Apolipoprotein E-η4 allele and familial risk in Alzheimer's disease

Recent studies have found an association between presence of apolipoprotein E (APOE) η4 allele and Alzheimer's disease (AD). The present study compared the cumulative risk of primary progressive dementia (PPD) in relatives of AD probands carrying at least one copy of the η4 allele with the relatives of AD probands not carrying η4 and with relatives of non-demented controls. Our aim was to determine whether the familial aggregation of PPD in relatives of AD probands is primarily due to those carrying η4. Seventy-seven neuropathologically diagnosed AD patients were obtained as probands through our Alzheimer's Disease Research Center Brain Bank. AD probands were genotyped for APOE. As a comparison group, 198 non-demented probands were also included. Through family informants, demographic and diagnostic data were collected on 382 first-degree relatives (age ≥ 45 years) of AD probands and 848 relatives of the controls. We found that the cumulative risk of PPD in both relatives of AD probands with and without the η4 allele was significantly higher than that in the relatives of non-demented controls. However, the increased risk in the relatives of AD probands with the η4 allele was marginally, but not significantly, lower than the risk in the relatives of probands without η4. A greater likelihood of death by heart diseases over developing PPD in relatives of AD probands with η4 (3.1-fold increase) was found compared to relatives of probands without η4 (1.7-fold increase), especially prior to age 70, although the difference was not statistically significant. The increased familial risk for PPD in the relatives of AD probands with the APOE-η4 allele relative to controls suggests that familial factors in addition to APOE-η4 are risk factors for AD. Differential censorship from increased mortality of heart diseases may have prevented a higher incidence of PPD among the relatives of probands with η4. © 1996 Wiley-Liss, Inc.     

E2 allele of the Apolipoprotein E gene polymorphism is predictive for obesity status in Roma minority population of Croatia

Background and Aims  

The Roma (Gypsies) are a transnational minority, founder population characterized by unique genetic background modeled by culturally determined endogamy. The present study explores whether the widely found cardiovascular diseases (CVD) risk effects of ACE I/D, APOE (ε2, ε3, ε4), eNOS-VNTR and LEP G2548A polymorphisms can be replicated in this specific population.     

Apolipoprotein E4 allele and Alzheimer disease: Examination of Allelic association and effect on age at onset in both early-and late-onset cases

An increased frequency of the apolipoprotein E type 4 allele (APOE-4) has previously been associated with both late-onset sporadic and late-onset familial Alzheimer disease (AD) [Strittmatter et al. (1993) Proc Natl Acad Sci USA 90:1977–1981; Saunders et al. (1993a) Neurology 43:1467–1472]. To further investigate this association we genotyped affected individuals from 92 separate AD pedigrees including both early- and late-onset cases. An increased frequency of the APOE-4 allele was found only among the late-onset cases, both familial and sporadic, confirming the earlier reports. In addition, age at onset was significantly decreased in the APOE-4 homozygotes (in late onset families) compared to either APOE-4 heterozygotes or individuals not carrying an APOE-4 allele. We also observed a significantly decreased frequency of the APOE-2 allele in both the early-and late-onset familial cases. These results strengthen the argument for a direct role of APOE in susceptibility to AD. © Wiley-Liss, Inc.     

Apolipoprotein E genotype and gallbladder disease risk in a large population-based cohort

PURPOSE: The aim of the study is to describe the association between apolipoprotein E (apoE) genotype and gallbladder disease incidence. METHODS: Cases of incident hospitalized gallbladder disease were ascertained in nearly 13,000 middle-aged men and women participating in the Atherosclerosis Risk in Communities (ARIC) Study, a prospective cohort study in four US communities. RESULTS: Between the ARIC baseline examination (1987 to 1989) and December 31, 2001, a total of 639 participants were hospitalized for gallbladder disease. After adjustment for age, sex, race, obesity, plasma lipid level, and diabetes, the relative risk for hospitalized gallbladder disease associated with the presence of an epsilon4 allele (i.e., genotypes E4/4, E3/4, and E2/4 versus other genotypes) was 0.72 (95% confidence interval [CI], 0.60-0.87). Stratification by race showed that the inverse association with epsilon4 was stronger in whites (relative risk, 0.69; 95% CI, 0.56-0.85) than African Americans (relative risk, 0.86; 95% CI, 0.58-1.30). The presence of the other rare isoform, epsilon2 (i.e., genotypes E2/2, E2/3, and E2/4 versus others) was associated with a modest increased risk for gallbladder disease (relative risk, 1.28; 95% CI, 1.05-1.57). CONCLUSIONS: These results suggest that independent of traditional risk factors, apoE genotype may influence gallbladder disease risk, particularly in whites. The exact biologic mechanism for such an association remains unclear and requires further investigation.     

A proinflammatory state is associated with hyperhomocysteinemia in the elderly

BACKGROUND: The mechanism by which high circulating homocysteine concentrations are a risk factor for atherothrombosis is incompletely understood. A proinflammatory state is related to atherosclerosis, and recent studies suggest that acute phase reactants correlate with circulating concentrations of homocysteine. OBJECTIVE: We determined whether high concentrations of inflammatory markers are associated with hyperhomocysteinemia independently of dietary vitamin intakes, vitamin concentrations, and cardiovascular disease risk factors in a large, representative sample of the general population. DESIGN: Five hundred eighty-six men and 734 women were randomly selected from the inhabitants of 2 small towns near Florence, Italy. RESULTS: After adjustment for multiple potential confounders, interleukin 1 receptor antagonist (IL-1ra) and interleukin 6 (IL-6) concentrations were significantly (P < 0.001) associated with plasma homocysteine concentrations in older (>65 y) populations. Compared with participants in the lowest IL-6 tertile, those in the highest tertile had a higher risk of having homocysteine concentrations that were high (>30 micromol/L; odds ratio: 2.6; 95% CI: 1.1, 5.6; P = 0.024) or in the intermediate range 15-30 micromol/L (odds ratio: 1.6; 95% CI: 1.2, 2.2; P = 0.0014). Sedentary state, intakes of vitamin B-6 and folic acid, and serum folate, vitamin B-12, vitamin B-6, and alpha-tocopherol concentrations were significant independent correlates of homocysteine. CONCLUSIONS: High circulating concentrations of IL-1ra and IL-6 are independent correlates of hyperhomocysteinemia and may explain, at least in part, the association between homocysteine and atherosclerosis.     

不同人群载脂蛋白E基因多态性分布状态的研究

为研究不同人群载脂蛋白（Ａｐｏ）Ｅ基因多态性的分布特征,采用聚合酶链－限制性片段长度多态性（ＰＣＲ－ＲＦＬＰ）方法,先扩增出ＡｐｏＥ基因第４外显子内的２２７ｂｐ片段,经以限制性内切酶ＣｆｏＩ酶解消化,８％聚丙烯酰胺凝胶电泳,最后银染显带判定基因型,结果正常汉族、朝族、回族和蒙古族ＡｐｏＥ等基因频率,ε２等痊基因频率分别是８．０％、１２．９％、１１．３％、和１２．６％,ε３分别是８５．７％、７８．６     

Apolipoprotein E polymorphism in Turkish subjects with Type 2 diabetes mellitus: allele frequency and relation to serum lipid concentrations

The role of apolipoprotein E (apoE) genotypes in modulating plasma lipid and apolipoprotein levels was studied in 112 patients with Type 2 diabetes mellitus (T2DM) and 94 healthy individuals. ApoE genotypes were identified by PCR amplification and subsequent restriction endonuclease digestion. The apoE allele and genotype frequencies were similar in both the diabetic and control subjects. The apoE allele frequencies were found to be 74.3 for e3, 10.1 for e2, 15.6 for e4 in the diabetic group, and 68.1 for e3, 13.2 for e2 and 18.7 for e4 in the control group. Sex-specific genotypic distribution of apoE polymorphism did not differ between the study groups. To elucidate the association of apoE with lipid abnormalities with respect to gender, serum lipid and apolipoprotein levels were compared among apo e2 (e2/2 and e3/2), e3 (e3/3) and e4 (e4/3 and e4/4) groups of T2DM and control subjects. Apo e2 allele was found to be associated to triglycerides for both sexes, and associated to glucose, and BMI only in females. Subjects with e2 allele had higher levels of BMI, glucose and triglyceride in comparison to e3 and e4. Our data suggest that genetic variation at the apoE locus in Turkish subjects is a genetic factor that influences lipid levels. Further studies attempting to correlate apoE polymorphism with lipid profile in a large number of individuals would be helpful in establishing the true significance of this polymorphism in the Turkish population.     

老年期痴呆与载脂蛋白Eε4等位基因的关联研究

[目的] 探讨上海地区老年期痴呆与载脂蛋白E (APOE)ε4等位基因之间关联.[方法] 采用聚合酶链反应和限制性片段长度多态性分析技术,对70例老年性痴呆(AD)患者和58例血管性痴呆(VD)患者及55位健康老人的APOE基因进行分型,计算基因频率,并验证APOE基因多态性与疾病的关联性.[结果] APOEε4等位基因与AD显著相关,OR＝2.83(P＜0.05).AD患者的ε4基因频率较正常对照及VD患者明显增高,三组APOE基因频率分别为25.0%、10.0%及11.2%,且随着ε4基因剂量增加,AD患病率明显增高,发病年龄下降.APOEε4等位基因与VD无关联.[结论] 本研究结果提示,APOEε4等位基因与AD发病有关,可能是AD发病的危险因子之一.     

Association of Apolipoprotein e polymorphism with SARS-CoV-2 infection

Coronavirus 2019 (COVID-19) is a viral disease caused by severe acute respiratory syndrome coronavirus-2 (SARS CoV-2). The disease resulted in global morbidity and mortality that led to considering as pandemic. The human body response to COVID-19 infection was massively different from being asymptomatic to developing severe symptoms. Host genetic factors are thought to be one of the reasons for these disparities in body responses. Few studies have suggested that Apolipoprotein Epsilon (Apo E) is a candidate gene for playing roles in the development of the disease symptoms. This work aims to find an association between different Apo E genotypes and alleles to COVID-19 infection comparing a general population and a group of COVID-19 patients. For the first time, the results found that Apo E4 is associated with COVID-19 disease in a Kurdish population of Iraq. Further study is required to reveal this association in different ethnic backgrounds all over the world.     

Vitamin E dietary supplementation significantly affects multiple risk factors for cardiovascular disease in baboons

BACKGROUND: Oxidative stress is a widely accepted risk factor for cardiovascular disease (CVD), but the CVD benefit of dietary antioxidants, such as vitamin E, is controversial. OBJECTIVE: Therefore, we have investigated, in the baboon model, the effects of dietary vitamin E supplementation on risk factors for CVD. DESIGN: Pedigreed baboons (n = 251) were fed 2 atherogenic diets, high in fat and cholesterol, that differed in vitamin E concentrations. After 7 wk on each diet, blood samples were taken, and a panel of CVD risk factor traits (ie, indicators of lipoprotein metabolism and oxidative stress) were measured. RESULTS: Vitamin E supplementation caused significantly higher total antioxidant status (TAS) and lower oxidized LDL as expected. In addition, vitamin E caused 2 paradoxical effects on HDL metabolism: higher apolipoprotein A-I (apo A-I) concentrations and lower HDL sizes. We calculated a difference (Delta) variable for each trait as the value on the high-vitamin E diet minus that on the low-vitamin E diet and determined that several HDL concentration Delta variables were significantly correlated with Delta TAS, but only one, Delta apo A-I, was independently correlated. Genetic analyses showed that 2 Delta variables, Delta paraoxonase and Delta HDL(2), were significantly heritable, but that neither Delta TAS nor Delta apo A-I were heritable. CONCLUSIONS: Thus, our data show that dietary vitamin E improves TAS and LDL quality. They also show 2 apparently paradoxical effects on HDL metabolism: lower HDL(2), which is mediated by genes, and higher apo A-I, which is not. These effects have contrasting associations with CVD risk and may help account for the mixed results from clinical trials of dietary vitamin E.     

Apolipoprotein E genotypes of fertile and infertile men

Lipid components of spermatozoa have an important role in the functional activity of this cell. The protein, apolipoprotein E (apoE), has a central role in lipid transport. The aim of this study was to investigate the distribution of APOE genotypes, ?3?3, ?3?4, and ?2?3, and the corresponding alleles in fertile and infertile males, and to assess the semen parameters from the patients carrying the different alleles. In addition, the levels of cholesterol, phospholipid, and triacylglycerol in spermatozoa, isolated by PureSperm gradient and from seminal plasma in samples from infertile males was compared with respect to the APOE genotype. APOE genotypes were determined by PCR-RFLP on DNA extracted from peripheral blood leucocytes in 108 fertile and 107 infertile men. There was a significant difference between the distribution of APOE genotypes in fertile as compared to infertile males (χ²?=?9.1, df?=?2, p?=?0.011). The presence of genotype ?3?4 conferred a 3.82 risk factor for male infertility {Odds ratio?=?3.82 (1.46-10, p?=?0.006)}. Our findings showed that the distribution of APOE genotypes and alleles differed between fertile and infertile individuals and may be a risk factor for male infertility. We suggest that the effects of APOE genotypes may be linked to differences in the efficacy of the expressed apoE isoforms in promoting sperm maturation during epididymal transit.     

Apolipoprotein E genotypes of fertile and infertile men

Lipid components of spermatozoa have an important role in the functional activity of this cell. The protein, apolipoprotein E (apoE), has a central role in lipid transport. The aim of this study was to investigate the distribution of APOE genotypes, ?3?3, ?3?4, and ?2?3, and the corresponding alleles in fertile and infertile males, and to assess the semen parameters from the patients carrying the different alleles. In addition, the levels of cholesterol, phospholipid, and triacylglycerol in spermatozoa, isolated by PureSperm gradient and from seminal plasma in samples from infertile males was compared with respect to the APOE genotype. APOE genotypes were determined by PCR-RFLP on DNA extracted from peripheral blood leucocytes in 108 fertile and 107 infertile men. There was a significant difference between the distribution of APOE genotypes in fertile as compared to infertile males (χ(2)?=?9.1, df?=?2, p?=?0.011). The presence of genotype ?3?4 conferred a 3.82 risk factor for male infertility {Odds ratio?=?3.82 (1.46-10, p?=?0.006)}. Our findings showed that the distribution of APOE genotypes and alleles differed between fertile and infertile individuals and may be a risk factor for male infertility. We suggest that the effects of APOE genotypes may be linked to differences in the efficacy of the expressed apoE isoforms in promoting sperm maturation during epididymal transit.     

载脂蛋白E基因多态性对血脂的影响

[目的]探讨载脂蛋白E（ApoE）基因多态性对血脂的影响。[方法]采用聚合酶链式反应-限制性片段长度多态性分析方法（PCR-RFLP），测定252名河南省汉族研究对象的血脂及ApoE基因型。[结果]ApoE基因型以E3／3型常见为77．0％，等位基因频率ε2、ε3和ε4分别为5．7％、87．1％和7．5％。在不同基因型组间，总胆固醇（TC）和低密度脂蛋白胆固酵（LDL-C）水平均按E3／4＋E4／4〉E3／3〉E2／2＋E2／3顺序递减（P〈0．05），甘油三脂（TG）、高密度脂蛋白胆固醇（HDL-C）水平在各组间比较无差异（P〉0．05）。[结论]ApoE基因多态性影响血脂水平，ε4等位基因携带者有较高的TC，LDL-C水平（P〈0．05），ApoE基因多态性是个体间血脂水平差异的独立遗传因素。     

B vitamin supplementation improves cognitive function in the middle aged and elderly with hyperhomocysteinemia

Objective: An intervention study was performed to determine if supplement containing folic acid, vitamin B₆, and vitamin B₁₂ could improve cognitive function and lower homocysteine in middle-aged and elderly patients with hyperhomocysteinemia.

Methods: One hundred and four participants with hyperhomocysteinemia were recruited in Tianjin, China, aged 55–94 years old. Fifty-seven individuals with hyperhomocysteinemia were included in the intervention group (vitamin B group, which received 800 µg/day of folate, with 10 mg of vitamin B₆ and 25 µg of vitamin B₁₂) and 47 patients in the placebo group. The endpoint was the improvement in cognitive function as evaluated by Basic Cognitive Aptitude Tests (BCATs). All parameters were measured before and after the treatment period of 14 weeks.

Results: The BCAT total score and four sub-tests scores (digit copy, Chinese character rotation, digital working memory, and recognition of meaningless figure) of BCAT at 14 weeks significantly increased only for the vitamin B group. Serum total homocysteine (tHcy) levels significantly decreased in the intervention group, while serum concentrations of folate, vitamin B₆, and vitamin B₁₂ significantly increased in the intervention group.

Conclusion: The results demonstrated that supplement containing folate, vitamin B₆, and vitamin B₁₂ in middle-aged and elderly patients with hyperhomocysteinemia could improve their cognitive function partly and reduce serum tHcy levels.     

Risk of dementia in parents of probands with and without the apolipoprotein E4 allele. The EVA study

STUDY OBJECTIVE: Age, family history of dementia and the epsilon 4 allele of the apolipoprotein E gene have been associated with Alzheimer's disease (AD). Considering the strength of APOE-epsilon 4 as a genetic risk factor for AD, this factor might explain a large part of the association between AD and a family history of dementia. Therefore, in the general population, a higher frequency of dementia should be observed among parents of probands with at least one epsilon 4 allele than in parents of probands without this allele. DESIGN, SETTING, AND PARTICIPANTS: The study investigated a sample of 1153 volunteers between 59 and 71 years old, genotyped for the APOE gene, all participating in the EVA study. Dementia in their parents was determined using a self reported questionnaire. MAIN RESULTS: The frequency of dementia in 2164 parents was examined and it was found that 245 were demented. The percentage of demented parents was 13.0% in the subgroup of parents of subjects having one or two epsilon 4 alleles and 10.8% in the other subgroup. The relative risk of dementia among parents according to the APOE-epsilon 4 status of probands, was calculated using a Cox model adjusted for the educational level of parents and their history of stroke: RR = 1.21 (95% CI 0.90, 1.63). CONCLUSION: This lack of association supports the observation that in the general population, APOE-epsilon 4 cannot explain a large part of family history of dementia.     

Apolipoprotein E genotype and hepatitis C,HIV and herpes simplex disease risk: a literature review

Apolipoprotein E is a polymorphic and multifunctional protein with numerous roles in lipoprotein metabolism. The three common isoforms apoE2, apoE3 and apoE4 show isoform-specific functional properties including different susceptibilities to diseases. ApoE4 is an accepted risk factor for Alzheimer's disease and cardiovascular disorders. Recently, associations between apoE4 and infectious diseases have been demonstrated. This review summarises how apoE4 may be involved in the infection incidence and associated pathologies of specific infectious diseases, namely hepatitis C, human immunodeficiency virus disease and herpes simplex.     

载脂蛋白E基因多态性与子痫前期的相关性

目的 探讨载脂蛋白 E(ApoE)基因多态性与血脂水平、子痫前期(PE)发生的相关性.方法 选取2007年1月至10月于广州医学院附属深圳沙井医院(深圳市宝安区沙井人民医院)住院分娩的孕产妇120例为研究对象,年龄为20～35岁.将其中诊断为PE者纳入PE组(n=50),其余正常妊娠孕妇纳入对照组(n=70)(本研究遵循的程序符合本院人体试验委员会制定的伦理学标准,得到该委员会批准,分组征得受试者的知情同意,并与其签订临床研究知情同意书).两组孕妇的平均年龄及体重指数(BMI)比较,差异无统计学意义(P＞0.05).应用聚合酶链反应-限制性内切酶片段长度多态性(PCR-RFLP)检测受试者ApoE基因型及其血脂[总胆固醇(TC)、甘油三酯(TG)、低密度脂蛋白(LDL)-C、高密度脂蛋白(HDL)-C]水平,并进行统计学分析.结果 PE组孕妇血清TC,TG与LDL-C水平明显高于对照组,而HDL-C水平低于对照组,两组比较,差异均有统计学意义(P<0.05);PE组孕妇携带ApoE ε3/4基因型者明显高于对照组,两组比较,差异有统计学意义(P<0.05);PE组孕妇携带ApoE ε3/4基因型者脂代谢异常程度高于其他基因型.结论 ApoE基因多态性与PE孕妇存在脂代谢异常有关,可能为PE孕妇发病的遗传因素之一.     

Simultaneous Mass Spectrometry-Based Apolipoprotein Profiling and Apolipoprotein E Phenotyping in Patients with ASCVD and Mild Cognitive Impairment

Apolipoprotein E (apoE) occurs on the majority of plasma lipoproteins and plays a major role in the lipid metabolism in the periphery and in the central nervous system. ApoE is a polymorphic protein with three common isoforms, apoE2, apoE3 and apoE4, derived from respective alleles ε2, ε3 and ε4. The aim of this study was to develop a sample pretreatment protocol combined with rapid mass spectrometry (MS)-based assay for simultaneous apolipoprotein profiling and apoE phenotype identification. This assay was validated in 481 samples from patients with stable atherosclerotic cardiovascular disease (ASCVD) and applied to study association with mild cognitive impairment (MCI) in the LIFE Adult study, including overall 690 study subjects. Simultaneous quantification of 8–12 major apolipoproteins including apoA-I, apoB-100 and apoE could be performed within 6.5 min. Phenotyping determined with the developed MS assay had good agreement with the genotyping by real-time fluorescence PCR (97.5%). ApoE2 isoform was associated with the highest total apoE concentration compared to apoE3 and apoE4 (p < 0.001). In the subgroup of diabetic atherosclerotic cardiovascular disease (ASCVD) patients, apoE2 isoform was related to higher apoC-I levels (apoE2 vs. apoE3, p < 0.05), while in the subgroup of ASCVD patients under statin therapy apoE2 was related to lower apoB-100 levels (apoE2 vs. apoE3/apoE4, p < 0.05). A significant difference in apoE concentration observed between mild cognitive impairment (MCI) subjects and controls was confirmed for each apoE phenotype. In conclusion, this study provides evidence for the successful implementation of an MS-based apoE phenotyping assay, which can be used to assess phenotype effects on plasma lipid and apolipoprotein levels.     

载脂蛋白E基因多态性与中国人群冠心病的关联

目的 研究载脂蛋白E（ApoE）基因多态性与中国人群冠心病的关联。方法 选择63例冠心病患者及年龄、性别相匹配的90例正常对照组,聚合酶链反应－限制性片段长度多态性（PCR－RFLP）方法检测ApoE基因型。比较两组基因硎圾等位基因频率分布。结果 冠心病组ε4等位基因频率（12．70％）明显高于对照组（5．55％）（P＜0．05）。结论 ε4等位基因可能是冠心病的遗传易患因子。