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
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.
Publications
None. See parent grant details.