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首页> 外文学位 >Genetic Variation in Platelet Function as a Risk Factor for Ischemic Stroke.
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Genetic Variation in Platelet Function as a Risk Factor for Ischemic Stroke.

机译：血小板功能的遗传变异是缺血性卒中的危险因素。

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摘要

Background. Ischemic stroke is a leading cause of disability and mortality in the US. Studies in twins and families suggest that ischemic stroke is genetically controlled; however, the genetic determinants remain largely unknown. One mechanism through which genes might influence stroke susceptibility is through their effects on platelet function. Antiplatelet medications have been shown effective in reducing the risk of ischemic stroke and several studies have shown platelet aggregation traits to be heritable. Therefore, we sought to identify loci associated with platelet aggregation and test them for association with ischemic stroke.;Methods. Using data from two genetic studies of platelet aggregation in the Amish, we performed principal components analyses to reduce the dimensionality of the data into a smaller number of phenotypes. We assessed the properties of resulting components by identifying their correlates, estimated the genetic contributions to each and assessed evidence for pleiotropy among them. We then performed genetic association analyses on resulting traits to identify associated loci. Top loci were then tested for association with ischemic stroke using a case control study in young adults.;Results. Platelet aggregation traits were reduced to three principal components in our first Amish study and one component in the second study. All were heritable and the first and third components showed evidence for pleiotropy in our first Amish study (rgenetic=-0.45). Previously identified covariates were also associated with our principal components. At the genome-wide alpha level of significance, three SNPs were significantly associated with the third principal component (rs12618009 p=5.0 x 10 -9; rs1527075 p=5.9 x 10-8; rs1684918 p=7.0 x 10-8). The first component was also associated with rs12041331 (PEAR1) (p=0.002) in the first Amish study. Of the SNPs tested for association with ischemic stroke, rs12041331 was significantly associated with large artery ischemic stroke (OR=2.04, 95% CI=1.28--3.23).;Conclusions. One strategy for identifying stroke susceptibility genes is to study intermediate phenotypes. Using this approach we created novel platelet aggregation traits using principal components analysis and identified several associated loci. When tested for association with ischemic stroke, rs12041331 was significantly associated with large artery ischemic stroke.
机译：背景。在美国，缺血性中风是导致残疾和死亡的主要原因。对双胞胎和家庭的研究表明，缺血性中风是由基因控制的。然而，遗传决定因素仍然未知。基因可能影响中风敏感性的一种机制是通过其对血小板功能的影响。已显示抗血小板药物可有效降低缺血性中风的风险，并且多项研究表明血小板聚集性是可遗传的。因此，我们试图鉴定与血小板聚集相关的基因座，并测试它们与缺血性中风的相关性。使用来自Amish血小板聚集的两项遗传研究的数据，我们进行了主要成分分析，以将数据的维数减少为较少的表型。我们通过鉴定它们之间的相关性来评估所得组分的性质，估算它们的遗传贡献，并评估其中的多效性证据。然后，我们对产生的性状进行了遗传关联分析，以鉴定相关的基因座。然后使用病例对照研究在年轻人中测试了最高位点与缺血性卒中的相关性。在我们的第一项阿米什人研究中，血小板凝集特征减少为三个主要成分，而在第二项研究中，血小板聚集性状减少为一个成分。所有这些都是可遗传的，并且在我们的第一项阿米什人研究（rgenetic = -0.45）中，第一和第三部分显示出多效性的证据。先前确定的协变量也与我们的主要成分相关。在全基因组的显着性水平，三个SNP与第三个主要成分显着相关（rs12618009 p = 5.0 x 10 -9; rs1527075 p = 5.9 x 10-8; rs1684918 p = 7.0 x 10-8）。在第一项阿米什人研究中，第一个成分也与rs12041331（PEAR1）（p = 0.002）相关。在测试的与缺血性卒中相关的SNP中，rs12041331与大动脉缺血性卒中显着相关（OR = 2.04，95％CI = 1.28--3.23）。识别中风易感基因的一种策略是研究中间表型。使用这种方法，我们使用主成分分析创建了新颖的血小板凝集特征，并确定了几个相关的基因座。当测试与缺血性中风的相关性时，rs12041331与大动脉缺血性中风显着相关。

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  • 作者

    Dueker, Nicole Diane.;

  • 作者单位

    University of Maryland, Baltimore.;

  • 授予单位 University of Maryland, Baltimore.;
  • 学科 Epidemiology.;Genetics.
  • 学位 Ph.D.
  • 年度 2012
  • 页码 205 p.
  • 总页数 205
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 地球物理学;
  • 关键词

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