Genetics of Early Onset-Stroke

产品说明：（申请人提供）本申请的长期目的是表征缺血性卒中易感性的遗传基础，以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-蛋白C和纤维蛋白溶解系统的基因是有希望的候选中风易感基因，因为它们在血栓形成调节和炎症反应中具有关键的重要性。我们假设：1）血栓调节蛋白、内皮蛋白C受体和纤溶酶原激活物抑制剂-1基因中的新的遗传变异体易于发生卒中，特别是感染相关的卒中，和2）内皮蛋白C受体多态性与大血管卒中相关，而血栓调节蛋白多态性与腔隙性（小血管）卒中相关。为了获得足够的样本量来检验这些假设，我们提出了一项基于人群的缺血性卒中病例对照研究（1,033例病例和1,064例对照），研究对象为年轻的非洲裔美国人和白人男性和女性。为了补充现有的女性病例和对照样本，将使用巴尔的摩-华盛顿地区59家医院的网络招募男性病例（n=600）。将通过随机数字拨号招募年龄、性别和外消旋对照组（n=600）。神经科专家小组将进行卒中表型分析。将通过面对面访谈获得用于遗传研究的历史风险因素数据和血液样本。将对这三个候选基因的编码区、启动子区和内含子区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卒中相关。除了个体多态性分析外，还将构建基因内单倍型，并检测常见单倍型与卒中的相关性。将使用群体子结构分析来识别和解释分析中的群体分层偏倚。这项研究将补充老年中风患者的其他相关研究，并将成为了解中风风险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.