Admixture Mapping of Ischemic Stroke in African Americans

描述(由申请人提供)： 非洲裔美国人(Afram)退伍军人承担着不成比例的中风风险负担，因为他们患中风的风险比高加索人高1.5-2.5倍，死于中风的风险估计高出21%。中风风险与基因有很大的关系 尽管到目前为止发现的中风易感基因还很少。绝大多数中风遗传学研究是在高加索人群中进行的，很少有研究在非洲裔等少数族裔人群中进行。 目标。这项研究的目的是确定影响AFrAms中缺血性中风(IS)发展的基因。我们假设，AFrAM人群中较高的中风风险至少部分归因于起源于非洲的基因变异，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)在大量的非裔美国人IS病例中进行混合作图分析，以确定与中风风险相关的染色体区域；2)使用密集间隔的标记进行SNP关联和基因与吸烟的相互作用分析，以精细定位与混合关联最强的区域，并评估当前吸烟是否会改变对缺血性中风的遗传影响；以及3)使用在样本子集中的靶向测序来跟踪与缺血性中风显著相关的假定基因，以发现在病例中丰富的新变异。为了实现这些研究目标，应聘者制定了包括以下内容的培训计划：1)现代遗传学研究方法的进一步培训；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)多中心协作研究的工作经验；5)与科学界交流研究成果。 方法：研究方法。该项目将包括1,215个Afram病例和12,000个Afram对照，年龄在18-89岁，来自四项先前存在的研究：社区动脉粥样硬化风险研究(ARIC)、早发性中风遗传学研究(GEOS)、预防中风的维生素干预研究(VISP)和妇女健康倡议(WHI)研究。我们将在这些研究中选择一组共有约3,000个祖先信息标记(AIM)，在IS病例之间进行仅病例混合作图，以确定目标1中与IS相关的基因组区域。然后，我们将使用密集分布的标记，通过病例对照/病例队列设计执行特定研究的SNP关联，然后对研究特定结果进行荟萃分析，以精确定位与IS相关的基因(目标2)，从而精细地定位相关基因组区域。对于目标3，我们将针对每个假定的IS相关基因在500~600 kb的区域对50例患者和50名对照进行定向测序，以确定在中风病例中丰富的新变异。所有的基因分型和统计分析将在巴尔的摩的马里兰大学医学院进行。调查结果。在这项提案中汇集了大量的Afram卒中病例，我们可以很好地识别相对风险大于1.50倍的卒中基因。通过这项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退伍军人管理局内开展基因流行病学研究的独立职业生涯的工具，其中将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。状况。此项目是新提交的，没有关于项目状态的更新。 冲击力。在Afram中识别中风的易感基因可以揭示与AfrAms和欧洲美国人相关的新的中风机制，并最终导致在退伍军人和普通人群中制定更有效的中风预防和治疗策略。 公共卫生相关性： 在非裔美国退伍军人中，缺血性中风在很大程度上导致残疾和死亡。 这项研究项目的目的是利用一种新的统计方法，在确定每个基因座上等位基因的祖先来源的基础上，确定影响非裔美国人缺血性中风风险的基因。深入了解缺血性中风的遗传学和发病机制将有助于我们制定预防、治疗和提高美国退伍军人生活质量的策略。培训部分的目的是让郑博士掌握技能，开始研究退伍军人的健康问题的独立研究生涯。

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. PUBLIC HEALTH RELEVANCE: Ischemic stroke contributes substantially to disability and mortality in African American veterans. The objective of this research project is to identify genes that influence the risk of ischemic stroke in African Americans using a novel statistical approach based on identifying the ancestral origin of alleles at each locus. A deeper understanding of the genetics and pathogenesis of ischemic stroke will facilitate us to develop strategies for stroke prevention, treatment and improving quality of life in US veterans. The objective of the training component is to equip Dr. Cheng with skills to launch an independent research career in studying the health problems of Veterans.