; Sotoodehnia, Nona ; Siscovick, David S. ; Burke, Gregory L. ; Marban, Eduardo ; Spooner, Peter M. ; Chakravarti, Aravinda ; Chugh, Sumeet S. / Genome-wide association study identifies GPC5 as a novel genetic locus protective against sudden cardiac arrest. In: PLoS One. 2010 ; Vol. 5, No. 3.
@article{e1503ff4fc6140f6bed4be05d82eecde,
title = "Genome-wide association study identifies GPC5 as a novel genetic locus protective against sudden cardiac arrest",
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:",
author = "Arking, {Dan E.} and Kyndaron Reinier and Wendy Post and Jonathan Jui and Gina Hilton and Ashley O'Connor and Prineas, {Ronald J.} and Eric Boerwinkle and Psaty, {Bruce M.} and Tomaselli, {Gordon F.} and Thomas Rea and Nona Sotoodehnia and Siscovick, {David S.} and Burke, {Gregory L.} and Eduardo Marban and Spooner, {Peter M.} and Aravinda Chakravarti and Chugh, {Sumeet S.}",
year = "2010",
month = "12",
day = "1",
doi = "10.1371/journal.pone.0009879",
language = "English (US)",
volume = "5",
journal = "PLoS One",
issn = "1932-6203",
publisher = "Public Library of Science",
number = "3",

}

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 - 2010/12/1

Y1 - 2010/12/1

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

VL - 5

JO - PLoS One

JF - PLoS One

SN - 1932-6203

IS - 3

M1 - e9879

ER -