Browsing by Author "Barber, Robert"
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Item Association between everyday perceived discrimination and cognitive function as mediated by depression in diverse populations: A HABS-HD Study(2024-03-21) Mendoza, Edna Patricia; Nolan, Emma; Phillips, Nicole; Barber, Robert; O'Bryant, Sid; Zhou, ZhengyangPurpose: Previous research suggests that perceived discrimination is associated with cognitive function impairment, and such association is mediated by depression. With minority populations continuously growing, it is crucial to investigate such relationships in diverse populations. This study aims to examine and compare the above relationships among non-Hispanic white (NHW), Mexican American (MA), and African American (AA) participants. Method: A sample size of 1,129 participants (640 AAs, 248 NHWs, 241 MAs) aged 50+ came from the Health and Aging Brain Study – Health Disparities (HABS-HD). Structural equation modelling (SEM) was conducted to explore the effect between perceived discrimination, measured by the Everyday Discrimination Scale mean score, and cognitive function, measured by the Mini Mental State Examination (MMSE) Score. The mediation effect of depression, measured by the Geriatric Depression Scale total score, was evaluated by the indirect effect estimate using SEM. Result: Everyday perceived discrimination negatively influenced cognitive function, and the effect was mediated by depression across the three populations (β= -0.15, 95% CI = [-0.22, -0.08]). When stratified, the mediation effect of depression on the association between discrimination and cognitive function remained significant for NHW (β= -0.37, 95% CI = [-0.60, -0.15]) and MA (β = -0.27, 95% CI = [-0.50, -0.05]). However, such mediation effect was not observed for the AA population. Conclusion: Depression mediates the link between everyday discrimination and cognitive decline, but differences between racial/ethnic groups underscore the need for further research into underlying mechanisms among minority groups, including Mexican American and African American populations. Depression interventions may mitigate negative cognitive effects from discrimination. Tailoring such interventions by race/ethnicity and targeting at-risk groups could optimally promote cognitive health.Item Case-Case Genome-Wide Association Study of Age-Related Cancer and Alzheimer’s Disease(2017-03-14) Barber, Robert; Phillips, Nicole R.; Olmstead, KeeganBackground: Research over the past five years has strengthened in support of an inverse epidemiological correlation between Alzheimer’s disease (AD) and cancer--individuals with cancer are less likely to develop AD and those with AD have reduced cancer risk. Since cancer is characterized by uncontrolled cell division, and AD by neuronal death (and limited neuronal regeneration), this inverse relationship may point to dysregulation in some common underlying pathways. Here, we aim to investigate the genetic underpinnings of this unique relationship which have not been fully explored, using a unique case-case genome-wide association study (GWAS) design between an AD and cancer cohort. Hypothesis: We hypothesize that suggestive association signals will be observed when comparing the AD to cancer group, with the most interesting signals being those that are stronger when comparing cases-to-cases than when comparing cases-to-controls. Methods: Genome-wide SNP data for AD, Cancer, and Control groups were created using two publically available datasets: Breast Cancer (BrCa) and Prostate Cancer (PCa) Cohort Consortium and Alzheimer’s Disease Neuroimaging Initiative. Breast and prostate cancer were combined to form the Cancer group, which according to Cancer Research UK, are the most prevalent forms of adult and elderly cancers. All samples were typed with the Illumina Human610-Quad BeadChip. Rigorous data management and quality control measures were taken: group matching, updating map location, permutations test, sex check and filtering of low genotyping individuals and loci as well as loci with HWE issues. Three association analyses were performed: AD–Control, Cancer–Control, and AD–Cancer. Results: After matching for age, gender, and Caucasian ethnicity 492 individuals were included in the AD group (Avg age: 75 years, 37% female), 691 individuals in Cancer group (Avg age: 67.7 years, 37% female), and 1150 individuals in the combined Control group (avg age: 71 years, 37% female). Association analysis of the AD–Cancer study indicated one marker, rs2075650, as significant at p -8. Initial analysis also indicated possible clustering of significant SNPs on chromosomes 8 and 11. Conclusions: Case-case GWAS provides a novel means for identifying novel loci involved in the dichotomous relationship of risk of AD and risk of BrCa/PCa. These signals may point to critical genomic regions involved in age-related pathologies of cancer and AD.Item Comparing Methylation of CRP and IL-6 Associated Genes in Cognitively Impaired Mexican Americans to Non-Hispanic Whites(2024-03-21) Sotelo, Joseph; DeLeon, Justin; Housini, Mohammad; Phillips, Nicole; Barber, RobertPurpose: A large pool of literature shows that Alzheimer’s Disease (AD) results from inflammatory processes and neuronal loss via tau proteins and amyloid-β plaques. Mexican Americans are among those with the highest risk of developing Alzheimer’s and research into the epigenetics of this association is lacking. Methylation alterations are influenced by both genetic and lifestyle factors, which can help us identify the root cause of mild cognitive impairment, a precursor for Alzheimer’s Disease. C-reactive protein and interleukin 6 are well known for their roles in measuring systemic inflammation. This study seeks to explore if there is a significant difference between DNA methylation of CpG Islands for CRP and IL6-associated genes in Cognitively Impaired Mexican Americans (MA) and Non-Hispanic Whites (NHW). Methods: Participants were selected from the Texas Alzheimer’s Research and Care Consortium (TARCC) database. The final cohort (n = 551) consisted of 252 NHW (143 normal cognition (NC), and 109 cognitively impaired (CI)) and 299 MA participants (177 NC and 122 CI). Each participant underwent neurocognitive tests such as Clinical Dementia Rating (CDR) and Mini-Mental State Exam (MMSE) to determine cognitive status. Methylation at CpG sites was measured by array probes as beta values with 0=unmethylated, to 1=fully methylated site. CpG sites associated with CRP are cg06126421, cg10636246, cg18181703, cg19821297, and cg25325512. CpG sites associated with IL6 are cg12929678, cg17412005, cg19638572, cg20789595. Any differences between cognitively impaired participants and normal controls were assessed using the standard two-sample t-test assuming unequal variances in Rstudio. Linear Regression was performed in Rstudio, and covariates that were adjusted for include age, sex, education level (in years), APOE ɛ4 allele status, CD8 T-cells, CD4 T-cells, natural killer cells, B-cells, monocytes, and neutrophils. Results: In Mexican Americans, the CRP-associated sites showed: cg25325512 (gene FGD2) with significant hypomethylation in the CI group (p=0.0003). Cg19821297 (gene DNASE2) with significant hypomethylation in the CI group (p=0.015). Cg10636246 (genes AIM2 & IF116) had significant CI group hypomethylation (p=0.02). In Non-Hispanic Whites, one CRP-associated site showed significant hypermethylation in the CI group, cg06690548 (gene TUBB) (p=0.026). In Mexican Americans, the IL6-associated sites showed: cg17412005 (gene MUTYH & TOE1) with significant hypomethylation in the CI group (p=0.022). Cg19638572 (gene RASSF5) with significant hypermethylation in the CI group (p=0.013). Cg20789595 (gene ADCY5) with significant hypomethylation in the CI group (p<0.001). In Non-Hispanic Whites, zero IL6-associated sites showed any significant methylation between the CI and NC groups. Conclusion: Epigenetics related to AD is still being further investigated. This study suggests an association between hypomethylated CRP and IL6 genes and cognitive impairment in the Mexican American population. Limitations in this study include a limited number of CpG sites investigated, as well as possible comorbidities that should be adjusted for. There were also an unequal number of MA to NHW participants. Further studies should adjust for inflammatory comorbidities, such as metabolic syndrome, and further investigation is warranted into the FGD2 gene and ADCY5 gene as they were strongly correlated with hypomethylation in the cognitively impaired Mexican American population.Item Epigenetic Changes of Nuclear-Encoded Oxidative Phosphorylation Genes and Cognitive Function: A Study of Mexican Americans and Non-Hispanic Whites(2024-03-21) Swami, Anjana; Daniel, Ann Abraham; Silzer, Talisa; Sun, Jie; Barber, Robert; Phillips, NicolePurpose: There is a higher prevalence of metabolic disease and Alzheimer’s Disease (AD) in Mexican Americans (MA). Despite this data, there has been minimal research done on the methylation status of genes involved in mitochondrial oxidative phosphorylation (OXPHOS)/cellular metabolism and how this influences the risk for developing cognitive impairment (CI). Methods: Results were derived from 299 MAs and 252 non-Hispanic Whites (NHW), all of whom were participants of the Texas Alzheimer’s Research and Care Consortium (TARCC). Themethylation status of CpG sites was assessed by running peripheral blood samples on the InfiniumMethylationEPIC BeadChip array. Results: Based on a Bonferroni adjusted alpha of7.36485 x 10⁶, six differentially methylated sites were significant in MAs: cg07470503, cg10057295, cg13823120, cg26891598, cg21490662, and cg17904988. All the sites were hypomethylated in CI/AD cohorts compared to NC except for cg26891598. There were no sites of significance in NHWs. Conclusions: The strongest association with CI/AD within the MA cohort was at cg07470503, with a p-value of 1.00 x 10⁶ in MAs. This CpG site is found within the DGUOK gene. The DGUOK gene is responsible for making the enzyme deoxyguanosine kinase, which is needed to properly create mitochondrial DNA; a dysfunctional gene leads to impaired mitochondrial function that could decrease the efficiency of OXPHOS. The abnormal cellular metabolism that ensues could set up the foundation for neurodegeneration to occur. Moving forward, the cg07470503 site could serve as a marker to identify the risk of metabolic disease and consequent CI/AD in MA patients.Item Epistatic impact of APOE and ACE2 genetic variants on SARS-CoV-2 and RAS dependent blood-brain barrier dysregulation.(2024-03-21) Tate, Amanda; Barber, Robert; Park, Inwoo; Jones, Harlan; Phillips, NicoleCoronavirus disease 2019 (COVID-19) is associated with respiratory and neurodegenerative symptoms, creating a need to understand the additional impact the pandemic might have on neurodegeneration and risk for neurodegenerative diseases, such as Alzheimer’s disease (AD) in aging populations post 2020. The blood-brain barrier (BBB) is an important interface that connects the periphery to the brain through the vasculature. When this protective barrier becomes dysregulated, the brain is vulnerable to infection, neuroinflammation, and cellular stress, which over time can lead to neurodegeneration and cognitive decline. The renin-angiotensin system (RAS) is an important regulator of vasculature via the activity of the hormone angiotensin II (Ang II). As a mediator of vasoconstrictive, oxidation, and inflammatory responses, its prolonged activity can be damaging and promote neurodegeneration at the BBB. Angiotensin-converting enzyme 2 (ACE2) is highly expressed in endothelial cells which cleaves Ang II into less harmful fragments to offset these potentially toxic effects. Genetic variants of ACE2 are increasingly considered risk factors for the development of vascular disorders (e.g. hypertension) due to their role in RAS-mediated dysregulation of body vasculature. Recent genetic studies have identified a relationship between genetic variants for ACE2, an obligate receptor for the severe acute respiratory syndrome coronavirus 2 (SCoV2), and increased risk and or/severity of COVID-19. Alzheimer’s disease (AD) is the greatest neurological risk among aging individuals and can be caused by both environmental & genetic risk factors. The strongest genetic risk factor for AD is variants in the apolipoprotein E gene (APOE), with the ɛ4 allele being associated with increased levels of amyloid β (Aβ), Tau proteins (p-Tau), neuroinflammation, and BBB permeability. A recent study by Wang et al also suggests a correlation between APOE ɛ4 and increased severity of COVID-19, suggesting some interplay between APOE and host factors related to SCoV2 infection. Furthermore, both ACE2 and APOE genetic variants disproportionately impact minority populations, highlighting a need to understand the health disparity of AD and COVID-19 risk across demographic groups. We hypothesize gene interactions (epistatic interactions) between genetic variants in ACE2 and APOE may exacerbate RAS-mediated BBB dysregulation, leading to increased AD phenotypes and SCoV2 neurological dysregulation. To address this hypothesis, we will create endothelial cells, astrocytes, and neurons containing APOE and ACE2 genetic variants of interest. These epistatic cells will be assessed for expression and functional changes related to BBB integrity. Using Ang II treatments and SCoV2 pseudo-virus models, we will assess the impact of COVID-19 and RAS on BBB integrity and functions. This study will help us understand the mechanisms and interplay of genetic risks for AD and COVID-19 related to RAS-mediated BBB dysregulation, potentially highlighting comorbidities among the aging population. By focusing on ACE2 variants disproportionately found in minority populations, we will provide knowledge surrounding two co-morbidities for neurodegeneration and elevate those at the highest risk for developing AD and/or COVID-19. Funding: This work is supported by the Neurobiology of Aging and Alzheimer’s Disease T32 Training Fellowship, and the IMSD Fellowship, Grant # 5 R25 GM125587-05 from the National Institutes of General Medical Sciences (NIGMS).Item Genetic Differentiation of Hispanic Populations Using Ancestry Informative Markers(2017-03-14) Cross, Deanna; Chakraborty, Ranajit; Planz, John; Eisenberg, Arthur; Barber, Robert; Setser, CasandraHypothesis: There are at least 10,500 unidentified human remains in the US as of August 2015, with 2,041 of presumed Hispanic origin (NamUs 2015). Conventional DNA analysis identifies an individual through comparison with reference profiles. For those with no reference, panels of ancestry informative single nucleotide polymorphisms (SNPs) exist (Kidd 2014, Seldin 2009), but they focus on global differentiation and are not useful for ancestry determination of admixed populations (e.g. Hispanics). We hypothesize that a small panel of SNPs ascertained from appropriate populations with great genetic differentiation can distinguish ancestry within Hispanic populations. Materials: This bioinformatics study uses the Genomic Origins and Ancestry in Latinos (GOAL) data set of 250 individuals with ancestry from Columbia, Cuba, Dominican Republic, Haiti, Honduras, or Puerto Rico, genotyped using the Affymetrix 6.0 chip to develop an informative Hispanic SNP panel. Methods: Starting with 897,336 SNPs, we trimmed to 531,878 SNPs using linkage disequilibrium of 0.7. We then calculated pairwise FST for each SNP with each population pair using PLINK software (Haiti excluded). SNPs that met the 0.15 threshold for the four comparisons were included in a 1217 SNP panel. We used STRUCTURE to visualize population separation. To determine if a smaller SNP set could be utilized while retaining information, we used the SNPs with the top ten mean FST values from each population plus five extra to try to distinguish Cuba vs. Dominican Republic for a condensed panel of 56 SNPs. Additionally, we combined 1000 Genomes and GOAL data to verify whether the countries differentiate ancestrally or geographically. Results: STRUCTURE analysis showed Honduras was easily distinguished from other countries in the 1217 and 56 SNP panels. Other countries were also separated based on contribution from ancestral populations; however, the separation was less than ideal. Notably, Honduras contributed 71% of the SNPs in the 1217 panel. When analyzed with 1000 Genomes data, Honduras separated with the Chinese population for K=1-3, but was the first GOAL population to separate from the ancestral line. Conclusions: Utilizing an efficient SNP panel consistently separated Honduras from other populations demonstrating proof of concept. Greater separation of country of origin may be seen with a larger data set and alternative selection of each population’s number of SNPs by a cumulative mean FST threshold.Item Longitudinal microRNA profiling of neuronal-enriched exosomes associated with cognitive function and decline(2024-03-21) Subasinghe, Kumudu; Hall, Courtney; Zhou, Zhengyang; Barber, Robert; Phillips, NicoleBackground. Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that disproportionately affects several racial/ethnic groups, including Mexican Americans (MAs). Evidence suggests that early alterations in the AD brain can propagate to local and distal cells through small biological packages called exosomes. Exosomes secreted by neurons are capable of mediating cell-to-cell communication through their bioactive cargo, leading to metabolic and epigenetic reprogramming in target cells. Exosomes derived from neurons have been detected in plasma and isolated from other subpopulations using the neural cell adhesion molecule CD171. These neuronal-enriched exosomes (NEEs) cross the blood-brain barrier and thus represent an easily accessible derivative of otherwise inaccessible brain tissue in living humans. Small, non-coding RNAs called microRNAs (miRNA) are transcribed from nuclear DNA and function as strong intracellular expression regulators. miRNAs, which can be selectively packaged and transported by exosomes, have been shown to significantly alter the expression patterns of target cells. This project aims to identify the aberrant miRNA profiles that correlate with disease progression and key comorbidities (e.g., type 2 diabetes (T2D), hyperlipidemia, hypertension) in NEEs of plasma from MAs and Non-Hispanic Whites (NHWs). Hypothesis. We hypothesize that population-specific differences in NEE miRNA cargo will reflect cognitive function and decline. Methods. Longitudinal plasma samples (two time points, 2 years apart) received from the Texas Alzheimer’s Research and Care Consortium (TARCC) were processed using a two-step method that involves precipitation of total exosomes followed by NEE capture with a biotinylated antibody against the neuronal surface marker, CD171. After isolating RNA from NEEs, miRNAs were then profiled using next-generation sequencing. These profiles were then analyzed for differential miRNA expression in individuals with cognitive impairment compared to the normal control group. Results. Our preliminary quality control and sequencing data confirmed the successful isolation of miRNA from NEEs. We identified specific miRNA candidates that were differentially expressed in NEEs from cognitively impaired subjects compared to healthy controls. These miRNAs target gene networks that have been implicated in AD pathophysiology. Conclusion. This innovative workflow along with the unique sample type provides novel insight into the role of exosomal miRNA cargo in AD pathogenesis, identifying novel, population-specific targets for biomarker/diagnosis as well as therapeutic design. Further, this approach provides a conceptual framework for blood-based exosomal profiling in other complex diseases characterized by epigenetic dysregulation and systemic inflammation.Item Methylation of IL-6 & TNF-α Associated Genes in Cognitive Impairment: A Texas Alzheimer's Research & Care Consortium (TARCC) Study(2024-03-21) Deleon, Justin; Sotelo, Joseph; Housini, Mohammad; Phillips, Nicole; Barber, RobertPurpose: The Mexican American (MA) population poses one of the highest risk groups for the development of Alzheimer’s Disease (AD). Inflammatory biomarkers, such as IL-6 and TNF-a, have been associated with cognitive decline but most only in non-Hispanic Whites (NHWs). Epigenetic DNA methylation of CpG islands associated with inflammatory markers (IL-6 and TNF-a) have been studied and identified in other diseases but literature for its effects on cognitive impairment (CI), especially in MAs, is quite sparse. This study aims to determine if DNA methylation of CpG islands for IL-6 and TNF-a are associated with CI in a MA and NHW cohort. Methods: Utilizing the TARCC cohort (N = 551), participants within ethnic groups (N = 299 MAs, N = 252 NHWs) were stratified by cognitive status (normal cognition (NC) or CI). Methylation data at CpG sites were measured as beta values by array probes using the Illumina EPIC array. Linear regression analysis was performed in R comparing the beta value and cognitive diagnosis (NC or CI) for MA and NHW. Covariates include age, sex, education, CD8T cells, CD4T cells, B cells, monocytes, neutrophils, and the APOE gene. Result: The methylation sites cg04381957 and cg04583842 (both associated with IL-6) were significant within MAs. Those sites suggest hypomethylation and hypermethylation, respectively, in CI compared to the NC. Methylation site cg16411857 (associated with TNF-a) was not significant with CI in either MAs or NHWs. Conclusion: There was a stronger association with IL-6 related CpG sites and CI especially in MA at cg04381957 (p = 0.0035) within the RFTN1 gene. Future research plans to include inflammatory syndromes, such as diabetes, which could be a potential confounding variable affecting levels of IL-6 or TNF-a.Item The genomic architecture of the latent variable δ homolog (dEQ) in Mexican Americans and non-Hispanic whites(2020) Phillips, Nicole; Silzer, Talisa; Barber, Robert; Royall, Don; Palmer, Raymond; Colmenarez, MicaelaThe latent variable δ homolog (dEQ) has been established as a reliable indicator of cognitive performance and a predictor of future dementia. Here, we sought to identify genetic variants underlying dEQ in both non-Hispanic White (NWH) and Mexican American (MA) populations, hypothesizing that novel genomic risk loci for dementia will be implicated in the MA cohort. Genotyping was performed on the TARCC cohort using the Illumina® MEGA Array, which includes ~1.7 million SNPs. dEQ was generated by Donald Royall and Ray Palmer (UT Health Science Center @ San Antonio) for the entire genotyped cohort (nNHW= 1572; nMA=1030). Association testing was conducted using PLINK (Purcell et al., 2007) according to standard procedures (Anderson et al., 2010). The primary genetic association with dEQ in NHW is the TOMM40/APOE locus (rs4420638, p=9.477x10-32); the association for this locus in the MA cohort was much less significant (p=3.886x10-5). Among MAs, three interesting and unique loci emerged as suggestive: XIRP2 (chr2, rs7595556 p=8.165x10-6), KIF13A (chr6, rs7766167, p= 3.404x10-6), and LINC00907 (chr18, rs237972, p=7.88x10-7). The loci discovered in the MA cohort have not previously been implicated in dementia/Alzheimer's disease; however, variants in these genes have been associated with metabolic phenotypes that are particularly relevant to the pathophysiology of cognitive decline in MAs: diabetic neuropathy, epigenetic aging, and childhood obesity. Further investigation of these genomic regions may illuminate mechanisms by which metabolic syndromes may confer risk for earlier onset of age-related cognitive decline in MAs.