Center for Complex Diseases Genomics, McKusick-Nathans Institute of Genetic Medicine, the Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
PLoS One. 2010 Mar 25;5(3):e9879. doi: 10.1371/journal.pone.0009879.
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.
现有研究表明，心搏骤停（SCA）存在显著的遗传因素，全基因组关联研究（GWAS）为鉴定新基因提供了一种无偏倚的方法。我们进行了 GWAS 以鉴定 SCA 的遗传决定因素。
方法/主要发现：我们在正在进行的俄勒冈州突发意外死亡研究（Oregon-SUDS）中使用了病例对照设计。病例（n=424）为居住在波特兰的患有冠状动脉疾病（CAD）的 SCA 患者（2002-07 年，人口约 100 万），对照（n=226）为患有 CAD 但无 SCA 病史的居民。所有受试者均为白种欧洲血统，GWAS 使用 Affymetrix 500K/5.0 和 6.0 芯片进行。从动脉粥样硬化风险社区研究（ARIC）和心血管健康研究（CHS）中鉴定出 SCA 病例（n=521）中的高信号标记物进行基因分型（合并 n=19611）。没有 SNP 达到全基因组显著水平（p<5x10(-8)）。主要基于 p<10(-4) 和与已知基因（CSMD2、GPR37L1、LIN9、B4GALNT3、GPC5 和 ZNF592）的接近程度，对 6 个位点的 SNP 进行了优先排序。Oregon-SUDS 中，SNP 位于 GPC5（GLYPICAN 5，rs3864180）的次要等位基因与 SCA 风险降低相关，这一效应也在 ARIC/CHS 白人和黑人中观察到（p<0.05 和 p<0.04）。在调整种族的联合 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 至 0.98；p<0.01）。
结论/意义：从俄勒冈州突发意外死亡研究（Oregon-SUDS）中鉴定出 SCA 的一个新遗传位点 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，包括心脏疾病。这种特定关联的机制需要进一步研究。
