Impact of APOE and FOXO3 Genotype on Hemorrhagic Stroke in Japanese-American Men

APOE 和 FOXO3 基因型对日裔美国男性出血性中风的影响

• 批准号: 10493196
• 负责人: Kazuma Nakagawa
• 金额: $ 21.28万
• 依托单位: KUAKINI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-10 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10493196
• 关键词: Address; Aging; Alleles; American; Apolipoprotein E; Arteries; Blood Pressure; Blood Vessels; Blood capillaries; Brain; Brain hemorrhage; Cardiovascular system; Case-Control Studies; Center for Translational Science Activities; Centers of Research Excellence; Cerebral Amyloid Angiopathy; Cerebral cortex; Cerebral hemisphere hemorrhage; Cholesterol; Cohort Studies; Data; Elderly; FOXO3A gene; Frequencies; Future; General Hospitals; Genes; Genetic; Genotype; Haplotypes; Heart; Human; Incidence; Japanese; Japanese American; Lead; Leptomeninges; Link; Longevity; Longitudinal Studies; Massachusetts; Mediating; Mediation; Minor; Morbidity - disease rate; Outcome; Population; Recurrence; Research; Resources; Risk; Risk Factors; Single Nucleotide Polymorphism; Stroke; Testing; Time; Translational Research; Tunica Adventitia; United States; Work; abeta deposition; base; early onset; genetic risk factor; high risk population; improved; men; mortality; multidisciplinary; population based; programs; risk stratification

ABSTRACT Intracerebral hemorrhage (ICH) is a severe form of hemorrhagic stroke that occurs with increasing frequency in the elderly. Among the elderly population, cerebral amyloid angiopathy (CAA) is the most common cause of ICH and results from deposition of β-amyloid or “aging plaque” within the blood vessel walls of the brain. To date, little is known about the genetic causes of this phenomenon. The only specific genetic risk factors consistently identified for CAA-related ICH have been the apolipoprotein E (APOE) ε2 or ε4 alleles, one of only two genes consistently associated with human longevity. However, prior studies that demonstrated associations between APOE genotype and the risk of CAA-related ICH were mainly case-control studies that did not quantify risk over time, but rather tested for association with an outcome. There has not been a study that assessed the impact of possessing the APOE ε2 or ε4 allele on the long-term risk of ICH occurrence. Also, several minor alleles of forkhead box O-3 (FoxO3) single nucleotide polymorphisms (SNPs), which form a longevity haplotype of the only other gene linked to human longevity, have never been explored in the ICH population. In this proposed study, we will examine ~7,000 American men of Japanese ancestry from the Kuakini Honolulu Heart Program who have been followed since 1965 to assess the impact of APOE ε2 or ε4 alleles on the 34-year incidence of ICH. Furthermore, this study will explore the possible association of the longevity-associated minor alleles of FoxO3 and the 34-year incidence ICH. Findings from this study will lead to an improved understanding about genetically-mediated risk factors for ICH among American men of Japanese ancestry. Identifying the high-risk group for ICH based on the APOE and FoxO3 genotype may lead to an improved risk stratification strategy for future ICH trials.

摘要 脑出血(ICH)是出血性中风的一种严重形式，在 老年人。在老年人中，脑淀粉样血管病(CAA)是最常见的病因 脑梗塞是由于β-淀粉样蛋白或“老化斑块”在脑血管壁上沉积所致。至 迄今为止，人们对这种现象的遗传原因知之甚少。唯一特定的遗传风险因素 与慢性再障相关的脑出血一直被确认为载脂蛋白E(ApoE)ε2或ε4等位基因，仅有的 有两个基因一直与人类的长寿有关。然而，之前的研究表明， 载脂蛋白E基因与CAA相关性脑出血风险的关系主要是病例对照研究， 没有量化随时间推移的风险，而是测试与结果的相关性。目前还没有一项研究 评估了拥有载脂蛋白Eε2或ε4等位基因对脑出血发生的长期风险的影响。另外， 叉头盒O-3(FOX03)单核苷酸多态(SNPs)的几个次要等位基因，形成一个 唯一与人类长寿有关的其他基因的长寿单倍型，在非物质文化遗产中从未被探索过 人口。在这项拟议的研究中，我们将检查来自美国的约7000名日裔男性 自1965年以来一直在跟踪的Kuakini火奴鲁鲁心脏计划，以评估APOEε2或ε4的影响 等位基因对34年来脑出血发病的影响。此外，这项研究将探索与 FOXO_3与长寿相关的次要等位基因与34岁脑出血发病率的关系。这项研究的发现将导致 为了提高美国男性对脑出血遗传因素的认识 日本血统。根据APOE和FOXO3型确定脑出血的高危人群可能会导致 为未来的非物质文化遗产试验改进风险分层战略。