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

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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.