Apolipoprotein E Gene Research Articles

Biyoinformatik araçlar aracılığıyla insan APOE (Apolipoprotein E) genindeki yanlış anlamlı SNV'lerin değerlendirilmesi

Apolipoprotein E (APOE) is one of the main proteins responsible for cholesterol transport. It has three major isoforms, APOE2, APOE3, and APOE4. The purpose of this study is to investigate the possible effects of single nucleotide variations (SNVs) in the APOE gene, which cause amino acid substitution, on the function, structure and stabilization of the APOE protein using bioinformatics/s tools. SNVs and protein sequence information were obtained from NCBI and UniProt databases. Bioinformatical analysis was performed using a series of tools such as SIFT, PolyPhen-2, SNPs&GO, Mutation Assessor, PROVEAN, SNAP2, I-Mutant-3, MUPro, and Project HOPE. As a result, 321 missense SNVs were analyzed and rs7412 (R176C), rs769455 (R163C), rs11542029 (R50C), rs121918393 (R154S), rs121918394 (K164Q), rs200703101 (R154P), rs387906567 (R160C), rs11542040 (P102T), rs11542041 (R132S) and rs41382345 (E139V) were predicted to be deleterious/disease related after functional analysis and pathological effect analysis via all of the bioinformatics/s tools. According to the protein stabilization results, it was determined that all SNVs decreased protein stabilization with the MUPro software tool, and two SNVs (rs121918394, rs41382345) increased protein stabilization with the I-Mutant-3 software tool. The models of protein and amino acid properties were obtained via Project HOPE for all high-risk SNVs. We hope our analysis will be valuable for further proteomic, genomic, and clinical research.

Association of Apolipoprotein E4-related Microvascular Disease in the Alzheimer’s Disease Hippocampal CA1 Stratum Radiatum

Current data suggest a hypothesis of vascular pathogenesis for the development and progression of Alzheimer’s disease (AD). To investigate this, we studied the association of apolipoprotein E4 (APOE4) gene on microvessels in human autopsy-confirmed AD with and without APOE4, compared with age/sex-matched control (AC) hippocampal CA1 stratum radiatum. AD arterioles (without APOE4 gene) had mild oxidative stress and loss of vascular endothelial growth factor (VEGF) and endothelial cell density, reflecting aging progression. In AD + APOE4, an increase in strong oxidative DNA damage marker 8-hydroxy-2′-deoxyguanosine (8-OHdG), VEGF, and endothelial cell density were associated with increased diameter of arterioles and perivascular space dilation. In cultured human brain microvascular cells (HBMECs), treatment of ApoE4 protein plus amyloid-β (Aβ) oligomers increased superoxide production and the apoptotic marker cleaved caspase 3, sustained hypoxia inducible factor-1α (HIF-1α) stability that was associated with an increase in MnSOD, VEGF, and cell density. This cell over-proliferation was inhibited with the antioxidants N-acetyl cysteine and MnTMPyP, the HIF-1α inhibitor echinomycin, the VEGFR-2 receptor blocker SU1498, the protein kinase C (PKC) ε knock-down (KD) and the extracellular signal-regulated kinase 1/2 (ERK) inhibitor FR180204. The PKCε KD and echinomycin decreased VEGF and/or ERK. In conclusion, AD capillaries and arterioles in hippocampal CA1 stratum radiatum of non-APOE4 carriers are related with aging, while those in APOE4 carriers with AD are related with pathogenesis of cerebrovascular disease.

APOE4 expression confers a mild, persistent reduction in neurovascular function in the visual cortex and hippocampus of awake mice

Vascular factors are known to be early and important players in Alzheimer’s disease (AD) development, however the role of the ε4 allele of the Apolipoprotein (APOE) gene (a risk factor for developing AD) remains unclear. APOE4 genotype is associated with early and severe neocortical vascular deficits in anaesthetised mice, but in humans, vascular and cognitive dysfunction are focused on the hippocampal formation and appear later. How APOE4 might interact with the vasculature to confer AD risk during the preclinical phase represents a gap in existing knowledge. To avoid potential confounds of anaesthesia and to explore regions most relevant for human disease, we studied the visual cortex and hippocampus of awake APOE3 and APOE4-TR mice using 2-photon microscopy of neurons and blood vessels. We found mild vascular deficits: vascular density and functional hyperaemia were unaffected in APOE4 mice, and neuronal or vascular function did not decrease up to late middle-age. Instead, vascular responsiveness was lower, arteriole vasomotion was reduced and neuronal calcium signals during visual stimulation were increased. This suggests that, alone, APOE4 expression is not catastrophic but stably alters neurovascular physiology. We suggest this state makes APOE4 carriers more sensitive to subsequent insults such as injury or beta amyloid accumulation.

#6143 FAMILIAL LECITHIN: CHOLESTEROL ACYLTRANSFERASE (LCAT) DEFICIENCY AS A CAUSE OF CHRONIC KIDNEY DISEASE – A CASE REPORT

Abstract Background and Aims Genetic causes of chronic kidney disease are becoming more recognized. Familial lecithin: cholesterol acyltransferase (LCAT) deficiency (FLD) is a rare genetic disorder caused by loss of function mutations in LCAT gene. Patients present with abnormal lipid profile characterized with markedly reduced HDL-C, corneal opacification, anemia, and renal disease, which eventually progresses to kidney failure. Several studies reported genetic variants in LCAT gene that are associated with FLD, and others in certain apolipoprotein genes that act as risk factors for the disease. Incomplete form of FLD, caused by certain mutation, leads to fish-eye disease characterized by progressive corneal opacification. FLD was described in studies from Europe, Latin and North America, Australia and Japan. In Jordan, genetic and clinical studies in FLD patients are absent. Method We present a 36-year-old female who presented with nephrotic-range proteinuria, high serum creatinine, hypertension and corneal opacity. Further examination showed a severely reduced HDL level, an increased triglycerides level, anemia and mild thrombocytopenia. Patient's laboratory values at presentation are shown in Table 1. Her blood film showed normocytic and normochromic red blood cells, anisopoikilocytosis and target cells. Light and electron microscopy examination of the kidney biopsy revealed intramembranous, subendothelial and mesangial lipid deposition and vacuolization. In addition, the patient was found to have a family history of corneal opacity and chronic kidney disease. Therefore, FLD was suspected. Whole exome sequencing was employed to identify FLD variants. Results The patient was found to be homozygous at 154+5delG in LCAT gene, heterozygous at 388T>C in apolipoprotein E gene (APOE) and homozygous at 1114G>C in WW domain-containing oxidoreductase gene (WWOX). The patient's chronic kidney disease was managed supportively with low salt diet, moderate protein intake, statins, angiotensin receptor blockers and blood pressure control. After one year of follow up, her serum creatinine is 220 μmol/l and estimated proteinuria is 1.2 gm/24 hrs. Conclusion FLD should be suspected in patients who present with kidney disease associated with significantly low HDL cholesterol and corneal opacity. Family members should also be screened for kidney disease and genetic mutation in LCAT gene. To date, treatment is mainly supportive and enzyme replacement therapy is not yet widely available.

Lack of significant associations between single nucleotide polymorphisms in LPAL2-LPA genetic region and all cancer incidence and mortality in Japanese population: The Japan public health center-based prospective study

BackgroundHigh lipoprotein (a) level is an established cardiovascular risk, but its association with non-cardiovascular diseases, especially cancer, is controversial. Serum lipoprotein (a) levels vary widely by genetic backgrounds and are largely determined by the genetic variations of apolipoprotein (a) gene, LPA. In this study, we investigate the association between SNPs in LPA region and cancer incidence and mortality in Japanese. MethodsA genetic cohort study was conducted utilizing the data from 9923 participants in the Japan Public Health Center-based Prospective Study (JPHC Study). Twenty-five SNPs in the LPAL2-LPA region were selected from the genome-wide genotyped data. Cox regression analysis adjusted for the covariates and competing risks of death from other causes, were used to estimate the relative risk (hazard ratios (HR) with 95% confidence intervals (CI)) of overall and site-specific cancer incidence and mortality, for each SNP. ResultsNo significant association was found between SNPs in the LPAL2-LPA region and cancer incidence or mortality (overall/site-specific cancer). In men, however, HRs for stomach cancer incidence of 18SNPs were estimated higher than 1.5 (e.g., 2.15 for rs13202636, model free, 95%CI: 1.28–3.62) and those for stomach cancer mortality of 2SNPs (rs9365171, rs1367211) were estimated 2.13 (recessive, 95%CI:1.04–4.37) and 1.61 (additive, 95%CI: 1.00–2.59). Additionally, the minor allele for SNP rs3798220 showed increased death risk from colorectal cancer (CRC) in men (HR: 3.29, 95% CI:1.59 – 6.81) and decreased CRC incidence risk in women (HR: 0.46, 95%CI: 0.22–0.94). Minor allele carrier of any of 4SNPs could have risk of prostate cancer incidence (e.g., rs9365171 dominant, HR: 1.71, 95%CI: 1.06–2.77). ConclusionsNone of the 25 SNPs in the LPAL2-LPA region was found to be significantly associated with cancer incidence or mortality. Considering the possible association between SNPs in LPAL2-LPA region and colorectal, prostate and stomach cancer incidence or mortality, further analysis using different cohorts is warranted.

Bidirectional Mendelian randomization analyses reveal APOE status mediates the effects of statin medications on Alzheimer’s disease

AbstractBackgroundThere is currently no unanimous conclusion on the statin medications and Alzheimer’s disease (AD) risk, which has long been one of the most concerns in lipid‐lowering and anti‐atherosclerosis treatment. We performed a bidirectional Mendelian Randomization (MR) to evaluate whether there were causal links between statin medications and AD.MethodSingle nucleotide polymorphisms (SNPs) identified from genome‐wide association studies (GWAS) were used as instrumental variables. One GWAS of statin medications (N = 462,933) and AD (N = 63,926) with summary statistics available was included in the MR analysis. All statistical analyses were conducted using the TwoSampleMR package with default parameters. Inverse variance weighted (IVW) was used as the primary method to calculate the causal estimates (β), accompanied by two complement methods, MR‐Egger and weighted median. Pleiotropic effects and heterogeneity driving causal association were also assessed.ResultIVW results showed that genetically predicted use of statins was causally associated with increased risk of AD (atorvastatin: β = 33.67, P = 0.048; simvastatin: β = 4.88, P = 0.044). However, after removing SNPs inside the apolipoprotein E (APOE) gene region (CHR19:45,111,942‐45,711,941 based on GRCh37/hg19), the causal links of statin medications on AD disappeared (Figure 1A). Two SNPs, rs429358 (C;C) and rs7412 (C;C) known as APOE4 mainly contributed to the controversial data involved in use of statins and AD risk. The results of reverse causal analysis showed that patients with AD tended to have a higher exposure to statins (atorvastatin: β = 0.005, P = 0.001; simvastatin: β = 0.012, P = 0.004). Consistently, when discarding the SNPs within the APOE gene region, no relationship was found between diagnosis of AD and statins exposure (Figure 1B). The directional horizontal pleiotropy and heterogeneities found in MR‐PRESSO global and MR‐Egger regression test were largely disappeared after excluding SNPs inside APOE cluster region.ConclusionOur results suggested that the inconsistent association between statins use and AD risk observed in previous observational investigations might be mainly attributed to various APOE status (APOE2, APOE3, and APOE4). Thus, it reminds clinicians that statins can be used with confidence in lipid‐lowering and anti‐atherosclerosis and are unlikely to affect AD risk.

Editing of APOL1 mRNA reduces APOL1 expression and activation of innate immunity

The APOL1 gene encodes Apoliprotein L1, an innate immune response protein that confers protection against Trypanosomal diseases and likely other infectious diseases. 1 Thomson R. Genovese G. Canon C. et al. Evolution of the primate trypanolytic factor APOL1. Proc Natl Acad Sci U S A. 2014; 111: E2130-2139 Crossref PubMed Scopus (160) Google Scholar ,2 Limou S. Dummer P.D. Nelson G.W. et al. APOL1 toxin, innate immunity, and kidney injury. Kidney Int. 2015; 88: 28-34 Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar The G1 and G2 variants of APOL1, which are enriched in persons of West African ancestry, provide enhanced protection against Trypanosome infection, but persons with APOL1 high risk (HR) genotypes (two risk alleles) have markedly increased risk of progressive CKD. 2 Limou S. Dummer P.D. Nelson G.W. et al. APOL1 toxin, innate immunity, and kidney injury. Kidney Int. 2015; 88: 28-34 Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar Because most individuals with HR genotypes do not develop kidney disease, it is likely that a “second hit” may be necessary to unmask the HR genotype-associated risk. APOL1 HR genotype is most strongly associated with severe kidney disease occurring in the setting of high interferon levels due to infection (HIV or COVID-19), 3 Kopp J.B. Nelson G.W. Sampath K. et al. APOL1 genetic variants in focal segmental glomerulosclerosis and HIV-associated nephropathy. J Am Soc Nephrol. 2011; 22: 2129-2137 Crossref PubMed Scopus (602) Google Scholar ,4 Kudose S. Batal I. Santoriello D. et al. Kidney Biopsy Findings in Patients with COVID-19. J Am Soc Nephrol. 2020; 31: 1959-1968 Crossref PubMed Scopus (245) Google Scholar lupus nephritis, 5 Freedman B.I. Langefeld C.D. Andringa K.K. et al. End-stage renal disease in African Americans with lupus nephritis is associated with APOL1. Arthritis Rheumatol. 2014; 66: 390-396 Crossref PubMed Scopus (203) Google Scholar interferon treatment, 6 Nichols B. Jog P. Lee J.H. et al. Innate immunity pathways regulate the nephropathy gene Apolipoprotein L1. Kidney Int. 2015; 87: 332-342 Abstract Full Text Full Text PDF PubMed Scopus (234) Google Scholar and kidney transplantation. 7 Santoriello D. Husain S.A. De Serres S.A. et al. Donor APOL1 high-risk genotypes are associated with increased risk and inferior prognosis of de novo collapsing glomerulopathy in renal allografts. Kidney Int. 2018; 94: 1189-1198 Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar As APOL1 expression is strongly induced by interferons, 6 Nichols B. Jog P. Lee J.H. et al. Innate immunity pathways regulate the nephropathy gene Apolipoprotein L1. Kidney Int. 2015; 87: 332-342 Abstract Full Text Full Text PDF PubMed Scopus (234) Google Scholar upregulation of toxic G1 and G2 variants in the setting of high interferon is hypothesized to be an important contributor to kidney injury. Thus, improved understanding of the factors that regulate APOL1 expression may provide new strategies to prevent or treat kidney disease in individuals with HR genotypes.

Interaction between APOE, APOA1, and LPL Gene Polymorphisms and Variability in Changes in Lipid and Blood Pressure following Orange Juice Intake: A Pilot Study.

Chronic orange juice intake is associated with reduced risk of cardiovascular disease, however, a large inter-individual variability in response to orange juice for lipid profile and blood pressure has been observed. This heterogeneity in responsiveness could be associated with single nucleotide polymorphism (SNP), which has not been previously addressed. This study aims to investigate the influence of SNP in apolipoprotein E (APOE), apolipoprotein A1 (APOA1), mevalonate (MVK), and lipase lipoprotein (LPL) genes in the biological response after chronic orange juice intake. Forty-six volunteers ingested 500 mL daily for 60 days and blood pressure and biochemical parameters are measured. Also, SNPs in APOE, APOA1, MVK, and LPL genes are genotyped in the volunteers that are medium/high excretors of flavanone metabolites. GenotypesCC (APOA1), AA, and GG (LPL) are associated with positive health effects of orange juice and the CC (APOE), GG (APOA1), GG, and AA (LPL) genotypes are associated with no effects of orange juice consumption (p < 0.05). These results identify for the first-time SNP associated with effects of orange juice on lipid levels and blood pressure, results that may provide bases for future precise nutritional recommendations regarding this flavanone-rich food to lower the risk for cardiovascular disease.

Visit-to-Visit Blood Pressure Variability and Cognitive Decline in Apolipoprotein ɛ4 Carriers versus Apolipoprotein ɛ3 Homozygotes.

Blood pressure variability (BPV) is associated with cognitive decline and Alzheimer's disease (AD), but relationships with AD risk gene apolipoprotein (APOE) ɛ4 remain understudied. Examined the longitudinal relationship between BPV and cognitive change in APOE ɛ4 carriers and APOE ɛ3 homozygotes. 1,194 Alzheimer's Disease Neuroimaging Initiative participants (554 APOE ɛ4 carriers) underwent 3-4 blood pressure measurements between study baseline and 12-month follow-up. Visit-to-visit BPV was calculated as variability independent of mean over these 12 months. Participants subsequently underwent ≥1 neuropsychological exam at 12-month follow-up or later (up to 156 months later). Composite scores for the domains of memory, language, executive function, and visuospatial abilities were determined. Linear mixed models examined the 3-way interaction of BPV×APOE ɛ4 carrier status x time predicting change in composite scores. Higher systolic BPV predicted greater decline in memory (+1 SD increase of BPV: β= -0.001, p < 0.001) and language (β= -0.002, p < 0.0001) among APOE ɛ4 carriers, but not APOE ɛ3 homozygotes (memory: +1 SD increase of BPV: β= 0.0001, p = 0.57; language: β= 0.0001, p = 0.72). Systolic BPV was not significantly associated with change in executive function or visuospatial abilities in APOE ɛ4 carriers (ps = 0.08-0.16) or APOE ɛ3 homozygotes (ps = 0.48-0.12). Cognitive decline associated with high BPV may be specifically accelerated among APOE ɛ4 carriers.

The Relationship Between the Three Genes of Apolipoprotein E and the Hippocampus and Interference with Alzheimer's Disease

Glycoproteins in the Apolipoprotein E (APOE) class have a role in controlling lipid metabolism. In astrocytes, microglia, vascular wall cells, and choroid plexus cells of the central nervous system, it is abundantly expressed. According to the rapid advancement of contemporary medicine, numerous investigations have demonstrated the existence of ApoE in chylomicron (CM), very low density lipoprotein (VLDL), intermediate density lipoprotein (IDL), and certain high-density lipoprotein (HDL). ApoE has also been demonstrated to have a substantial impact on Alzheimer's disease (AD). To enhance the investigation of innovative medications and give researchers a theoretical foundation, research on ApoE is required in this area. Because damage to the hippocampus is a significant concern for the population in Alzheimer's research, we need to study the effects of ApoE on the hippocampus. This paper will discuss the relationship between age and sex of hippocampal atrophy after the ApoE gene has caused AD. The paper through a method of literature review and the analysis of some clinical cases explores the impact of the ApoE gene on health, followed by a comparison of the disease state before and after, as well as the clinical pattern of hippocampal atrophy, including a description of clinical symptoms. The paper finds that ApoE significantly impacts AD and that the hippocampus is significantly atrophied after the onset of Alzheimer's disease.

The differential effects of APOE ɛ4 on cerebral volumetric structures in different lifespan in community-dwelling populations (P12-6.002)

<h3>Objective:</h3> In this study, we aimed to explore the age-related effect of APOE gene on brain volume. We hypothesized that APOE might have differential effects on brain volume in different age stages. <h3>Background:</h3> Apolipoprotein E (APOE) ɛ4 is closely related to Alzheimer’s disease and other age-related diseases. In recent years, several studies have shown an interaction of APOE by age on brain volume. However, validation in larger cohorts is required. <h3>Design/Methods:</h3> Inhabitants in Shunyi District in Beijing aged 35 years and above and living independently were invited to join this study from 2013 to 2016. The baseline assessments, APOE genotyping and brain magnetic resonance imaging were performed. The detailed neuroimaging characteristics and brain volumes (global measures, cerebral lobes, subcortical nuclei and brainstem) were acquired. The general linear model was used to analyze the interaction of APOE genotypes by age on brain volumes, and the age of 60 years was chosen as a cut-off value for stratification analysis. <h3>Results:</h3> A total of 1,105 subjects were enrolled in the final analysis with a mean age of 56.18 (9.30) years, and 37.7% were men. APOE ɛ3/ɛ3 carriers accounted for 71.8%, ɛ2 allele 14.0%, and ɛ4 allele 14.2%. Compared with APOE ɛ3/ɛ3, a significant protective effect for APOE ɛ4 (+) on brain parenchyma fraction (β = 0.450, p = 0.048) was observed in subjects aged ≤60 years; in participants aged &gt;60 years, a negative effect for APOE ɛ4 (+) on hippocampus (β = 1.087, p = 0.021) was found. <h3>Conclusions:</h3> Our study reveals that APOE ɛ4 has differential effects on cerebral structures in different stages of lifespan, suggesting its complicated biological function and underlying antagonistic pleiotropy. <b>Disclosure:</b> Dr. Tang has nothing to disclose. Dr. Su has nothing to disclose. Ding-Ding Zhang has nothing to disclose. Yi Dai has nothing to disclose. Ming Yao has nothing to disclose. Lixin Zhou has nothing to disclose. Liying Cui has nothing to disclose. Shuyang Zhang has nothing to disclose. Yi-Cheng Zhu has nothing to disclose. Jun Ni has nothing to disclose.

Role of APOC3 3238C/G polymorphism in HIV-associated neurocognitive disorder

Apolipoprotein not only have a role in cholesterol metabolism but also play a role in normal brain function. Apolipoprotein gene polymorphisms are known risk factors for a number of mental and neurological disorders. The expression of brain apolipoproteins is significantly altered in several brain disorders. Therefore, we assed ApoC33238 C/G polymorphism in a total of 248 patient infected with HIV (45 with HAND, 89 without HAND, 114 without ART) and 134 healthy controls using PCR-RFLP. ApoC3 3238CG, 3238 GG genotypes and 3238G allele showed a non-significant increased risk for severity of HAND (P = 0.16, OR = 1.83; P = 0.32, OR = 2.78; P = 0.10, OR = 1.65) while comparing individuals with and without HAND. ApoC3 3238 GG genotype and 3238G allele revealed an increased risk for disease progression when compared between HIV patients with and without ART (P = 0.55, OR = 1.76; P = 0.65, OR = 1.12) though risk could not reach statistical significance. ApoC3 3238 GG genotype and 3238G allele were associated with the reduced risk of acquiring HIV infection when comparing HIV patients who are not on ART with healthy controls (P = 0.05, OR = 0.29; P = 0.04, OR = 0.66). In HIV patients on ART,ApoC3 3238 GG genotype showed an increased susceptibility to development of HAND (P = 0.48, OR = 2.24) when comparing alcohol drinkers and non-drinkers however risk could not reach statistical significance. In conclusion, the genotype ApoC33238GG displayed an inclination of risk for the severity of HAND and HIV disease progression. The polymorphism of APOC3 3238C/G may have a role to reduce the risk for acquisition of HIV infection. ApoC33238GG genotype in presence of alcohol may increase susceptibility to development of HAND.

Analysis of association of apolipoprotein genes APOA2, APOA5 and APOH variants with hyperlipidemia

Hyperlipidemia is one of the most common metabolic disorders in humans, leading to the atheros clerosis. It is known that lipid metabolism disorders can be associated with genetic predisposition. However, even in patients with clinically confirmed familial hypercholesterolemia, its genetic cause remains unknown in 30 % of cases. The search for genetic variants associated with primary hyperlipidemias is a promising direction in the development of diagnostics and personalized medicine. Aim of the study was to assess of the association of polymorphic sites rs3813627, rs3135506 and rs3785617 of the apolipoprotein genes APOA2, APOA5 and APOH, respectively, with lipid metabolism and atherogenic index in the population of Novosibirsk. Material and methods. Genotyping by polymerase chain reaction followed by analysis of restriction fragment length polymorphism at the rs3813627, rs3135506 and rs3785617 of the APOA2, APOA5 and APOH genes, respectively, was carried out in 522 people from 9360 a random population sample of Novosibirsk and in 266 people from the same sample with a total cholesterol content more than 300 mg/dl. A one-way ANOVA of the association of genetic variants with serum lipid levels and atherogenicity index was performed. Results. The allele frequencies of all studied polymorphic sites in the Novosibirsk population differed from those previously identified among Europeans. A significant increase (p = 0.02) in average total cholesterol content in AA – AG – GG genotype series for rs3785617 of the APOH was revealed. The frequency of the CC genotype for the rs3135506 of the APOA5 in the group with total cholesterol contentration exceeding 300 mg/dl was lower compared to the control group (p = 0.038, odds ratio 0.66, 95 % confidence interval 0.46–0.97). For rs3813627, there were no differences in genotype frequencies and in lipid metabolism. Conclusions. The rs3135506 and rs3785617 can modify the hyperlipidemia phenotype among the Caucasoid population of Western Siberia.

Amyloid β-Peptide Effects on Glucose Regulation Are Dependent on Apolipoprotein E Genotype.

The apolipoprotein E gene (APOE) confers the greatest genetic risk factor for Alzheimer's disease (AD), wherein the ε4 allele confers an elevated risk compared with the ε3 allele. Biological mechanisms that differ across these alleles have been explored in mouse models wherein the murine Apoe gene has undergone targeted replacement with sequences encoding human ApoE3 or ApoE4 (ApoE-TR mice). Such models have indicated that the two variants of ApoE produce differential effects on energy metabolism, including metabolic syndrome. However, glucose regulation has not been compared in ApoE-TR mice with and without amyloid β-peptide (Aβ) accumulation. We crossed ApoE3-TR and ApoE4-TR mice with a transgenic line that accumulates human Aβ1-42 In male ApoE3-TR mice, introduction of Aβ caused aberrations in glucose tolerance and in membrane translocation of astrocytic glucose transporter 1 (GLUT1). Phosphorylation of Tau at AD-relevant sites was correlated with glucose intolerance. These effects appeared independent of insulin dysregulation and were not observed in females. In ApoE4-TR mice, the addition of Aβ had no significant effects because of a trend toward perturbation of the baseline values.

Apolipoprotein E (APOE) Haplotypes in Healthy Subjects from Worldwide Macroareas: A Population Genetics Perspective for Cardiovascular Disease, Neurodegeneration, and Dementia

Human APOE is a 299-amino acid long protein expressed and secreted in several tissues and body districts, where it exerts different functions mainly related to lipid metabolism, with specific activities around cholesterol transport and absorption/elimination. It has three main isoforms, determined by the pair of mutations rs7412-C/T and rs429358-C/T, which gives rise to the functionally different APOE variants ε2, ε3, and ε4. These have a distinct impact on lipid metabolism and are differentially implicated in Alzheimer's disease and neurodegeneration, cardiovascular disease, and dyslipidemia. A plethora of other single nucleotide variants along the sequence of the APOE gene have been studied in cohorts of affected individuals, where they also modulate the influence of the three main isoforms to determine the risk of developing the disease. However, no contextual analysis of gene-long haplotypes has been carried out so far, and never extensively in cohorts of healthy individuals from different worldwide populations. Leveraging a rich population genomics dataset, this study elucidates the distribution of APOE variants and haplotypes that are shared across populations and to specific macroareas, revealing a variety of risk-allele associations that distinguish specific ancestral backgrounds and can be leveraged for specific ancestry-informed screenings in medicine and public health.

APOE and immunity: Research highlights.

At the Alzheimer's Association's APOE and Immunity virtual conference, held in October 2021, leading neuroscience experts shared recent research advances on and inspiring insights into the various roles that both the apolipoprotein E gene (APOE) and facets of immunity play in neurodegenerative diseases, including Alzheimer's disease and other dementias. The meeting brought together more than 1200 registered attendees from 62 different countries, representing the realms of academia and industry. During the 4-day meeting, presenters illuminated aspects of the cross-talk between APOE and immunity, with a focus on the roles of microglia, triggering receptor expressed on myeloid cells 2 (TREM2), and components of inflammation (e.g., tumor necrosis factor α [TNFα]). This manuscript emphasizes the importance of diversity in current and future research and presents an integrated view of innate immune functions in Alzheimer's disease as well as related promising directions in drug development.

The genetic link between systemic autoimmune disorders and temporal lobe epilepsy: A bioinformatics study.

We aimed to explore the underlying pathomechanisms of the comorbidity between three common systemic autoimmune disorders (SADs) [i.e., insulin-dependent diabetes mellitus (IDDM), systemic lupus erythematosus (SLE), and rheumatoid arthritis (RA)] and temporal lobe epilepsy (TLE), using bioinformatics tools. We hypothesized that there are shared genetic variations among these four conditions. Different databases (DisGeNET, Harmonizome, and Enrichr) were searched to find TLE-associated genes with variants; their single nucleotide polymorphisms (SNPs) were gathered from the literature. We also did a separate literature search using PubMed with the following keywords for original articles: "TLE" or "Temporal lobe epilepsy" AND "genetic variation," "single nucleotide polymorphism," "SNP," or "genetic polymorphism." In the next step, the SNPs associated with TLE were searched in the LitVar database to find the shared gene variations with RA, SLE, and IDDM. Ninety unique SNPs were identified to be associated with TLE. LitVar search identified two SNPs that were shared between TLE and all three SADs (i.e., IDDM, SLE, and RA). The first SNP was rs16944 on the Interleukin-1β (IL-1β) gene. The second genetic variation was ε4 variation of apolipoprotein E (APOE) gene. The shared genetic variations (i.e., rs16944 on the IL-1β gene and ε4 variation of the APOE gene) may explain the underlying pathomechanisms of the comorbidity between three common SADs (i.e., IDDM, SLE, and RA) and TLE. Exploring such shared genetic variations may help find targeted therapies for patients with TLE, especially those with drug-resistant seizures who also have comorbid SADs.

Association of APOE (rs429358 and rs7412) and PON1 (Q192R and L55M) Variants with Myocardial Infarction in the Pashtun Ethnic Population of Khyber Pakhtunkhwa, Pakistan.

Coronary Artery Diseases (CAD) remains the top among Non-communicable Diseases (NCDs). Variations in Apolipoprotein E (APOE) and Paroxonase 1 (PON1) have been associated with Myocardial Infarction (MI) in several populations. However, despite the high prevalence of CAD, no such study has been reported in the Pashtun ethnic population of Pakistan. We have conducted a two-stage (i.e., screening and validation) case-control study in which 200 cases and 100 control subjects have been recruited. In the first stage, Whole Exome Sequencing (WES) was used to screen for pathogenic variants of Myocardial Infarction (MI). In the second stage, selected variants of both APOE and PON1 genes (rs7412, rs429358, rs854560, and rs662) were analyzed through MassARRAY genotyping. Risk Allele Frequencies (RAFs) distribution and association of the selected SNPs with MI were determined using the Chi-square test and logistic regression analysis. WES identified a total of 12 sequence variants in APOE and 16 in PON1. Genotyping results revealed that APOE variant rs429358 (ɛ4 allele and ɛ3/ɛ4 genotype) showed significant association in MI patients (OR = 2.11, p value = 0.03; 95% CI = 1.25-2.43); whereas no significant difference (p˃ 0.05) was observed for rs7412. Similarly, the R allele of PON1 Q192R (rs662) was significantly associated with cases (OR = 1.353, p value = 0.048; 95% CI = 0.959-1.91), with particular mention of RR genotype (OR = 1.523, p value = 0.006; 95% CI = 1.087-2.132). Multiple logistic regression analysis showed that rs429358 (C allele) and rs662 (R allele) have a significantly higher risk of MI after adjustment for the conventional risk factors. Our study findings suggested that the rs429358 variant of APOE and PON1 Q192R are associated with MI susceptibility in the Pashtun ethnic population of Pakistan.

Association of Different Combinations of ALDH2 rs671, APOE rs429358, rs7412 Polymorphisms with Hypertension in Middle-Aged and Elderly People: A Case-Control Study.

Hypertensive patients have a younger trend, and studies on the role of genetic factors in hypertension susceptibility have been inconsistent. Aldehyde dehydrogenases 2 (ALDH2) and apolipoprotein E (APOE) are involved in the pathophysiological processes of hypertension. To investigate the relationship of ALDH2 and APOE polymorphisms with hypertension in middle-aged (30-59 years old) and elderly (≥60 years old) persons. Two thousand six hundred and ten hypertensive patients and 1921 controls were included (between 30 and 100 years old). The genotypes of common polymorphisms in APOE and ALDH2 genes (APOE rs429358, rs7412, and ALDH2 rs671) of the subjects were analyzed by polymerase-chain reaction (PCR)-microarray. Statistical analyses (Student's t-test, Mann-Whitney U-test, χ 2 test, and logistic regression analysis) were performed with SPSS v21.0. There were 4531 participants (66.60 ± 12.10 years old) in this study, including 3057 (67.5%) males and 1474 (32.5%) females. There were no significant differences in distributions of ALDH2 rs671, APOE rs429358/rs7412 genotypes and alleles between hypertensive patients and controls. Persons with ALDH2 rs671 G/A or A/A genotype were less likely to have hypertension (G/A+A/A vs G/G: gender-, age-, smoking-, and drinking-adjusted OR 0.885, 95% CI 0.785-0.997, P=0.045), while ALDH2 rs671 A/A+APOE rs429358 or rs7412 wild-type genotype may decrease the risk of hypertension. In middle-aged group, ALDH2 rs671 G/A+APOE rs429358 T/C carriers (adjusted OR 0.547, 95% CI 0.350-0.856, P=0.008), and ALDH2 rs671 A/A+APOE rs7412 C/C genotypes (adjusted OR 0.567, 95% CI 0.361-0.891, P=0.014) were less likely to have hypertension. In elderly group, APOE rs7412 T/T carriers were more likely to have hypertension (rs671 T/T vs C/C: adjusted OR 4.755, 95% CI 1.075-21.027, P=0.040; rs671 T/T vs C/C or C/T: adjusted OR 4.734, 95% CI 1.071-20.928, P=0.040). Polymorphism-polymorphism interactions of ALDH2 rs671 and APOE rs429358/rs7412 may effect on hypertension susceptibility. Different genotypes comparison shows different roles in middle-aged and elderly people, respectively.

Hypercholesterolemia Induced by Cholesterol- or Cystine-Enriched Diets is Characterized by Different Plasma Lipoprotein and Apolipoprotein Concentrations in Rats

This study examined the effects of diet-induced hypercholesterolemia on plasma apolipoprotein (apo) concentrations and hepatic apolipoprotein mRNA levels in rats. Hypercholesterolemia was induced by feeding rats diets containing an excess of either cholesterol or cystine. After cholesterol feeding, plasma apo E and apo B concentrations were lower (-65%, P < 0.001) and greater (+39%, P < 0.01), respectively, compared with control diet-fed rats. After cystine feeding, plasma apo B and apo E concentrations were greater (+46%, P < 0.01 and +75%, P < 0.001, respectively) and plasma apo A-IV concentration was lower (-29%, P < 0.001) than in rats fed control diet. After cholesterol or cystine feeding, a tendency (one-way ANOVA, P = 0.08) for greater apo B mRNA level (+42% and +47%, respectively) was observed compared with control diet-fed rats. No difference emerged between groups for apo E and apo A-I mRNA levels. An opposite effect of cholesterol and cystine feeding was shown for apo A-IV mRNA level, i.e., higher after cholesterol feeding (+47%, P < 0.05) and lower after cystine feeding (-65%, P < 0.01). From this work, it seems that hypercholesterolemia induced by dietary cholesterol or by increased cholesterogenesis in cystine-fed rats is characterized by different plasma lipoprotein and apolipoprotein concentrations and is associated with different apolipoprotein gene expression in the liver.