The Poliovirus Receptor Related 2 (PRR2) and Apolipoprotein E Genes and Coronary Heart Disease
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Background Recently, we localized the Human Poliovirus Receptor Related 2 Gene (PRR2) 17kb centromeric to the gene for apolipoprotein E (APOE). Common polymorphisms in the latter have been found, in some studies, to be related to coronary heart disease (CHD) but the PRR2 gene has not been studied in this context. Here, we examined relationships between a PRR2 Sau96I (A/G) polymorphism, the ∊2, 3 and 4 alleles of APOE and CHD. Design and methods Consecutive Caucasian patients (n=640) < 50 years with angiographically documented coronary obstructive disease and/or with unequivocal myocardial infarction were compared with 624 control subjects, aged 30–50 years, randomly selected from the community and without a history of CHD. Results An excess of PRR2-A homozygotes was observed in cases (20% vs. 15%; OR 1.4, CI 1.04–1.86, P=0.026) particularly in those with single vessel disease (OR 1.7, CI 1.2–2.4, P<0.01). The A allele was in linkage disequilibrium with the ∊4 allele and the G allele with the ∊2. Overrepresentation of the A allele and underrepresentation of the G allele in the CHD group did not reach significance (P=0.054). While the ∊2 allele was under-represented in the CHD group (OR 0.64, CI 0.46–0.89, P=0.009), the ∊4 allele was not significantly overrepresented. Conclusion The relationship between the PRR2 Sau96I (A/G) polymorphism and early onset coronary artery disease may be due to linkage disequilibrium with the APOE gene and underrepresentation, or a protective effect, of the ∊2 allele. Alternatively, since A allele homozygosity is particularly overrepresented, the relationship could be more direct, perhaps through a viral association.Keywords:
Linkage Disequilibrium
Apolipoprotein E
Abstract Background Alzheimer’s disease (AD) is the most common progressive dementia disease in people over 60 years of age. The pathogenesis of AD is thought to be complex and depends on environmental and genetic factors. The most important genetic factors responsible for AD include variants of the APOE gene, which encodes the protein apolipoprotein E (apoE). There are 2 polymorphisms in the APOE , which presence of three alleles: protective ‐ ε2, neutral ‐ ε3, and pathogenic ‐ ε4. On the other hand, the presence of the ε4 allele is associated with an approximately four times higher risk of developing AD in people with a heterozygous system and a twelve times higher risk in ε4/4ε. Disorders of epigenetic mechanisms affecting the concentration of apoE may participate in the development of AD. Disturbed levels of apoE may impair clearance of Aβ from the brain and exacerbate disease progression. It is not known what level of apoE ensures the removal of Aβ and whether genetic and familial predispositions can regulate the efficiency of protective mechanisms. So far, there is little information on the level of apoE in AD patients and controls who are and are not APOE ε4 carriers. The aim was to analyze genetic variants of the APOE gene and apoE protein concentration in AD patients, control subjects related to AD cases (CR), and controls subjects without a family history of AD (CU), carriers and non‐carriers of the APOE ε4 variant. Method The studies were conducted on 156 individuals (AD and controls). The APOE genotype was determined by real‐time PCR. The apoE concentration was determined by the ELISA method. Result The highest concentration of apoE was found in CR compared to AD and CU (p<0.001). In both APOE ε4 carriers (p<0.05) and non‐carriers (p<0.001), the highest levels of apoE were found in CR. At the same time, in all tested subjects, carriers of APOE ε4, the level of apoE was lower compared to non‐carriers of this pathogenic variant. Conclusion It seems that the ε4 pathogenic variant of the APOE gene may lead to the development of AD by regulating the level of apoE.
Apolipoprotein E
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Objective To study the distribution of Apo E gene in patients with Alzheimer desease, and analyse the relation between them . Methods ApoE genotyes of patients with Alzheimer desease and age-matched healthy controls were determined by using the polymerphism technique,subsequently to require the ralation between ApoE allele and AD . Results ApoE e4 allele of patients with AD was 20.4%,which obviously was higher than 7.5% of cotrols, but e3 allele of patients with AD was 64.8%, which was lower than 83.2% of cotrols.Conclusions In ApoE allele, e4 allele is a genetic suscetible factor in AD,and e3 allele is a protection factor.
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Linkage Disequilibrium
Disequilibrium
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The strongest risk-determinant for the development of sporadic Alzheimer's disease (AD) is the polymorphic APOE gene. In humans APOE has three variants, APOEε2, APOEε3 and APOEε4 whereof the latter increases the risk of disease 4–15 fold in a dose-dependent manner whilst APOEε2 appears to be protective. The biological mechanisms underlying the modified risk of disease in APOEε2 and APOEε4 carriers are not known. We previously showed that APOEε4-carriers exhibit a prominent plasma apolipoprotein E (apoE) deficiency caused by a specific reduction of the apoE4 isoform. This apoE deficiency was not observed in cerebrospinal fluid. In cognitively intact APOEε3/ε4 carriers an increased relative ratio of plasma apoE4 to apoE3 correlated to glucose hypometabolism and gray matter volume reductions in brain areas most often affected in AD. Hence, we speculate that peripheral apoE levels are linked to processes driving the risk of developing AD brain pathology. In order to determine the cause of the observed phenotype of plasma apoE deficiency in APOEε4-carriers we aimed to investigate the expression of different APOE alleles in liver biopsies from individuals with an APOEε3/ε4 versus an APOEε2/ε3 genotype. Liver biopsies from liver explants were received from n=3 APOEε3/ε4 and n=3 APOEε2/ε3 carriers who had undergone liver transplantation at the Karolinska University Hospital in Sweden. Total RNA (≥80% in DV200 score) was isolated according to routine laboratory methods and used for RNA sequencing employing the high-throughput Illumina platform. Paired-end sequencing reads were aligned to the human reference genome (hg19), using TopHat, and gene counts for expression determined using HTseq-count. Differential expression between the genotype groups was calculated using DEseq2. Preliminary analyses revealed differential expression of n=624 genes between individuals with an APOEε3/ε4 versus an APOEε2/ε3 genotype. In total n=624 genes are differentially expressed in livers from APOEε3/ε4 versus APOEε2/ε3 carriers. Further analyses will reveal the identity of the differentially expressed genes and whether there is a specific difference in the expression of APOE alleles that could explain the observed APOEε4 related plasma apoE deficiency
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Apolipoprotein E (apoE) is associated with lipoproteins in the cerebrospinal fluid (CSF). APOE4 increases and APOE2 decreases the risk for Alzheimer disease (AD) compared to the risk associated with APOE3 Because apoE4 is less efficient at cholesterol efflux than apoE2 or apoE3 in vitro, we hypothesized that APOE genotype may affect apoE particle size in vivo and that these size differences may be related to AD risk. We used nondenaturing gel electrophoresis to test for differences in the size of apoE complexes in human CSF samples of various APOE genotypes and created profiles of each sample to compare the patterns of apoE distribution. For middle-aged adults with no dementia, APOE 2.3 individuals had significantly larger apoE complexes than APOE 3.3 subjects, who had significantly larger apoE complexes than APOE 3.4 and APOE 4.4 individuals. Similarly, in an independent cohort of older adults, CSF apoE complexes of APOE4-positive individuals were smaller than those of the APOE4-negative individuals. Compared to individuals with no dementia, those with the mildest stages of dementia had similar sized CSF apoE complexes. These results identify a novel phenotypic difference in the size of CSF apoE complexes in middle age that correlate with the risk of AD later in life.
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Linkage Disequilibrium
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Epistasis
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Abstract Background Restrictions on mouse models have significantly impacted research towards understanding the most common genotype contributing to dementia in the human population – APOE ε3/ε4 . To address this, as part of MODEL-AD, we created new versions of humanized APOE ε4 and APOE ε3 mice on a C57BL/6J background that allow for unrestricted distribution and breeding. Methods To determine similarities and differences between APOE ε3/ε4 and APOE ε4/ε4 risk genotypes, we analyzed peripheral lipid concentrations as well as performed unbiased transcriptional profiling of the cortex at two and four months of age, comparing APOE ε3/ε4 and APOE ε4/ε4 to the reference APOE ε3/ε3 . To further compare APOE genotypes, cohorts of APOE ε3/ε3 , APOE ε3/ε4 , and APOE ε4/ε4 mice were exercised by voluntary running from 1 month to 4 months of age. Results Cholesterol composition was significantly influenced by APOE genotype as early as 2 months, while triglycerides were affected by APOE genotype at 4 months. Importantly, RNA-sequencing of the cortex followed by linear modeling or weighted gene co-expression network analysis (WGCNA) revealed that the APOE ε3/ε4 genotype showed unique transcriptomic signatures to that of APOE ε4/ε4 . Functional enrichment of the APOE ε3/ε4 , but not APOE ε3/ε4 genotype, revealed sulfur and heparin binding as significant terms at 2 months, and extracellular matrix and blood coagulation at 4 months. Further, cell specific contributions of significant genes identified endothelial cells as overrepresented in the APOE ε3/ε4 but not APOE ε4/ε4 genotype. WGCNA analysis confirmed findings from linear modeling but also predicted that running at a young age affects myelination and gliogenesis across APOE genotypes. Conclusions In summary, APOE ε3/ε4 genotype-specific effects were observed in cortical transcriptional profiles, suggesting therapies aimed at modifying APOE biology to treat dementias may need to be targeted to specific APOE genotypes.
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The ε4 allele of apolipoprotein E (APOE) is currently the major genetic risk factor identified for Alzheimer's disease (AD). Previous in vivo data from our laboratory has demonstrated that amyloid-β (Aβ) is rapidly removed from the plasma by the live
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Allele epsilon 4 of the apolipoprotein E (APOE) gene is associated with higher risk of Alzheimer's disease (AD) in many, though not all, ethnic groups. The APOE allele and genotype frequency distributions were studied in 207 AD patients without cerebrovascular disorders, 62 AD patients with cerebrovascular disorders (combined AD), and 206 control individuals (ethnic Russians from the Russian population). The frequency of allele epsilon 4 in patients with early-onset and late-onset AD was three times higher than in control individuals (p < 0.000001). Compared with control people, patients with cerebrovascular disorders displayed a twofold higher frequency of allele epsilon 4; the difference between the two groups was significant (p = 0.0019). Relative risk of AD in carriers of allele epsilon 4 was five times higher than in carriers of alleles epsilon 2 and epsilon 3 (p < 0.000001). Allele epsilon 2 had a protective effect with respect to AD onset until 65 years of age (p = 0.015). Thus, APOE allele epsilon 4 proved to be a universal factor of early-onset, late-onset, and combined AD in ethnic Russians from Russia.
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Genetic Association
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