ERICH-GENE

埃里希基因

基本信息

批准号：
10250540
负责人：
Christopher David Anderson
金额：
$ 199.06万
依托单位：
UNIVERSITY OF CINCINNATI
依托单位国家：
美国
项目类别：
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/10250540
关键词：
Address Adult Affect Alzheimer&apos s Disease Alzheimer&apos s disease related dementia Amyloid beta-Protein Amyotrophic Lateral Sclerosis Asians Atrophic Basement membrane Biological Biological Assay Biological Process 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 Diagnostic radiologic examination Disabled Persons Disease Endothelial Cells Ensure Ethnic Origin Ethnic group Foundations Funding Future Genetic Genetic Risk Genomics Genotype Hematoma Hemorrhage Heterogeneity Hispanics 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 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&apos 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 racial and ethnic recruit risk prediction risk stratification sex sharing platform study population therapeutic development tool whole genome

项目摘要

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.

项目摘要/摘要中风是曼联史蒂斯的主要死亡原因和成人残疾的主要原因。成人每个人都会陷入困境！或帕金森氏病估计有40％的ICH受害者将死亡，超过80％的幸存者仍然残疾与其他形式的大脑小血管疾病（CSVD）共享组织病理学特征高血压和脑淀粉样蛋白血管病。阿尔茨海默氏病和血管性痴呆，几乎一半的ICH幸存者在4年内发展出痴呆症。我们的研究人员以前已经合作发布了最大的ICH基因组广泛协会研究约有1500例病例，发现在CSVD中固定的新遗传因素包括白质高强度和小血管的表型。发现ICH以及这些机制，阿尔茨海默氏症和血管痴呆的其他风险因素。脑出血（Erich）研究的种族/种族变化最初招募了3000个Casses 在白色，黑色和西班牙裔卡斯的自发性出血开始。有了以下哲学，即可能存在种族特异性和非特异性风险因素，并且许多埃里希（Erich）出版物也支持这一点最大化我们的研究的力量，以识别跨种族的变异。 21,000个CAUSS已经完成了基因分型或可以评估ICH遗传风险的样品。但是，关键的第一步是进行仔细的表型协调，特别是在在临床，组织病理学和遗传学上分层的出血。不同的位置定义，如果不统一将限制由于案例而导致的研究能力在我们的两个中心进行ICH案件状态和位置，在我们的两个中心进行了表型协调在3项NIH资助的研究中，> 5,000个Casses。并扩展到相关的成像CSVD表型和临床结果。基因组数据创建多基因风险评分（PRS），以分层个体的ICH累积遗传风险水平，这可能会提供近期的机会统一，以利用基因组关联数据来改善临床护理。最后，我们将最大程度地共享所有关联结果和脑脉体疾病知识门户网站是一种在Ninds支持下建立的可自由可供选择的在线协作资源。如果成功，我们将确定ICH，亚型按位置以及跨CSVD神经影像的危险因素特征将是有价值的，作为理性疗法发展的目标。 ICH风险和结果，是通过ICH风险分层并提供有关结果的预后信息的工具。