Overwhelming scientific evidence indicates that nutritional landscapes of contemporary populations interact with genetic variation among human populations resulting in evolutionary discordance and enhanced inflammatory responses associated with numerous diseases. As demanding as gene-diet interactions are for overall populations in developed countries, they manifest themselves in particularly negative ways in certain racial/ethnic groups. This is seen in Alzheimer?s disease (AD) in the US where data indicate that African Americans (AfAm) are about twice as likely to have AD and other dementias as European Americans (EuAm). The Central Hypothesis of the parent grant for this Supplement (Role of PUFA-Gene Interactions in Health Disparities [R01 AT008621]) is that a particular gene-diet interaction resulting from rapid changes in levels of polyunsaturated fatty acids in the modern Western diet leads to enhancement of biochemical networks that drive inflammation and exacerbate health disparities. The emergence of sophisticated technologies such as metabolomics/lipidomics along with the capacity to analyze large amounts of data and establish biochemical networks is dramatically enhancing the ability to determine mechanisms driving human diseases and identify molecular signatures that can determine disease status. The current supplement expands our hypotheses and leverages the experimental strategies and technological/data analysis advances (particularly lipidomics) made in the parent grant to address the question of whether there are different pathogenetic mechanisms that drive the disparities seen in the incidence of AD between AfAm versus EuAm patients. The transition to AD research by Dr. Chilton is catalyzed by a growing collaboration with Dr. Roberta Brinton, a leading international authority on AD and Director of the Center for Innovation in Brain Science at the University of Arizona. This Supplement tests three key hypotheses: 1) There are race-dependent biological mechanisms that contribute to the expression of AD; (2) Metabolic utilization of n-6 PUFAs in Western diets differs in AfAm and EuAm as a result of differences in allele frequencies of variants in desaturase enzymes (FADS 1 and 2). This results in increased ARA- relative to DHA-containing lyso-phospholipids and free fatty acids in the circulation of AfAm patients that can be transported across the BBB into the brain. (3) Combinations of lipid metabolic intermediates in circulation and/or cerebrospinal fluid (CSF) have the potential to serve as key biomarkers for AD status. These hypotheses will be tested utilizing lipidomic analyses of plasma and CSF from AfAm and EuAm cases and controls.

Public Health Relevance

This project will test the hypothesis that a dramatic increase in a certain type of dietary fat (an omega-6 polyunsaturated fatty acid) over the past 50 years, together with altered metabolism based on genetics and ancestral background of human populations, contribute to Alzheimer?s disease and plays a key role in health disparities observed between African and European Ancestry populations. Thus, genetics may interact with dietary fat to impact the balance of fat metabolites that in turn drive brain inflammation and Alzheimer?s diseases more negatively in certain racial/ethnic populations more than others.

National Institute of Health (NIH)
National Center for Complementary & Alternative Medicine (NCCAM)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Weber, Wendy J
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University of Arizona
Earth Sciences/Resources
United States
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Reynolds, Lindsay M; Howard, Timothy D; Ruczinski, Ingo et al. (2018) Tissue-specific impact of FADS cluster variants on FADS1 and FADS2 gene expression. PLoS One 13:e0194610
Rahbar, Elaheh; Waits, Charlotte Mae K; Kirby Jr, Edward H et al. (2018) Allele-specific methylation in the FADS genomic region in DNA from human saliva, CD4+ cells, and total leukocytes. Clin Epigenetics 10:46
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Rahbar, Elaheh; Ainsworth, Hannah C; Howard, Timothy D et al. (2017) Uncovering the DNA methylation landscape in key regulatory regions within the FADS cluster. PLoS One 12:e0180903
Chilton, Floyd H; Dutta, Rahul; Reynolds, Lindsay M et al. (2017) Precision Nutrition and Omega-3 Polyunsaturated Fatty Acids: A Case for Personalized Supplementation Approaches for the Prevention and Management of Human Diseases. Nutrients 9:
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