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Functional characterization of three single-nucleotide polymorphisms present in the human APOE promoter sequence: Differential effects in neuronal cells and on DNA-protein interactions.

ABSTRACT: Variations in levels of apolipoprotein E (ApoE) have been tied to the risk and progression of Alzheimer's disease (AD). Our group has previously compared and contrasted the promoters of the mouse and human ApoE gene (APOE) promoter sequences and found notable similarities and significant differences that suggest the importance of the APOE promoter's role in the human disease. We examine here three specific single-nucleotide polymorphisms within the human APOE promoter region, specifically at -491 (A/T), -427 (T/C), and at -219 (G/T) upstream from the +1 transcription start site. The -219 and -491 polymorphic variations have significant association with instance of AD, and -491AA has significant risk even when stratified for the APOEepsilon4 allele. We also show significant effects on reporter gene expression in neuronal cell cultures, and, notably, these effects are modified by species origin of the cells. The -491 and -219 polymorphisms may have an interactive effect in addition to any independent activity. DNA-protein interactions differ between each polymorphic state. We propose SP1 and GATA as candidates for regulatory control of the -491 and -219 polymorphic sites. This work's significance lies in drawing connection among APOE promoter polymorphisms' associations with AD to functional promoter activity differences and specific changes in DNA-protein interactions in cell culture-based assays. Taken together, these results suggest that APOE expression levels are a risk factor for AD irrespective of APOEepsilon4 allele status.

SUBMITTER: Maloney B

PROVIDER: S-EPMC5875733 | biostudies-literature | 2010 Jan

REPOSITORIES: biostudies-literature

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Functional characterization of three single-nucleotide polymorphisms present in the human APOE promoter sequence: Differential effects in neuronal cells and on DNA-protein interactions.

Maloney Bryan B Ge Yuan-Wen YW Petersen Ronald C RC Hardy John J Rogers Jack T JT Pérez-Tur Jordi J Lahiri Debomoy K DK

American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 20100101 1

Variations in levels of apolipoprotein E (ApoE) have been tied to the risk and progression of Alzheimer's disease (AD). Our group has previously compared and contrasted the promoters of the mouse and human ApoE gene (APOE) promoter sequences and found notable similarities and significant differences that suggest the importance of the APOE promoter's role in the human disease. We examine here three specific single-nucleotide polymorphisms within the human APOE promoter region, specifically at -49 ...[more]

PMID: 19504470

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Project description:Over the past two decades, the APOE gene and its polymorphisms have been among the most studied risk factors of Alzheimer disease (AD) development; yet, there are discrepancies between various studies regarding their impact. For this reason, the evaluation of the APOE genotype has not been included in the current European Federation of Neurological Societies guidelines for AD diagnosis and management. This aim of this study was to add to this discussion by assessing the possible influence of multiple polymorphisms in the promoter region of the APOE gene and genotypes of its allele E on the risk for dementia.We performed a comprehensive analysis of APOE gene polymorphisms, assessed the detected genotypes and correlated molecular findings with serum apolipoprotein E concentrations. The study comprised 110 patients with AD and 110 age-matched healthy individuals from the Polish population.Four polymorphisms of the APOE gene had minor allele frequency exceeding 5% and were included in the analysis: -491A/T (rs449647), -427T/C (rs769446), -219T/G (rs405509) in the promoter region and +113G/C (rs440446) in intron 1. A protective effect of the -219G allele on AD development was observed. Also, the -491T and -219G alleles were found to be underrepresented in the carriers of the APOE E4 variant. On the basis of the genotype and linkage disequilibrium studies, a relative score was attributed to given genotypes with respect to the estimated probability of their protective effects against AD, giving rise to the 'preventive score'. This 'preventive score', based on the total sums of the relative scores, expresses the protective effect deriving from the synergistic action of individual single-nucleotide polymorphisms. The 'preventive score' was identified as an independent predictive factor.We propose a novel, more complex approach to AD risk assessment based on the additive effect of multiple polymorphic loci within the APOE promoter region, which on their own may have too weak an impact to reach the level of significance. This has potentially practical implications, as it may help to improve the informative potential of APOE testing in a clinical setting. Subsequent studies of the proposed system in large, multi-ethnic cohorts are necessary for its validation and to assess its potential practical value for clinical applications.

Project description:ObjectiveTo analyze the relationship between plasma metal elements, ApoE gene polymorphisms and the interaction between the two and impaired cognitive function in elderly population.MethodA stratified sample was drawn according to the age of the study population, and 911 subjects were included. Baseline information and health indicators were obtained, and cognitive function status was assessed by health examination, a general questionnaire and Mini-Mental Status Examination. Plasma metal elements were measured, and SNP typing was performed. Binary logistic regression was used to analyze the factors influencing cognitive function status and the association between the SNP genetic pattern of the ApoE gene and cognitive function.ResultsThe differences in gene frequencies and genotype frequencies of the ApoE rs7412 and rs7259620 genotype frequencies were statistically different between the cognitive impairment group and the control group (P < 0.05). statistically differences were found for the codominant model in rs7412-TT compared with the CC genotype (OR = 3.112 (1.159-8.359), P = 0.024) and rs7259620-AA compared with the GG genotype (OR = 1.588 (1.007-2.504), P = 0.047). Statistically differences were found in the recessive models rs7412-TT compared with (CC + CT) (OR = 2.979 (1.112-7.978), P = 0.030), rs7259620-AA compared with (GG + GA), and rs405509-GG compared with (TT + TG) (OR = 1.548(1.022-2.344), P = 0.039) all of which increased the risk of developing cognitive impairment. The differences in plasma Fe, Cu, and Rb concentrations between the case and control groups were significant (P < 0.05). The regression results showed that the plasma Cd concentrations in the Q1 range was a protective factor for cognitive function compared with Q4 (0.510 (0.291-0.892), P = 0.018). Furthermore, there was a multiplicative interaction between the codominant and recessive models for the Q2 concentrations of Cd and the rs7259620 loci, and the difference was significant, indicating increased risk of developing cognitive impairment (codominant model OR = 3.577 (1.496-8.555), P = 0.004, recessive model OR = 3.505 (1.479-8.307), P = 0.004). There was also a multiplicative interaction between Cd and the recessive model at the rs405509 loci, and the difference was significant, indicating increased risk of developing cognitive impairment (OR = 3.169 (1.400-7.175), P = 0.006).ConclusionThe ApoE rs7412, rs7259620 and rs405509 loci were associated with cognitive impairment in the elderly population, and there was an interaction between plasma metalloid Cd and the rs7259620 and rs405509 loci that increased the risk of cognitive impairment in the elderly population.

Dataset Information

Functional characterization of three single-nucleotide polymorphisms present in the human APOE promoter sequence: Differential effects in neuronal cells and on DNA-protein interactions.

Publications

Functional characterization of three single-nucleotide polymorphisms present in the human APOE promoter sequence: Differential effects in neuronal cells and on DNA-protein interactions.

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