Genetics of Early Onset-Stroke

描述：(申请人提供)这项申请的长期目标是确定缺血性中风易感性的遗传基础，以便开发更有效的预防和治疗策略。目前的证据表明，编码血栓调节蛋白C和纤溶系统的基因是很有希望的候选卒中易感基因，因为它们在血栓形成调节和炎症反应中起着关键作用。我们推测：1)血栓调节蛋白、内皮蛋白C受体和纤溶酶原激活物抑制物-1基因的新的遗传变异易导致卒中，特别是感染相关性卒中；2)内皮细胞蛋白C受体基因多态性与大血管卒中有关，而血栓调节蛋白基因多态性与腔隙(小血管)卒中有关。为了获得足够的样本量来检验这些假说，我们建议在年轻的非裔美国人和高加索人男性和女性中进行一项基于人群的缺血性中风病例对照研究(1033例病例和1064例对照)。为了补充现有的女性病例和对照样本，将利用巴尔的摩-华盛顿地区的59家医院网络招募男性病例(n=600)。年龄、性别和外消旋体对照(n=600)将通过随机数字拨号招募。神经科专家小组将进行中风表型鉴定。用于基因研究的历史风险因素数据和血液样本将在面对面的访谈中获得。将对三个候选基因的编码、启动子和内含子区域进行全面的分子分析，以确定这些基因座的序列变异是否与中风有关。除了个体多态分析外，还将构建基因内单倍型，并测试常见单倍型与中风的关联。在分析中，将使用人口亚结构分析来确定和解释人口分层偏差。这项拟议的研究将补充其他老年中风患者的关联研究，并将成为了解中风风险的遗传基础的持续资源。

DESCRIPTION: (provided by applicant) The long-term objective of this application is to characterize the genetic basis for ischemic stroke susceptibility in order to develop more effective prevention and treatment strategies. Current evidence suggests that the genes encoding the thrombomodulin - protein C and fibrinolysis systems are promising candidate stroke susceptibility genes because of their pivotal importance in thrombosis regulation and response to inflammation. We postulate that: 1) novel genetic variants in the thrombomodulin, endothelial protein C receptor, and plasminogen activator inhibitor-1 genes predispose to the development of stroke, particularly infection-associated stroke and 2) endothelial protein C receptor polymorphisms are associated with large vessel stroke, while thrombomodulin polymorphisms are associated with lacunar (small vessel) stroke. To obtain a sample size adequate to test these hypotheses, we propose a population-based case-control study of ischemic stroke (1,033 cases and 1,064 controls) among young African-American and Caucasian men and women. To complement an existing sample of female cases and controls, male cases (n=600) will be recruited using a network of 59 hospitals in the Baltimore-Washington area. Age, gender, and racematched controls (n=600) will be recruited by random digit dialing. A neurologist panel will perform stroke phenotyping. Historical risk factor data and blood samples for genetic studies will be obtained at a face-to-face interview. A comprehensive molecular analysis of the coding, promotor, and intronic regions of the three candidate genes will be performed to determine if sequence variation in these loci is associated with stroke. In addition to analyses of individual polymorphisms, intragenic haplotypes will be constructed and common haplotypes tested for association with stroke. Population substructure analysis will be used to identify and account for population stratification bias in the analyses. The proposed study will complement other association studies of older stroke patients and will be a continuing resource for understanding the genetic basis of stroke risk.