Genetic evaluation of two novel loci associated with recurrent stroke

与复发性卒中相关的两个新位点的遗传评估

• 批准号: 9232492
• 负责人: Michael Scott Brewer
• 金额: $ 44.24万
• 依托单位: EAST CAROLINA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-30 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9232492
• 关键词: Academic Research Enhancement Awards; Accounting; Address; African; African American; Alteplase; American; Anticoagulation; Antihypertensive Agents; Atrial Fibrillation; Bioinformatics; Biotechnology; Cause of Death; Clinical Trials; DNA; DNA Sequence; Data; Dose; Double-Blind Method; Employee Strikes; Environment; Epidemiology; European; Evaluation; Event; FDA approved; Folic Acid; Gene Frequency; Generations; Genes; Genetic; Genetic Risk; Genetic study; Genomics; Genotype; Goals; Haplotypes; Health; Hypertension; Individual; Institutes; Intake; Intervention; Ischemic Stroke; Lead; Learning; Libraries; Maps; Methods; Minor; National Institute of Neurological Disorders and Stroke; Participant; Patients; Pharmaceutical Preparations; Phenotype; Population; Population Genetics; Predisposition; Preparation; Prevention; Recurrence; Research; Research Support; Risk; Risk Assessment; Risk Factors; Role; Sampling; Scientist; Single Nucleotide Polymorphism; Stroke; Stroke prevention; Students; Techniques; Technology; Testing; United States; United States National Institutes of Health; Universities; Validation; Variant; Vitamin B6; Vitamins; abstracting; disability; genetic risk factor; genetic variant; genome wide association study; genome-wide; health disparity; improved; insight; minority health; nervous system disorder; next generation; next generation sequencing; novel; phenotypic data; post stroke; prevention clinical trial; risk variant; sequencing platform; skills; stroke treatment; treatment response

Abstract Stroke is the fourth leading cause of death in the United States and the number one cause of serious, long term disability. Of the nearly 800,000 annual strokes, approximately 25% will be recurrent events. Unfortunately, recurrent strokes are more deadly and most likely to cause disability when compared to a first stroke. Genetic studies focusing on recurrent stroke have been extremely limited. We have identified two novel gene regions associated with recurrent stroke and aim to use next generation DNA sequencing (NGS) to fine-map these regions to hone in on the likely causal variants. For 182 recurrent stroke patients from the Vitamin Intervention for Stroke Prevention (VISP) clinical trial, we will utilize NGS platforms to identify all genetic variants across 1.5 Mb spanning the two novel gene regions associated with recurrent stroke. High priority variants will be genotyped in all 2,100 VISP participants and analyzed for association with recurrent stroke. NGS is a cutting edge technology that provides a powerful approach to identify novel and important genetic contributors to recurrent stroke, a phenotype that has been poorly studied. This approach may allow improved personalization of risk assessment and targeted prevention. Moreover, VISP participants include both African Americans (AA) and European Americans, therefore this proposal may identify genetic risk variants specific to populations of African descent that might not otherwise be identified in other studies focused primarily on populations of European ancestry. These variants may help address why African Americans have nearly 2x greater risk of suffering a stroke, and are more likely to die following a stroke, as compared to European Americans. Furthermore, these findings may have broader implications by providing insight on other issues influencing recurrent stroke such as the ability to control manageable risk factors (e.g. hypertension and atrial fibrillation) and likewise one’s response to treatment for anticoagulation, antiplatelet, and antihypertensive medications. Moreover, these finding may reflect post stroke treatment response to tissue plasminogen activator (tPA), the only FDA approved treatment for ischemic stroke. Aligned with the goals of the NIH Academic Research Enhancement Award (AREA) Program (R15), we aim to explore a significant research question while exposing students to research, in particular learning cutting edge skills in Genomics, Population Genetics, Biotechnology techniques involving NGS library preparations, and Bioinformatics skills focused on analyzing NGS data and performing statistical analyses for genetic studies.

抽象的 中风是美国第四大死因，也是第一大死因 严重的、长期的残疾。在每年近 80 万例中风中，大约 25% 反复发生的事件。不幸的是，复发性中风更加致命，并且最有可能导致 与第一次中风相比的残疾。专注于复发性中风的遗传学研究 受到了极大的限制。我们已经确定了两个与复发相关的新基因区域 中风，并旨在使用下一代 DNA 测序 (NGS) 精细绘制这些区域以 专注于可能的因果变异。维生素为 182 名复发性中风患者提供帮助 中风预防干预（VISP）临床试验，我们将利用NGS平台来识别所有 跨越 1.5 Mb 的遗传变异，跨越与复发相关的两个新基因区域 中风。高优先级变异将对所有 2,100 名 VISP 参与者进行基因分型并进行分析 与复发性中风的关联。 NGS 是一项尖端技术，提供了一种强大的方法来识别新颖的和 复发性中风的重要遗传因素，这种表型尚未得到充分研究。 这种方法可以改进风险评估的个性化和有针对性的预防。 此外，VISP参与者包括非洲裔美国人（AA）和欧洲裔美国人， 因此，该提案可能会识别非洲人群特有的遗传风险变异 在其他主要针对人群的研究中可能无法识别的血统 具有欧洲血统。这些变体可能有助于解决为什么非裔美国人有近 2 倍 与其他人相比，中风的风险更大，并且中风后死亡的可能性更大 欧洲裔美国人。此外，这些发现可能会产生更广泛的影响： 对影响复发性中风的其他问题的见解，例如控制可管理风险的能力 因素（例如高血压和心房颤动）以及患者对治疗的反应 抗凝、抗血小板和抗高血压药物。此外，这些发现可能 反映中风后治疗对组织纤溶酶原激活剂 (tPA) 的反应，这是唯一的 FDA 批准治疗缺血性中风。与 NIH 学术研究的目标保持一致 增强奖（AREA）计划（R15），我们的目标是探索一个重要的研究问题 同时让学生接触研究，特别是学习基因组学的前沿技能， 群体遗传学、涉及 NGS 文库制备的生物技术，以及 生物信息学技能侧重于分析 NGS 数据并进行统计分析 遗传学研究。