Rare and Coding Region Genetic Variants Associated With Risk of Ischemic Stroke: The NHLBI Exome Sequence Project.
Rare and Coding Region Genetic Variants Associated With Risk of Ischemic Stroke: The NHLBI Exome Sequence Project.
复制标题
DOI：
10.1001/jamaneurol.2015.0582
复制
发表时间：
2015-07
期刊：
影响因子：
29
通讯作者：
National Heart, Lung, and Blood Institute Exome Sequencing Project
中科院分区：
文献类型：
--
作者：
Auer PL;Nalls M;Meschia JF;Worrall BB;Longstreth WT Jr;Seshadri S;Kooperberg C;Burger KM;Carlson CS;Carty CL;Chen WM;Cupples LA;DeStefano AL;Fornage M;Hardy J;Hsu L;Jackson RD;Jarvik GP;Kim DS;Lakshminarayan K;Lange LA;Manichaikul A;Quinlan AR;Singleton AB;Thornton TA;Nickerson DA;Peters U;Rich SS;National Heart, Lung, and Blood Institute Exome Sequencing Project
中风是死亡的第二大原因，也是寿命损失的第三大原因。遗传因素有助于中风的患病率，候选基因和全基因组关联研究（GWAS）已经确定了与缺血性中风风险相关的变异。这些变体通常具有小的影响，没有明显的生物学意义。外显子组测序可能发现预测的蛋白质改变变体，对缺血性卒中风险具有潜在的巨大影响。通过靶向人类基因组的蛋白质编码区，研究罕见和常见遗传变异对缺血性卒中风险的贡献。美国国家心脏、肺和血液研究所（NHLBI）外显子组测序项目（ESP）分析了来自欧洲和非洲血统众多队列的约6000名参与者。为了发现，对365例缺血性卒中（小血管和大血管亚型）和809例欧洲血统对照进行了测序;为了复制，对47例与卒中亚型一致的受累同胞和一个非裔美国人病例对照系列进行了测序，对1672例病例和4509例欧洲血统对照进行了基因分型。ESP的外显子组测序和基因分型于2010年1月1日开始，并持续到2012年6月30日。对2012年7月12日至2013年7月13日期间的完整数据集进行了分析。发现导致缺血性卒中风险和亚型的新变体或基因（主要分析），并确定支持先前发表的候选基因中导致风险的蛋白质编码变体（次要分析）。我们发现了2个与缺血性卒中风险增加相关的新基因：PDE 4DIP中的蛋白编码变体（rs 1778155;比值比，2.15; P = 2.63 × 10−8）与细胞内信号转导机制和ACOT 4（rs35724886;比值比，2.04; P = 1.24 × 10−7），具有脂肪酸代谢;在患有大血管卒中亚型的受累同胞家系和非裔美国人中观察到PDE 4DIP的确认。在先前报道的2种GWAS相关性中观察到候选基因中蛋白编码变体的复制：ZFHX 3（心源性卒中）和ABCA 1（大血管卒中）。外显子组测序发现了2个新的基因和机制，PDE 4DIP和ACOT 4，与缺血性卒中风险增加相关。此外，ZFHX 3和ABCA 1被发现具有与缺血性卒中相关的蛋白质编码变体。这些结果表明，新途径的遗传变异有助于缺血性卒中风险，并可作为预测、预防和治疗的靶点。
Stroke is the second leading cause of death and the third leading cause of years of life lost. Genetic factors contribute to stroke prevalence, and candidate gene and genome-wide association studies (GWAS) have identified variants associated with ischemic stroke risk. These variants often have small effects without obvious biological significance. Exome sequencing may discover predicted protein-altering variants with a potentially large effect on ischemic stroke risk. To investigate the contribution of rare and common genetic variants to ischemic stroke risk by targeting the protein-coding regions of the human genome. The National Heart, Lung, and Blood Institute (NHLBI) Exome Sequencing Project (ESP) analyzed approximately 6000 participants from numerous cohorts of European and African ancestry. For discovery, 365 cases of ischemic stroke (small-vessel and large-vessel subtypes) and 809 European ancestry controls were sequenced; for replication, 47 affected sibpairs concordant for stroke subtype and an African American case-control series were sequenced, with 1672 cases and 4509 European ancestry controls genotyped. The ESP's exome sequencing and genotyping started on January 1, 2010, and continued through June 30, 2012. Analyses were conducted on the full data set between July 12, 2012, and July 13, 2013. Discovery of new variants or genes contributing to ischemic stroke risk and subtype (primary analysis) and determination of support for protein-coding variants contributing to risk in previously published candidate genes (secondary analysis). We identified 2 novel genes associated with an increased risk of ischemic stroke: a protein-coding variant in PDE4DIP (rs1778155; odds ratio, 2.15; P = 2.63 × 10−8) with an intracellular signal transduction mechanism and in ACOT4 (rs35724886; odds ratio, 2.04; P = 1.24 × 10−7) with a fatty acid metabolism; confirmation of PDE4DIP was observed in affected sibpair families with large-vessel stroke subtype and in African Americans. Replication of protein-coding variants in candidate genes was observed for 2 previously reported GWAS associations: ZFHX3 (cardioembolic stroke) and ABCA1 (large-vessel stroke). Exome sequencing discovered 2 novel genes and mechanisms, PDE4DIP and ACOT4, associated with increased risk for ischemic stroke. In addition, ZFHX3 and ABCA1 were discovered to have protein-coding variants associated with ischemic stroke. These results suggest that genetic variation in novel pathways contributes to ischemic stroke risk and serves as a target for prediction, prevention, and therapy.