The combined risk effect among BIN1, CLU, and APOE genes in Alzheimer’s disease

Santos, Lígia Ramos dos; Almeida, Jucimara Ferreira Figueiredo; Pimassoni, Lucia Helena Sagrillo; Morelato, Renato Lírio; Paula, Fabiana Martins de

doi:10.1590/1678-4685-gmb-2018-0320

Cited by 9 publications

(3 citation statements)

References 42 publications

(50 reference statements)

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“…The CLU is located on chromosome 8p21.1 and contains nine exons. 18 A previous genome wide association study (GWAS) reported that variant in rs9331896 of CLU was significantly associated with AD in European populations, 15 suggesting that rs9331896 might be a potential polymorphism marker of neurodegenerative disease. As a result of the basically similar pathological features shared by AD and PD, they may have some common genetic modifiers/pathways.…”

Section: Discussionmentioning

confidence: 99%

Association of CLU gene polymorphism with Parkinson's disease in the Chinese Han population

Lin

Lü

Zhou

et al. 2020

The Journal of Gene Medicine

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Background: Clusterin (CLU) plays important role in the pathology of neurodegenerative disorders. Recently, a genetic variant of CLU rs9331896 has been reported as a risk estimate for Alzheimer's disease (AD). However, the association between this variant and the risk of Parkinson's disease (PD) in the Chinese Han population remains elusive. Methods: We sequenced CLU rs9331896 in 353 PD patients and 326 healthymatched individuals of the Chinese Han population. The genotypes of rs9331896 were analyzed using MassArray (Agena Bioscience, San Diego, CA, USA) in accordance with the manufacturer's instructions. The distribution of genotypes and allelic frequencies was analyzed by a chi-squared test. Additionally, the expression of CLU protein in plasma was evaluated by an enzyme-linked immunosorbent assay and analysed with a t-test. Results: The TT genotype in rs9331896 in a recessive model was found to be associated with the increased risk of PD (odds ratio = 1.408, 95% confidence interval = 1.034-1.916, p = 0.029). Subgroup analysis indicated that TT genotype carriers showed a significantly higher risk in male PD patients compared to male healthy controls (odds ratio = 1.611, 95% confidence interval = 1.046-2.483, p = 0.030). In addition, CLU levels in the plasma of PD patients were significantly higher than controls (p = 0.024). Conclusions: The CLU-rs9331896-TT genotype was a risk factor for PD, particularly in males. PD patients also expressed a high level of CLU in plasma.

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Section: Discussionmentioning

confidence: 99%

Association of CLU gene polymorphism with Parkinson's disease in the Chinese Han population

Lin

Lü

Zhou

et al. 2020

The Journal of Gene Medicine

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“…At the genetic markers level, several genes associated with the corpus of the oligodendrocyte ecosystem have been described as risk factors in late-onset AD [ 124 ]. In genomic association studies, the BIN1 (bridging integrator 1) gene is considered to be significantly involved in late AD behind the APOE gene [ 169 ]. It is mainly expressed in mature oligodendrocytes and white matter in rodents and humans, where it regulates membrane dynamics in the phenomena of endocytosis and membrane remodeling [ 37 ].…”

Section: Brain Markers Of Myelin In Alzheimer’s Patientsmentioning

confidence: 99%

Myelin in Alzheimer’s disease: culprit or bystander?

Maître

Jeltsch-David

Okechukwu

et al. 2023

acta neuropathol commun

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Alzheimer’s disease (AD) is a neurodegenerative disorder with neuronal and synaptic losses due to the accumulation of toxic amyloid β (Αβ) peptide oligomers, plaques, and tangles containing tau (tubulin-associated unit) protein. While familial AD is caused by specific mutations, the sporadic disease is more common and appears to result from a complex chronic brain neuroinflammation with mitochondriopathies, inducing free radicals’ accumulation. In aged brain, mutations in DNA and several unfolded proteins participate in a chronic amyloidosis response with a toxic effect on myelin sheath and axons, leading to cognitive deficits and dementia. Αβ peptides are the most frequent form of toxic amyloid oligomers. Accumulations of misfolded proteins during several years alters different metabolic mechanisms, induce chronic inflammatory and immune responses with toxic consequences on neuronal cells. Myelin composition and architecture may appear to be an early target for the toxic activity of Aβ peptides and others hydrophobic misfolded proteins. In this work, we describe the possible role of early myelin alterations in the genesis of neuronal alterations and the onset of symptomatology. We propose that some pathophysiological and clinical forms of the disease may arise from structural and metabolic disorders in the processes of myelination/demyelination of brain regions where the accumulation of non-functional toxic proteins is important. In these forms, the primacy of the deleterious role of amyloid peptides would be a matter of questioning and the initiating role of neuropathology would be primarily the fact of dysmyelination.

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“…The genetic component of AD risk, or genetics score, queries genetic evidence attributable to all loci identified by Ensembl (GRCh38, version 104)(8) as "gene", "pseudogene" or "ncRNA_gene" resulting in a total 60,664 loci. The score is based on evidence retrieved from both genome wide association studies (GWAS) as well as GWAS by proxy (GWAX) studies 15,16,74,[111][112][113][114][115][116][117][118][119][120][121][122][123] and quantitative trait locus (QTL) studies 40,50 (see Supp Table 3). For consistency across the different GWAS studies used, nominally significant variants (unadjusted p value < 0.05) from anywhere within a 200 kb window surrounding a given target gene's coordinates are assigned to the gene.…”

Section: Target Risk Score (Trs) Development and Processmentioning

confidence: 99%

Genetic and Multi-omic Risk Assessment of Alzheimer’s Disease Implicates Core Associated Biological Domains

Cary

Wiley

Gockley

et al. 2022

Preprint

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Alzheimer's disease (AD) is the predominant dementia globally, with heterogeneous presentation and penetrance of clinical symptoms, variable presence of mixed pathologies, potential disease subtypes, and numerous associated endophenotypes. Beyond the difficulty of designing treatments that address the core pathological characteristics of the disease, therapeutic development is challenged by the uncertainty of which endophenotypic areas and specific targets implicated by those endophenotypes to prioritize for further translational research. However, publicly-funded consortia driving large-scale open science efforts have produced multiple omic analyses that address both disease risk relevance and biological process involvement of genes across the genome. Here we report the development of an informatic pipeline that draws from genetic association studies, predicted variant impact, and linkage with dementia associated phenotypes to create a genetic risk score. This is paired with a multi-omic risk score utilizing extensive sets of both transcriptomic and proteomic studies to identify systems level changes in expression associated with AD. These two elements combined constitute our target risk score that ranks AD risk genome-wide. The ranked genes are organized into endophenotypic space through the development of 19 biological domains associated with AD in the described genetics and genomics studies and accompanying literature. The biological domains are constructed from exhaustive gene ontology (GO) term compilations, allowing automated assignment of genes into objectively defined disease-associated biology. This rank and organize approach, performed genome-wide, allows the characterization of aggregations of AD risk across biological domains. The top AD-risk associated biological domains are Synapse, Immune Response, Lipid Metabolism, Mitochondrial Metabolism, Structural Stabilization, and Proteostasis, with slightly lower levels of risk enrichment present within the other 13 biological domains. This provides an objective methodology to localize risk within specific biological endophenotypes, and drill down into the most significantly associated sets of GO-terms and annotated genes for potential therapeutic targets.

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The combined risk effect among BIN1, CLU, and APOE genes in Alzheimer’s disease

Cited by 9 publications

References 42 publications

Association of CLU gene polymorphism with Parkinson's disease in the Chinese Han population

Association of CLU gene polymorphism with Parkinson's disease in the Chinese Han population

Myelin in Alzheimer’s disease: culprit or bystander?

Genetic and Multi-omic Risk Assessment of Alzheimer’s Disease Implicates Core Associated Biological Domains

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