Genome-Wide Association Study Identifies GPC5 as a Novel Genetic Locus Protective against Sudden Cardiac Arrest
Genome-Wide Association Study Identifies GPC5 as a Novel Genetic Locus Protective against Sudden Cardiac Arrest
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DOI：
10.1371/journal.pone.0009879
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发表时间：
2010-03-25
期刊：
影响因子：
3.7
通讯作者：
Chugh, Sumeet S.
中科院分区：
文献类型：
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作者：
Arking, Dan E.;Reinier, Kyndaron;Chugh, Sumeet S.
背景：现有研究表明心脏骤停（SCA）的重要遗传成分和全基因组关联研究（GWAS）为鉴定新基因提供了公正的方法。我们进行了GWAS鉴定SCA的遗传决定因素。方法学/主要发现：我们在正在进行的俄勒冈州意外猝死研究（Oregon- suds）中采用病例对照设计。俄勒冈州波特兰市（2002- 2007年，人口约为1,000,000）居民中的SCAs合并冠心病（CAD）病例（n = 424）和对照组（n = 226）为患有CAD但无SCA病史的居民。所有受试者均为欧洲白人血统，GWAS采用Affymetrix 500K/5.0和6.0阵列进行。从社区动脉粥样硬化风险研究（ARIC）和心血管健康研究（CHS）中发现的SCA病例（n = 521）的高信号标记物进行基因分型（n = 19611）。没有SNPs达到全基因组显著性（p < 5 × 10(-8)）。6个位点的snp优先进行随访，主要基于p < 10（-4）的显著性和与已知基因（CSMD2, GPR37L1, LIN9, B4GALNT3， GPC5和ZNF592）的接近性。GPC5的次要等位基因（GLYPICAN 5, rs3864180）与俄勒冈- suds的SCA风险降低相关，在ARIC/CHS白人和黑人中也观察到这种影响（p < 0.05）。在对种族进行校正的Cox比例风险模型分析中，次要等位基因的风险比为0.85 （95% CI 0.74 ~ 0.98; p < 0.01）。结论/意义：从俄勒冈- suds中发现了SCA的新基因座GPC5，并在ARIC和CHS队列中成功验证。Glypican家族的另外三个成员先前与人类疾病有关，包括心脏病。这种特殊关联的机制有待进一步研究。
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 similar to 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.