Genetic evaluation of two novel loci associated with recurrent stroke

摘要 中风是美国第四大死亡原因，也是美国第一大死亡原因。 长期严重残疾。在每年近80万次中风中，大约25%将是 复发性事件不幸的是，复发性中风更致命， 与第一次中风相比，针对复发性中风的遗传学研究 非常有限。我们已经确定了两个新的基因区域与复发性 中风，并旨在使用下一代DNA测序（NGS）来精细定位这些区域， 仔细研究可能的致病变异对于182例复发性卒中患者， 卒中预防干预（VISP）临床试验，我们将利用NGS平台识别所有 跨越1.5 Mb的遗传变异，跨越与复发性乳腺癌相关的两个新基因区域， 中风将对所有2，100例VISP受试者的高优先级变体进行基因分型，并分析 与复发性中风有关。 NGS是一种尖端技术，提供了一种强大的方法来识别新的和 复发性卒中的重要遗传因素，这种表型的研究很少。 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的参与者包括非洲裔美国人（AA）和欧洲裔美国人， 因此，这项建议可能会识别出非洲人群特有的遗传风险变异， 在其他主要集中于人口的研究中可能无法确定的血统 欧洲血统。这些变异可能有助于解决为什么非洲裔美国人有近2x 中风的风险更大，中风后死亡的可能性更大， 欧洲裔美国人。此外，这些发现可能具有更广泛的影响， 对影响复发性卒中的其他问题的见解，例如控制可管理风险的能力 因素（例如高血压和房颤）以及对治疗的反应 抗凝、抗血小板和抗高血压药物。此外，这些发现可能 反映卒中后治疗对组织纤溶酶原激活剂（tPA）的反应，FDA唯一的 缺血性中风的治疗方法符合NIH学术研究的目标 增强奖（区域）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尖端技能， 群体遗传学，涉及NGS文库制备的生物技术， 生物信息学技能侧重于分析NGS数据和进行统计分析， 基因研究。

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.