Low prevalence of lipid metabolism abnormalities in APOE ε2-genotype and male patients 60 years or older with schizophrenia.
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ABSTRACT: Background
Schizophrenia is a serious mental disorder largely manageable with atypical antipsychotics; however,
SUBMITTER: Ban C
PROVIDER: S-EPMC5727937 | biostudies-literature | 2017 Dec
REPOSITORIES: biostudies-literature
Publications
Low prevalence of lipid metabolism abnormalities in APOE ε2-genotype and male patients 60 years or older with schizophrenia.
Ban Chunxia C Zhang Qunying Q Feng Jie J Li Huijuan H Qiu Qi Q Tian Yuan Y Li Xia X
BMC psychiatry 20171212 1
<h4>Background</h4>Schizophrenia is a serious mental disorder largely manageable with atypical antipsychotics; however, these drugs have been associated with glucose/lipid metabolism issues such as diabetes and hyperlipidaemia. Apolipoprotein E (APOE) is the most abundant apolipoprotein, and APOE genotypes have been correlated with lipid metabolism phenotypes in an age-dependent manner. Studies examining the relationship between the APOE genotype and lipid abnormalities in patients with schizop ...[more]
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Project description:BackgroundDiabetic nephropathy (DN) contributes to end-stage renal failure. Microvascular injury resulted from reactive oxygen species is implicated in the pathogenesis of DN. Genetic polymorphism of Apolipoprotein E (APOE) influences the antioxidative properties of the protein. The relationship of APOE polymorphism with the risks of nephropathy in type 2 diabetes (T2DN) remains elusive.MethodsAn up-to-date meta-analysis was conducted on the basis of studies selected from PubMed, WanFang database, Embase, Vip database, Web of Science, Scopus, and CNKI database.ResultsA total of 33 studies conferring 3266 cases and 3259 controls were selected on the basis of criteria of inclusion and exclusion in this meta-analysis. For APOE alleles, the pooled odds ratio (OR) of ε2 vs. ε3 was 1.89 (95% confidence intervals [95% CI]: 1.49-2.38, P < 0.0001). With regard to APOE genotypes, ε2/ε2, ε2/ε3, and ε2/ε4 increased the risk of T2DN (ε2/ε2 vs. ε3/ε3: OR = 2.32, 95% CI: 1.52-3.56, P = 0.0001; ε2/ε3 vs. ε3/ε3: OR = 1.97, 95% CI: 1.50-2.59, P<0.0001; ε2/ε4 vs. ε3/ε3: OR = 1.69, 95% CI: 1.18-2.44, P = 0.0046).ConclusionsThis meta-analysis found that the APOE ε2 allele and the ε2-involved genotypes (ε2/ε2, ε2/ε3, and ε2/ε4) are the risk factors of T2DN.
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Project description:IntroductionThe apolipoprotein E (APOE) genotype is the strongest genetic risk factor for late-onset Alzheimer's disease. However, its effect on lipid metabolic pathways, and their mediating effect on disease risk, is poorly understood.MethodsWe performed lipidomic analysis on three independent cohorts (the Australian Imaging, Biomarkers and Lifestyle [AIBL] flagship study, n = 1087; the Alzheimer's Disease Neuroimaging Initiative [ADNI] 1 study, n = 819; and the Busselton Health Study [BHS], n = 4384), and we defined associations between APOE ε2 and ε4 and 569 plasma/serum lipid species. Mediation analysis defined the proportion of the treatment effect of the APOE genotype mediated by plasma/serum lipid species.ResultsA total of 237 and 104 lipid species were associated with APOE ε2 and ε4, respectively. Of these 68 (ε2) and 24 (ε4) were associated with prevalent Alzheimer's disease. Individual lipid species or lipidomic models of APOE genotypes mediated up to 30% and 10% of APOE ε2 and ε4 treatment effect, respectively.DiscussionPlasma lipid species mediate the treatment effect of APOE genotypes on Alzheimer's disease and as such represent a potential therapeutic target.
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Project description:Cancer-related cognitive decline (CRCD) has been linked to apolipoprotein E (APOE) gene ε4 polymorphisms. APOE ε4 polymorphisms are also the strongest genetic risk for late-onset Alzheimer disease (AD), whereas ε2 polymorphisms protect against AD. However, the effects of ε2 polymorphisms on CRCD have not been evaluated. We evaluated nonmetastatic breast cancer survivors (n = 427) and matched noncancer controls (n = 407) ages 60-98 years assessed presystemic therapy from August 2010 to December 2017 with annual follow-up to 24 months. Neuropsychological assessment measured attention, processing speed, executive function, and learning and memory. Linear mixed-effects models tested the effects of having an ε2 allele (vs none) on longitudinal cognitive domain z scores by treatment group (chemotherapy with or without hormonal therapy, hormonal therapy, and control) controlling for covariates; participants with ε2/ε4 genotype were excluded. Sensitivity analyses examined effects of other covariates and any ε4 positivity. There was an interaction with genotype for attention, processing speed, and executive functioning domain scores (Beta = 0.32, 95% confidence interval = 0.00 to 0.65); the chemotherapy group with an ε2 allele had higher scores at baseline and maintained higher scores over time compared with those without an ε2 allele, and this protective effect was not seen for other groups. There was no effect of ε2 on learning and memory domain scores. APOE ε2 polymorphisms may protect against CRCD in older breast cancer survivors receiving chemotherapy. With replication, this information could be useful for survivorship care and informing future studies of possible links to AD and defining mechanisms of protection.
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Project description:BackgroundThe apolipoprotein E (APOE) ε4 allele is the strongest genetic risk factor for late onset Alzheimer's disease, whilst the ε2 allele confers protection. Previous studies report differential DNA methylation of APOE between ε4 and ε2 carriers, but associations with epigenome-wide methylation have not previously been characterised.MethodsUsing the EPIC array, we investigated epigenome-wide differences in whole blood DNA methylation patterns between Alzheimer's disease-free APOE ε4 (n = 2469) and ε2 (n = 1118) carriers from the two largest single-cohort DNA methylation samples profiled to date. Using a discovery, replication and meta-analysis study design, methylation differences were identified using epigenome-wide association analysis and differentially methylated region (DMR) approaches. Results were explored using pathway and methylation quantitative trait loci (meQTL) analyses.ResultsWe obtained replicated evidence for DNA methylation differences in a ~ 169 kb region, which encompasses part of APOE and several upstream genes. Meta-analytic approaches identified DNA methylation differences outside of APOE: differentially methylated positions were identified in DHCR24, LDLR and ABCG1 (2.59 × 10-100 ≤ P ≤ 2.44 × 10-8) and DMRs were identified in SREBF2 and LDLR (1.63 × 10-4 ≤ P ≤ 3.01 × 10-2). Pathway and meQTL analyses implicated lipid-related processes and high-density lipoprotein cholesterol was identified as a partial mediator of the methylation differences in ABCG1 and DHCR24.ConclusionsAPOE ε4 vs. ε2 carrier status is associated with epigenome-wide methylation differences in the blood. The loci identified are located in trans as well as cis to APOE and implicate genes involved in lipid homeostasis.
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Project description:Apolipoprotein E (APOE) ε4 allele is the strongest genetic risk factor for late-onset Alzheimer's disease mainly by modulating amyloid-β pathology. APOE ε4 is also shown to exacerbate neurodegeneration and neuroinflammation in a tau transgenic mouse model. To further evaluate the association of APOE genotype with the presence and severity of tau pathology, we express human tau via an adeno-associated virus gene delivery approach in human APOE targeted replacement mice. We find increased hyperphosphorylated tau species, tau aggregates, and behavioral abnormalities in mice expressing APOE ε2/ε2. We also show that in humans, the APOE ε2 allele is associated with increased tau pathology in the brains of progressive supranuclear palsy (PSP) cases. Finally, we identify an association between the APOE ε2/ε2 genotype and risk of tauopathies using two series of pathologically-confirmed cases of PSP and corticobasal degeneration. Our data together suggest APOE ε2 status may influence the risk and progression of tauopathy.
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Project description:IntroductionWe examined whether sex modifies the association between APOE ε2 and cognitive decline in two independent samples.MethodsWe used observational data from cognitively unimpaired non-Hispanic White (NHW) and non-Hispanic Black (NHB) adults. Linear mixed models examined interactive associations of APOE genotype (ε2 or ε4 carrier vs. ε3/ε3) and sex on cognitive decline in NHW and NHB participants separately.ResultsIn both Sample 1 (N = 9766) and Sample 2 (N = 915), sex modified the association between APOE ε2 and cognitive decline in NHW participants. Specifically, relative to APOE ε3/ε3, APOE ε2 protected against cognitive decline in men but not women. Among APOE ε2 carriers, men had slower decline than women. Among APOE ε3/ε3 carriers, cognitive trajectories did not differ between sexes. There were no sex-specific associations of APOE ε2 with cognition in NHB participants (N = 2010).DiscussionIn NHW adults, APOE ε2 may protect men but not women against cognitive decline.HighlightsWe studied sex-specific apolipoprotein E (APOE) ε2 effects on cognitive decline. In non-Hispanic White (NHW) adults, APOE ε2 selectively protects men against decline. Among men, APOE ε2 was more protective than APOE ε3/ε3. In women, APOE ε2 was no more protective than APOE ε3/ε3. Among APOE ε2 carriers, men had slower decline than women. There were no sex-specific APOE ε2 effects in non-Hispanic Black (NHB) adults.
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Project description:Pneumococcal disease is frequent at the extremes of age. While several studies have looked at colonization among young children, much less is known among the elderly. We aimed to evaluate pneumococcal carriage among elderly adults living in Portugal. Between April 2010 and December 2012, nasopharyngeal and oropharyngeal swabs of adults over 60 years of age, living in an urban area (n = 1,945) or in a rural area (n = 1,416), were obtained. Pneumococci were isolated by culture-based standard procedures, identified by optochin susceptibility, bile solubility and PCR screening for lytA and cpsA, and characterized by antibiotype, serotype, and MLST. Associations between pneumococcal carriage, socio-demographic and clinical characteristics were evaluated by univariate analysis and multiple logistic regression. The global prevalence of carriage was 2.3% (95% CI: 1.8-2.8). In the multiple logistic regression analysis, smoking, being at a retirement home, and living in a rural area increased the odds of being a pneumococcal carrier by 4.4-fold (95% CI: 1.9-9.2), 2.0-fold (95% CI: 1.1-3.6) and 2.0-fold (95% CI: 1.2-3.5), respectively. Among the 77 pneumococcal isolates, 26 serotypes and 40 STs were identified. The most prevalent serotypes were (in decreasing order) 19A, 6C, 22F, 23A, 35F, 11A, and 23B, which accounted, in total, for 60.0% of the isolates. Most isolates (93.5%) had STs previously described in the MLST database. Resistance to macrolides, non-susceptibility to penicillin and multidrug resistance were found in 19.5%, 11.7%, and 15.6% of the isolates, respectively. We conclude that the prevalence of pneumococcal carriage in the elderly, in Portugal, as determined by culture-based methods, is low. Serotype and genotype diversity is high. Living in a rural area, in a retirement home, and being a smoker increased the risk of pneumococcal carriage. This study contributes to the establishment of a baseline that may be used to monitor how novel pneumococcal vaccines impact on colonization among the elderly.
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Project description:Optical neuritis (ON), otherwise known as optical nerve damage, is a term used to describe various environmental and body conditions that lead to optic nerve dysfunction. Neurologists are well aware of conditions that cause optic neuropathy, such as trauma, infections, malnutrition, and various toxins. As optic neuritis is a multifactorial demyelinating or infectious process, genetic predisposition may also influence the progression of optic neuritis. This study aimed to evaluate the association of ON (with and without multiple sclerosis) with APOE alleles and APOE serum levels. We found that the APOE ε3/ε3 genotype was statistically less common in the ON group of males than in the control group (p = 0.045). Moreover, the APOE ε3/ε3 genotype had a 3.7-fold increase in the odds of ON development in males (OR = 3.698; CI: 1.503-9.095; p = 0.004). In contrast, the APOE ε3/ε4 genotype had a 4.1-fold decrease in the odds of ON development in males (OR = 0.242; CI: 0.083-0.704; p = 0.009). APOE serum levels were statistically significantly higher in the ON group than in the control group (p = 0.042). The APOE ε3/ε3 genotype may increase males' risk of developing ON, while the ε3/ε4 genotype may reduce males' risk of developing ON.
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Project description:BackgroundApolipoprotein E (APOE) ε2 and APOE ε4 are the most distinct alleles among the three APOE alleles, both structurally and functionally. However, differences in cognition, brain function, and brain structure between the two alleles have not been comprehensively reported in the literature, especially in non-demented elderly individuals.MethodsA neuropsychological test battery was used to evaluate the differences in cognitive performance in five cognitive domains. Independent component analysis (ICA) and voxel-based morphometry (VBM) were used separately to analyze resting-state functional magnetic resonance imaging (rs-fMRI) data and the structure MRI data between the two groups. Finally, correlations between differential brain regions and neuropsychological tests were calculated.ResultsAPOE ε2 carriers had better cognitive performance in general cognitive, memory, attention, and executive function than APOE ε4 carriers (all p < 0.05). In ICA analyses of rs-fMRI data, the difference in the resting-state functional connectivity (rsFC) between two groups is shown in 7 brain networks. In addition, VBM analyses of the T1-weighted image revealed that APOE ε2 carriers had a larger thalamus and right postcentral gyrus volume and a smaller bilateral putamen volume than APOE ε4 carriers. Finally, differences in brain function and structure may be might be the reason that APOE ε2 carriers are better than APOE ε4 carriers in cognitive performance.ConclusionThese findings suggest that there are significant differences in brain function and structure between APOE ε2 carriers and APOE ε4 carriers, and these significant differences are closely related to their cognitive performance.
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Project description:Capturing the genetic architecture of Alzheimer's disease (AD) is challenging because of the complex interplay of genetic and non-genetic factors in its etiology. It has been suggested that AD biomarkers may improve the characterization of AD pathology and its genetic architecture. Most studies have focused on connections of individual genetic variants with AD biomarkers, whereas the role of combinations of genetic variants is substantially underexplored. We examined the associations of the APOE ε2 and ε4 alleles and polygenic profiles comprising the ε4-encoding rs429358, TOMM40 rs2075650, and APOC1 rs12721046 polymorphisms with cerebrospinal fluid (CSF) and plasma amyloid β (Aβ40 and Aβ42) and tau biomarkers. Our findings support associations of the ε4 alleles with both plasma and CSF Aβ42 and CSF tau, and the ε2 alleles with baseline, but not longitudinal, CSF Aβ42 measurements. We found that the ε4-bearing polygenic profiles conferring higher and lower AD risks are differentially associated with tau but not Aβ42. Modulation of the effect of the ε4 alleles by TOMM40 and APOC1 variants indicates the potential genetic mechanism of differential roles of Aβ and tau in AD pathogenesis.
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