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

摘要 脑出血（ICH）是一种严重的出血性卒中，在老年人中发生频率越来越高。 老人在老年人群中，脑淀粉样血管病（CAA）是最常见的原因， 脑出血是脑血管壁内β-淀粉样蛋白或“老化斑”沉积的结果。到 迄今为止，人们对这种现象的遗传原因知之甚少。唯一的特定遗传风险因素 在CAA相关的ICH中一致鉴定的是载脂蛋白E（APOE）ε2或ε4等位基因， 这两个基因一直与人类寿命相关。然而，先前的研究表明， APOE基因型与CAA相关ICH风险之间的关系主要是病例对照研究， 没有量化风险随时间的变化，而是测试了与结果的关联。还没有一项研究 评估了具有APOE ε2或ε4等位基因对ICH发生的长期风险的影响。还有， 叉头盒O-3（FoxO 3）单核苷酸多态性（SNP）的几个次要等位基因，它们形成了一个 长寿单倍型是唯一与人类长寿相关的基因，在ICH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7,000名日本血统的美国男性。 Kuakini檀香山心脏项目的研究人员，他们自1965年以来一直接受随访，以评估APOE ε2或ε4的影响 等位基因对34年ICH发病率的影响。此外，本研究还将探讨 FoxO 3的长寿相关次要等位基因和34年ICH发病率。这项研究的结果将导致 提高对美国男性ICH遗传介导的风险因素的理解， 日本血统。基于APOE和FoxO 3基因型识别ICH高危人群可能导致 为将来的ICH试验改进风险分层策略。

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.