The Human Brainome: changes in expression of VGF, SPECC1L, HLA-DRA and RANBP3L act with APOE E4 to alter risk for late onset Alzheimer's disease.
Ontology highlight
ABSTRACT:
SUBMITTER: Branciamore S
PROVIDER: S-EPMC10760217 | biostudies-literature | 2023 Dec
REPOSITORIES: biostudies-literature
Publications
The Human Brainome: changes in expression of VGF, SPECC1L, HLA-DRA and RANBP3L act with APOE E4 to alter risk for late onset Alzheimer's disease.
Branciamore Sergio S Gogoshin Grigoriy G Rodin Andrei S AS Myers Amanda J AJ
Research square 20231214
While there are currently over 40 replicated genes with mapped risk alleles for Late Onset Alzheimer's disease (LOAD), the <i>Apolipoprotein</i> E locus E4 haplotype is still the biggest driver of risk, with odds ratios for neuropathologically confirmed E44 carriers exceeding 30 (95% confidence interval 16.59-58.75). We sought to address whether the <i>APOE</i> E4 haplotype modifies expression globally through networks of expression to increase LOAD risk. We have used the Human Brainome data to ...[more]
Similar Datasets
Project description:Apolipoprotein E4 (ApoE4) is one of three (E2, E3 and E4) human isoforms of an α-helical, 299-amino-acid protein. Homozygosity for the ε4 allele is the major genetic risk factor for developing late-onset Alzheimer's disease (AD). ApoE2, ApoE3 and ApoE4 differ at amino acid positions 112 and 158, and these sequence variations may confer conformational differences that underlie their participation in the risk of developing AD. Here, we compared the shape, oligomerization state, conformation and stability of ApoE isoforms using a range of complementary biophysical methods including small-angle x-ray scattering, analytical ultracentrifugation, circular dichroism, x-ray fiber diffraction and transmission electron microscopy We provide an in-depth and definitive study demonstrating that all three proteins are similar in stability and conformation. However, we show that ApoE4 has a propensity to polymerize to form wavy filaments, which do not share the characteristics of cross-β amyloid fibrils. Moreover, we provide evidence for the inhibition of ApoE4 fibril formation by ApoE3. This study shows that recombinant ApoE isoforms show no significant differences at the structural or conformational level. However, self-assembly of the ApoE4 isoform may play a role in pathogenesis, and these results open opportunities for uncovering new triggers for AD onset.
| S-EPMC6556554 | biostudies-literature
Project description:A rare missense APOE variant (L28P; APOE*4Pittsburgh), which is present only in populations with European ancestry, has been reported to be a risk factor for late-onset Alzheimer's disease (LOAD). However, due to the complete linkage disequilibrium of L28P with APOE*4 (C112R), its independent genetic association is uncertain. The original association study implicating L28P with LOAD risk was carried out in a relatively small sample size. In the current study, we have re-evaluated this association in a large case-control sample of 15,762 White U.S. subjects and investigated its independent effect in APOE 3/4 subjects, as L28P has been observed only in the heterozygous state of APOE*4 carriers and 3/4 is the most common genotype containing the APOE*4 allele. The heterozygous carrier frequency of L28P, all with APOE*4, was about 3-fold higher in AD cases than in cognitively intact controls (0.845% vs. 0.277%). The age- and sex-adjusted meta-analysis odds ratio (OR) was 2.87 (95% CI: 1.34 - 6.13; = 0.0066). Among APOE 3/4 subjects, age- and sex-adjusted meta-analysis OR was 1.53 (95% CI: 0.70 - 3.36; p = 0.28), indicating its effect was independent of APOE*4. The lack of statistical significance appears mainly due to the low power of 4138 subjects with the 3/4 genotype (12% power at α= 0.05) compared to the required sample of 139,088 subjects with the 3/4 genotype to detect an OR of 1.5 at α= 0.05 and 80% power. Our data suggesting that L28P has an independent genetic effect on AD risk is reinforced by earlier experimental findings showing that this mutation leads to significant structural and conformational changes in the ApoE4 molecule and can induce functional defects associated with neuronal Aβ42 accumulation and oxidative stress. Additional functional studies in cell-based systems and animal models will help to delineate its functional significance in the etiology of AD.
| S-EPMC9839598 | biostudies-literature
Project description:BackgroundThe APOE-ε4 allele is an established risk factor for Alzheimer's disease (AD). TOMM40 located adjacent to APOE has also been implicated in AD but reports of TOMM40 associations with AD that are independent of APOE-ε4 are at variance.MethodsWe investigated associations of AD with haplotypes defined by three TOMM40 and two APOE single nucleotide polymorphisms in 73 and 71 autopsy cases with intermediate and high likelihood of AD (defined by BRAAK stages <V and V-VI), respectively, and in 150 controls without major neurodegenerative diseases.ResultsWe observed eight haplotypes with a frequency >0.02. The two haplotypes encoding APOE-E4 showed strong associations with AD that did not differ between intermediate and high likelihood AD. In contrast, a TOMM40 haplotype encoding APOE-E3 was identified as risk haplotype of high- (p = .0186), but not intermediate likelihood AD (p = .7530). Furthermore, the variant allele of rs2075650 located in intron 2 of TOMM40, increased the risk of high-, but not intermediate likelihood AD on the APOE-ε3/ε3 background (p = .0230).ConclusionThe striking association of TOMM40 only with high likelihood AD may explain some contrasting results for TOMM40 in clinical studies and may reflect an association with more advanced disease and/or suggest a role of TOMM40 in the pathogenesis of neurofibrillary tangles.
| S-EPMC7434743 | biostudies-literature
Project description:PurposeApoE-e4 has a well-established connection to late-onset Alzheimer disease (AD) and is available clinically. Yet, there have been no analyses of payer coverage policies for ApoE. Our objective was to analyze private payer coverage policies for ApoE genetic testing, examine the rationales, and describe supporting evidence referenced by policies.MethodsWe searched for policies from the eight largest private payers (by member numbers) covering ApoE testing for late-onset AD. We implemented content analysis methods to evaluate policies for coverage decisions and rationales.ResultsSeven payers had policies with positions on ApoE testing. Five explicitly state they do not cover ApoE and two apply generic preauthorization criteria. Rationales supporting coverage decisions include: reference to guidelines or national standards, inadequate data supporting testing, characterizing testing as investigational, or that testing would not alter patients' clinical management.ConclusionSeven of the eight largest private payers' coverage policies reflect standards that discourage ApoE testing due to a lack of clinical utility. As the field advances, ApoE testing may have an important clinical role, particularly considering that disease-modifying therapies are under evaluation by the US Food and Drug Administration. These types of field advancements may not be consistent with private payers' policies and may cause payers to reevaluate existing coverage policies.
| S-EPMC8035237 | biostudies-literature
Project description:Neuropsychiatric symptoms, previously denominated as behavioural and psychological symptoms of dementia, are common features of Alzheimer's disease (AD) and are one of the major risk factors for institutionalization. At present, the role of the apolipoprotein E (APOE) gene in the development of neuropsychiatric symptoms in AD patients is unclear. In this paper, we summarized the findings of the studies of neuropsychiatric symptoms and neuropsychiatric syndromes/endophenotypes in AD in relation to APOE genotypes, with special attention to the possible underlying mechanisms. While some studies failed to find a significant association between APOE and neuropsychiatric symptoms in late-onset AD, other studies reported a significant association between the APOE ε4 allele and an increase in agitation/aggression, hallucinations, delusions, and late-life depression or anxiety. Furthermore, some negative studies that focused on the distribution of APOE genotypes between AD patients with or without neuropsychiatric symptoms further emphasized the importance of subgrouping neuropsychiatric symptoms in distinct neuropsychiatric syndromes. Explanations for the variable findings in the existing studies included differences in patient populations, differences in the assessment of neuropsychiatric symptomatology, and possible lack of statistical power to detect associations in the negative studies.
| S-EPMC3090058 | biostudies-literature
Project description:BackgroundMass vaccination has dramatically reduced the incidence of severe COVID-19, with most cases now presenting as self-limiting upper respiratory tract infections. However, those with co-morbidities, the elderly and immunocompromised, as well as the unvaccinated, remain disproportionately vulnerable to severe COVID-19 and its sequelae. Furthermore, as the effectiveness of vaccination wanes with time, immune escape SARS-CoV-2 variants could emerge to cause severe COVID-19. Reliable prognostic biomarkers for severe disease could be used as early indicator of re-emergence of severe COVID-19 as well as for triaging of patients for antiviral therapy.MethodsWe performed a systematic review and re-analysis of 7 publicly available datasets, analysing a total of 140 severe and 181 mild COVID-19 patients, to determine the most consistent differentially regulated genes in peripheral blood of severe COVID-19 patients. In addition, we included an independent cohort where blood transcriptomics of COVID-19 patients were prospectively and longitudinally monitored previously, to track the time in which these gene expression changes occur before nadir of respiratory function. Single cell RNA-sequencing of peripheral blood mononuclear cells from publicly available datasets was then used to determine the immune cell subsets involved.FindingsThe most consistent differentially regulated genes in peripheral blood of severe COVID-19 patients were MCEMP1, HLA-DRA and ETS1 across the 7 transcriptomics datasets. Moreover, we found significantly heightened MCEMP1 and reduced HLA-DRA expression as early as four days before the nadir of respiratory function, and the differential expression of MCEMP1 and HLA-DRA occurred predominantly in CD14+ cells. The online platform which we developed is publicly available at https://kuanrongchan-covid19-severity-app-t7l38g.streamlitapp.com/, for users to query gene expression differences between severe and mild COVID-19 patients in these datasets.InterpretationElevated MCEMP1 and reduced HLA-DRA gene expression in CD14+ cells during the early phase of disease are prognostic of severe COVID-19.FundingK.R.C is funded by the National Medical Research Council (NMRC) of Singapore under the Open Fund Individual Research Grant (MOH-000610). E.E.O. is funded by the NMRC Senior Clinician-Scientist Award (MOH-000135-00). J.G.H.L. is funded by the NMRC under the Clinician-Scientist Award (NMRC/CSAINV/013/2016-01). S.K. is funded by the NMRC under the Transition Award. This study was sponsored in part by a generous gift from The Hour Glass.
| S-EPMC9934388 | biostudies-literature
Project description:BackgroundLow-grade gliomas (LGG) are WHO grade II tumors presenting as the most common primary malignant brain tumors in adults. Currently, LGG treatment involves either or a combination of surgery, radiation therapy, and chemotherapy. Despite the knowledge of constitutive genetic risk factors contributing to gliomas, the role of single genes as diagnostic and prognostic biomarkers is limited. The aim of the current study is to discover the predictive and prognostic genetic markers for LGG.MethodsTranscriptome data and clinical data were obtained from The Cancer Genome Atlas (TCGA) database. We first performed the tumor microenvironment (TME) survival analysis using the Kaplan-Meier method. An analysis was undertaken to screen for differentially expressed genes. The function of these genes was studied by Gene Ontology (GO) enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. Following which a protein-protein interaction network (PPI) was constructed and visualized. Univariate and multivariate COX analyses were performed to obtain the probable prognostic genes. The key genes were selected by an intersection of core and prognostic genes. A clinical correlation analysis of single-gene expression was undertaken. GSEA enrichment analysis was performed to identify the function of key genes. Finally, a single gene-related correlation analysis was performed to identify the core immune cells involved in the development of LGG.ResultsA total of 529 transcriptome data and 515 clinical samples were obtained from the TCGA. Immune cells and stromal cells were found to be significantly increased in the LGG microenvironment. The top five core genes intersected with the top 38 prognostically relevant genes and two key genes were identified. Our analysis revealed that a high expression of HLA-DRA was associated with a poor prognosis of LGG. Correlation analysis of immune cells showed that HLA-DRA expression level was related to immune infiltration, positively related to macrophage M1 phenotype, and negatively related to activation of NK cells.ConclusionsHLA-DRA may be an independent prognostic indicator and an important biomarker for diagnosing and predicting survival in LGG patients. It may also be associated with the immune infiltration phenotype in LGG.
| S-EPMC9118678 | biostudies-literature
Project description:Background and Objectives: Abnormal expressions of CD74 and human leukocyte antigen-DR alpha (HLA-DRA) have been reported in various cancers, though their roles in cervical cancer remain unclear. This study aimed to evaluate the gene and protein expressions of CD74 and HLA-DRA in the progression from normal cervix to precancerous cervical intraepithelial neoplasia (CIN) and finally to squamous cell carcinoma (SCC). Materials and Methods: The gene expression profiles of CD74 and HLA-DRA were determined in formalin-fixed paraffin-embedded tissues, with three samples each from normal cervixes, human papillomavirus type 16/18-positive, low-grade CIN (LGCIN), high-grade CIN (HGCIN), and squamous cell carcinoma (SCC) using Human Transcriptome Array 2.0. Immunohistochemical expression of the proteins was semi-quantitatively assessed in another cohort of tissue microarray samples comprising 7 normal cervix cases, 10 LGCIN, 10 HGCIN, and 95 SCC. Results: The transcriptomics profile and proteins' expression demonstrated similar trends of upregulation of CD74 and HLA-DRA from normal cervix to CIN and highest in SCC. There was a significant difference in both proteins' expression between the histological groups (p = 0.0001). CD74 and HLA-DRA expressions were significantly associated with CIN grade (p = 0.001 and p = 0.030, respectively) but not with the subjects' age or SCC stage. Further analysis revealed a positive correlation between CD74 and HLA-DRA proteins. Conclusions: CD74 appears to promote cervical carcinogenesis via oncogenic signalling mechanisms and may serve as a potential antitumour target. Additionally, the upregulation of HLA-DRA, often associated with stronger immunogenicity, could be a promising biomarker for developing immunotherapies.
| S-EPMC8877221 | biostudies-literature
Project description:Major histocompatibility complex class II (MHC-II) genes are fundamental components that contribute to adaptive immune responses. While characterization of the chromatin features at the core promoter region of these genes has been studied, the scope of histone modifications and the modifying factors responsible for activation of these genes are less well defined. Using the MHC-II gene HLA-DRA as a model, the extent and distribution of major histone modifications associated with active expression were defined in interferon-γ induced epithelial cells, B cells, and B-cell mutants for MHC-II expression. With active transcription, nucleosome density around the proximal regulatory region was diminished and histone acetylation and methylation modifications were distributed throughout the gene in distinct patterns that were dependent on the modification examined. Irrespective of the location, the majority of these modifications were dependent on the binding of either the X-box binding factor RFX or the class II transactivator (CIITA) to the proximal regulatory region. Importantly, once established, the modifications were stable through multiple cell divisions after the activating stimulus was removed, suggesting that activation of this system resulted in an epigenetic state. A dual crosslinking chromatin immunoprecipitation method was used to detect histone modifying protein components that interacted across the gene. Components of the MLL methyltransferase and GCN5 acetyltransferase complexes were identified. Some MLL complex components were found to be CIITA independent, including MLL1, ASH2L and RbBP5. Likewise, GCN5 containing acetyltransferase complex components belonging to the ATAC and STAGA complexes were also identified. These results suggest that multiple complexes are either used or are assembled as the gene is activated for expression. Together the results define and illustrate a complex network of histone modifying proteins and multisubunit complexes participating in MHC-II transcription.
| S-EPMC3365104 | biostudies-literature
Project description:Our aim is to explore the linkage between single nucleotide polymorphisms (SNPs) in human leukocyte antigen (HLA)-DRA and Parkinson's disease (PD). 542 sporadic PD patients and 674 healthy controls were recruited to investigate this association in the Chinese population by the screening of 15 SNPs in HLA-DRA, and the association of rs3129882 was further re-evaluated by performing meta-analysis and meta-regression analysis. No SNPs in HLA-DRA were significantly associated with PD in the Chinese patients. Although the rs3129882 allele-G frequency in the Caucasian population was lower than that in Chinese population, meta-analysis showed no association of rs3129882 allele-G with PD in the Chinese or Caucasian population. In consideration of the heterogeneity (I(2)=78.6%, Q=66.33, p<0.000), subgroup analysis was performed, revealing a significant association between rs3129882 and PD in the Caucasian patients from the genome-wide association studies (OR=1.22, 95% CI: 1.16, 1.27); however, this association was not consistently observed in the studies performed using other DNA sequencing techniques. Meta-regression analysis, which accounted for 58.3% of the heterogeneity, revealed that the impact of the sequencing technique used was significant (p=0.027) compared with ethnicity. Regression analysis of the Caucasian population further showed that the sequencing technique used contributed to 71.2% of the heterogeneity (p=0.033). Our data support the absence of a linkage between the risk loci in HLA-DRA and PD in Chinese patients. The different DNA sequencing techniques used in PD studies may largely account for the controversial conclusions concerning rs3129882.
| S-EPMC4788728 | biostudies-literature