Admixture Mapping of Ischemic Stroke in African Americans

非裔美国人缺血性中风的混合图谱

• 批准号: 8461075
• 负责人: YU-CHING CHENG
• 金额: --
• 依托单位: BALTIMORE VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8461075
• 关键词: 4 year old; Admixture; African; African American; Alleles; American; Atherosclerosis; Baltimore; Bioinformatics; Blood Clot; Blood Vessels; Blood coagulation; Brain; Caucasians; Caucasoid Race; Collection; Communication Research; Communities; Complement; DNA; Development; Disease; Elements; Environmental Risk Factor; Epidemiologic Studies; Epidemiology; Etiology; European; Functional disorder; Future; General Population; Genes; Genetic; Genomics; Genotype; Goals; Health; Intervention; Ischemic Stroke; K-Series Research Career Programs; Kidney Diseases; Knowledge; Lead; Linkage Disequilibrium; Malignant neoplasm of prostate; Maps; Maryland; Meta-Analysis; Methodology; Methods; Minority; Pathogenesis; Population; Predisposition; Quality of life; Relative Risks; Research; Research Project Grants; Risk; Risk Factors; Sampling; Smoking; Stroke; Stroke prevention; Study Subject; Subgroup; Susceptibility Gene; Testing; Training; Training Programs; Universities; Update; Ursidae Family; Variant; Veterans; Vitamins; Women' s Health; Work; aged; base; biobank; career; case control; cohort; design; disability; early onset; experience; follow-up; genetic epidemiology; genetic variant; genome wide association study; high risk; improved; innovation; insight; medical schools; mortality; novel; programs; racial and ethnic; skills; tool

DESCRIPTION (provided by applicant): African American (AfrAm) veterans bear a disproportionate burden of stroke risk as they experience a 1.5-2.5 fold increased risk of stroke compared to Caucasians and an estimated 21% increased risk of dying from stroke. There is a substantial genetic contribution to stroke risk although few stroke susceptibility genes have been identified to date. The overwhelming majority of stroke genetic studies have been conducted in Caucasian populations, with few studies conducted in minority populations such as AfrAms. Objective. The goal of this study is to identify genes that influence the development of ischemic stroke (IS) in AfrAms. We hypothesize that the higher risk of stroke among AfrAms is at least partially attributable to genetic variants of African origin and that environmental factors may modify the effects of genetic variants on the development of stroke. To test this hypothesis, we propose the following aims: 1) conduct an admixture mapping analysis in a large multicenter collection of African American IS cases to identify chromosomal regions associated with stroke risk; 2) perform SNP association and gene-by-smoking interaction analyses using densely-spaced markers to fine map the regions with strongest admixture associations and evaluate if current smoking will modify the genetic effects on ischemic stroke; and 3) follow up putative genes significantly associated with ischemic stroke using targeted sequencing in a subset of samples to discover novel variants that are enriched among cases. To complement these research objectives, the candidate has developed a training program that includes the following elements: 1) further training in contemporary methodologies used in genetic studies; 2) training in stroke epidemiology and pathophysiology; 3) knowledge and skills in bioinformatics; 4) experience in working with multicenter collaborative studies; 5) communication of research results with scientific community. Methods. The project will include 1,215 AfrAm IS cases and 12,000 AfrAm controls, aged 18-89 years old, from four pre-existing studies: Atherosclerosis Risk in Communities Study (ARIC), Genetics of Early Onset Stroke (GEOS) study, the Vitamin Intervention for Stroke Prevention (VISP) and Women Health Initiative (WHI) study. A common set of ~3,000 ancestry informative markers (AIMs) across these studies will be selected to perform case-only admixture mapping among IS cases to identify genomic regions associated with IS in Aim 1. We will then fine map associated genomic regions using densely-spaced markers by first performing study-specific SNP associations in a case-control/case-cohort design and then meta-analyzing study-specific results to pinpoint the genes associated with IS (Aim 2). For Aim 3, we will perform targeted sequencing of 50 cases and 50 controls in a 500~600 kb region for each putative IS- associated gene to identify novel variants that are enriched in stroke cases. All genotyping and statistical analyses will be performed at University of Maryland School of Medicine, Baltimore. Findings. With the large collection of AfrAm stroke cases assembled in this proposal, we are well- powered to identify stroke genes with a relative risk greater than 1.50-fold. The new methods and expertise acquired as a result of this Career Development Award will also equip Dr. Cheng with tools to launch an independent career in genetic epidemiology research within the VA, that will include making future use of DNA biobanking within the recently launched Million Veteran Program. Status. This project is a new submission and there is no update on the project status. Impact. Identifying genes predisposing to stroke in AfrAm could disclose novel stroke mechanisms relevant to both AfrAms and European Americans and ultimately lead to more effective strategies for stroke prevention and treatment in both veterans and the general population.

描述（由申请人提供）： 非裔美国人（AfrAm）退伍军人承担着不成比例的中风风险负担，因为与白人相比，他们的中风风险增加了1.5-2.5倍，死于中风的风险估计增加了21%。中风风险与遗传因素密切相关 尽管迄今为止很少有中风易感基因被鉴定。绝大多数中风遗传学研究都是在高加索人群中进行的，很少有研究是在非洲人等少数群体中进行的。 Objective.本研究的目的是鉴定影响AfrAms缺血性卒中（IS）发展的基因。我们假设，AfrAms中中风的风险较高至少部分归因于非洲起源的遗传变异，环境因素可能会改变遗传变异对中风发展的影响。为了验证这一假设，我们提出了以下目标：1）在一个大型多中心收集的非裔美国人IS病例中进行混合作图分析，以确定与卒中风险相关的染色体区域; 2）使用密集的-间隔的标记物，以精细绘制具有最强混合关联的区域，并评估当前吸烟是否会改变缺血性心脏病的遗传效应。中风;和3）在样本子集中使用靶向测序追踪与缺血性中风显著相关的推定基因，以发现在病例中富集的新变体。为了补充这些研究目标，候选人制定了一个培训计划，其中包括以下要素：1）遗传学研究中使用的当代方法的进一步培训; 2）中风流行病学和病理生理学的培训; 3）生物信息学的知识和技能; 4）与多中心合作研究的经验; 5）与科学界交流研究结果。 方法.该项目将包括1，215例AfrAm IS病例和12，000例AfrAm对照，年龄在18-89岁之间，来自四项先前存在的研究：社区动脉粥样硬化风险研究（ARIC），早发性卒中遗传学（GEOS）研究，预防卒中的维生素干预（VISP）和妇女健康倡议（WHI）研究。在这些研究中，将选择一组常见的约3，000个祖先信息标记（AIM），在IS病例中进行仅病例混合作图，以识别与Aim 1中IS相关的基因组区域。然后，我们将使用密集间隔的标记物对相关基因组区域进行精细定位，首先在病例对照/病例队列设计中进行研究特异性SNP关联，然后对研究特异性结果进行荟萃分析，以确定与IS相关的基因（目的2）。对于目标3，我们将在每个推定的IS相关基因的500~600 kb区域中对50例病例和50例对照进行靶向测序，以鉴定在卒中病例中富集的新变体。所有基因分型和统计分析将在马里兰州大学医学院（巴尔的摩）进行。调查结果。在这个提议中收集了大量的AfrAm中风病例，我们有很好的能力来鉴定相对风险大于1.50倍的中风基因。由于这个职业发展奖获得的新方法和专业知识也将使郑博士拥有在VA内开展遗传流行病学研究的独立职业生涯的工具，其中包括在最近启动的百万退伍军人计划中未来使用DNA生物库。Status.该项目是一个新提交的项目，没有关于项目状态的更新。 冲击在AfrAm中识别易患中风的基因可以揭示与AfrAm和欧洲美国人相关的新中风机制，并最终导致退伍军人和普通人群更有效的中风预防和治疗策略。