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Grant Details

Grant Number: 3R01CA229815-04S1 Interpret this number
Primary Investigator: Loo, Lenora
Organization: University Of Hawaii At Manoa
Project Title: The Role of 27-Hydroxycholesterol in Breast Cancer: a Population-Based Multiethnic Study
Fiscal Year: 2022


ABSTRACT This application is being submitted in response to NOT-AG-21-018. Abnormal cholesterol metabolism in the brain is a hallmark of neurodegenerative disease, including AD. There is increasing evidence that 27-hydroxycholesterol (27HC), a circulating cholesterol metabolite, serves as a key factor of altered brain cholesterol homeostasis. 27HC is one of the most abundant circulating oxysterols, primarily metabolized in the liver from dietary cholesterol. It has been implicated in multiple chronic diseases, such as atherosclerosis, cancer, and neurodegenerative diseases, including AD. Unlike circulating cholesterol, 27HC is able to cross the blood brain barrier, functioning to modulate cholesterol homeostasis. Studies have shown that circulating 27HC levels are positively correlated with 27HC levels in the brain, and that higher circulating and brain levels of 27HC have been associated with declines in cognition and memory. Two prior studies that reported a positive association of circulating 27HC with AD and cognitive decline, respectively, were conducted in European populations. There is a clear need to investigate the role of 27HC and AD across racially/ethnically diverse populations with the documented higher incidence of AD among African Americans and Native Hawaiians, followed by Latinos, Whites, and Asian Americans as evidenced in our analysis of the Multiethnic Cohort Study. To address this gap in knowledge, we propose to examine and characterize the associations between circulating levels 27HC and AD, leveraging the unique epidemiologic resources of the Multiethnic Cohort Study. Our first aim will examine the association of circulating levels of 27HC and lipids (total cholesterol, low-density lipoprotein, high-density lipoprotein, and triglycerides) with risk AD in a nested case-control study of 1,580 AD cases and 1,580 controls within the Multiethnic Cohort. The second aim will examine for differences in 27HC, lipids, and AD associations by demographics, lifestyle factors, and genetic susceptibility. The strengths of this proposal include: 1) a large population-based sample including robust representation of underrepresented and underserved racial/ethnic groups, with the potential to further our understanding of disparities in AD incidence; 2) the public health significance of addressing the influence of cholesterol homeostasis and AD development; 3) the rigorous epidemiologic design with the use of pre- diagnostic blood samples, validated and highly sensitive assays, and extensive high quality questionnaire information to assess key covariates. Findings from the proposed study will elucidate the contribution of 27HC to AD risk and identify subgroup specific effects. Such knowledge may inform prevention efforts particularly for understudied populations that experience an unequal burden of AD.


None. See parent grant details.

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