ERICH-GENE

埃里希基因

• 批准号: 10490307
• 负责人: Christopher David Anderson
• 金额: $ 202.84万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10490307
• 关键词: Address; Adult; Affect; Alzheimer' s Disease; Alzheimer' s disease related dementia; Amyloid beta-Protein; Amyotrophic Lateral Sclerosis; Asian population; Atrophic; Basement membrane; Biological; Biological Assay; Biological Process; Black Populations; Blinded; Brain hemorrhage; Cause of Death; Cell Proliferation; Cerebral Amyloid Angiopathy; Cerebral hemisphere hemorrhage; Cerebral small vessel disease; Cerebrovascular Disorders; China; Clinical; Committee Members; Data; Data Set; Dementia; Disabled Persons; Disease; Endothelial Cells; Ensure; Ethnic Origin; Ethnic group; Foundations; Funding; Future; Genetic; Genetic Risk; Genomics; Genotype; Hematoma; Hemorrhage; Heterogeneity; Hispanic; Hispanic Populations; Hypertension; Image; Incidence; Individual; International; Intervention; Japan; Knowledge Portal; Leukoaraiosis; Life; Lobar; Location; Maintenance; Mental Depression; Meta-Analysis; Multiple Sclerosis; National Institute of Neurological Disorders and Stroke; Neurologic; Outcome; Parkinson Disease; Patients; Persons; Phenotype; Philosophy; Population; Prevention strategy; Principal Investigator; Publications; Publishing; Research Design; Research Personnel; Resource Sharing; Resources; Risk; Risk Factors; Role; Sample Size; Sampling; Site; Stroke; Survivors; Syndrome; United States; United States National Institutes of Health; Variant; Vascular Dementia; White Matter Hyperintensity; Women' s Health; adjudication; biobank; clinical application; clinical care; clinical risk; cohort; cost effective; data sharing; design; disability; disease phenotype; ethnic difference; ethnic diversity; genetic association; genetic risk factor; genetic variant; genome sequencing; genome wide association study; genomic data; genomic locus; hypertension control; improved; innovation; insight; intraventricular hemorrhage; multi-ethnic; neuroimaging; novel; online resource; outcome prediction; patient population; patient stratification; polygenic risk score; prognostic; prognostication; racial and ethnic; radiological imaging; recruit; risk prediction; risk stratification; sex; sharing platform; study population; therapeutic development; tool; whole genome

Project Summary/Abstract Stroke is the third leading cause of death and the leading cause of adult disability in the United States. More adults are affected by stroke each year than Alzheimer’s disease, multiple sclerosis, amyotrophic lateral sclerosis or Parkinson’s disease. Intracerebral hemorrhage (ICH) represents the most severe subtype of stroke. An estimated 40-50% of ICH victims will die and more than 80% of survivors remain disabled. Patients with ICH share histopathological features with other forms of cerebral small vessel disease (CSVD) caused by hypertension and cerebral amyloid angiopathy. CSVD is a key component of progressive neurologic decline in Alzheimer’s disease and vascular dementia, and nearly half of ICH survivors develop dementia within 4 years. Our investigators have previously collaborated to publish the largest genome wide association study of ICH with ~1500 cases, which identified novel genetic factors that have since gone on to be replicated in CSVD phenotypes including white matter hyperintensity and small vessel stroke. With greater sample size, we will uncover additional risk factors for ICH and through those mechanisms, Alzheimer’s and vascular dementias. The Ethnic/Racial Variations of Intracerebral Hemorrhage (ERICH) study originally recruited over 3000 cases of spontaneous hemorrhage with equal power among white, black and Hispanic cases. The study design begins with the philosophy that both ethnicity-specific and non-specific risk factors for ICH may exist, and numerous ERICH publications support this. We propose to combine additional ICH cases from around the world to maximize the power of our study to identify novel genetic variants across ethnicities. We have identified over 21,000 cases that have either completed genotyping or have samples available to assess genetic risk of ICH. However, the critical first step is to perform careful phenotype harmonization, specifically in location of hemorrhage which stratifies patients clinically, histopathologically, and genetically. Different studies have used different location definitions which if not harmonized will limit study power due to case misclassification. We have previously performed phenotype harmonization across our two centers for both ICH case status and location in >5,000 cases across 3 NIH-funded studies. We intend to complete harmonization on cases with available data, and expand harmonization to related imaging CSVD phenotypes and clinical outcomes. Next, we will combine genomic data to create polygenic risk scores (PRS) to stratify cumulative genetic risk of ICH at the individual level, which may provide a near-term opportunity to leverage genomic association data to improve clinical care. Finally, we will maximally share all association results and phentoypes through the Cerebrovascular Disease Knowledge Portal, a freely-accessible on-line collaborative resource established with NINDS support. If successful, we will have identified risk factors for ICH, subtypes by location and across CSVD neuroimaging features, which will be valuable as targets for rational therapeutic development. We will also have built PRS for ICH risk and outcome, as a tool to stratify individuals by ICH risk and provide prognostic information on outcomes.

项目概要/摘要 中风是美国第三大死亡原因，也是导致成人残疾的主要原因。更多的 每年成年人中风的人数比阿尔茨海默病、多发性硬化症、肌萎缩侧索硬化症还要多 或帕金森病。脑出血（ICH）是最严重的中风亚型。一个 据估计，40-50% 的 ICH 受害者将死亡，超过 80% 的幸存者仍然残疾。脑出血患者 与其他形式的脑小血管病 (CSVD) 具有相同的组织病理学特征 高血压和脑淀粉样血管病。 CSVD 是进行性神经功能衰退的关键组成部分 阿尔茨海默病和血管性痴呆，近一半的脑出血幸存者会在 4 年内患上痴呆。 我们的研究人员此前曾合作发表了最大的 ICH 全基因组关联研究 大约 1500 例病例，其中发现了新的遗传因素，这些因素后来在 CSVD 中得到了复制 表型包括白质高信号和小血管卒中。随着样本量的增加，我们将 发现脑出血的其他危险因素，并通过这些机制发现阿尔茨海默病和血管性痴呆。 脑出血的民族/种族变异 (ERICH) 研究最初招募了 3000 多例病例 自发性出血在白人、黑人和西班牙裔病例中具有同等的功效。研究设计开始 认为 ICH 可能存在种族特异性和非特异性危险因素，并且许多 ERICH 出版物支持这一点。我们建议结合来自世界各地的其他 ICH 案例 最大限度地发挥我们研究的力量，识别跨种族的新遗传变异。我们已经确定超过 21,000 例已完成基因分型或具有可用于评估 ICH 遗传风险的样本。 然而，关键的第一步是进行仔细的表型协调，特别是在 出血根据临床、组织病理学和遗传学对患者进行分层。不同的研究使用了 不同的地点定义如果不统一，将因病例分类错误而限制研究能力。我们有 之前我们两个中心对 ICH 病例状态和位置进行了表型协调 NIH 资助的 3 项研究涉及超过 5,000 个病例。我们打算用现有数据完成案件的协调， 并扩大与相关影像学 CSVD 表型和临床结果的协调。接下来我们将结合 基因组数据创建多基因风险评分 (PRS)，对个体的 ICH 累积遗传风险进行分层 水平，这可能为利用基因组关联数据来改善临床护理提供近期机会。 最后，我们将通过脑血管疾病最大限度地共享所有关联结果和表型 知识门户，一个在 NINDS 支持下建立的可免费访问的在线协作资源。 如果成功，我们将确定 ICH 的风险因素、按位置划分的亚型以及整个 CSVD 神经影像学 特征，这将作为合理治疗开发的目标有价值。我们还将为 ICH 风险和结果，作为按 ICH 风险对个体进行分层并提供结果的预后信息的工具。