中国人群中肿瘤坏死因子α-308 A/G基因多态和α2-巨球蛋白基因缺失多态与晚发性阿尔茨海默病无相关性

晚发性阿尔茨海默病 (LOAD)是老年痴呆中最常见的一种 ,它是一种病因复杂、由遗传因素和环境等其他因素共同作用引起的老年期疾病。服用非甾类抗炎类药物能延缓或防止LOAD的发病说明炎症反应可能参与LOAD病理 ,肿瘤坏死因子 (TNF)是炎症反应中主要的细胞因子 ,并且能增加 β 淀粉样肽 (Aβ)的产生说明其可能是LOAD的易感基因。α2 巨球蛋白 (A2M)是一种血清蛋白酶抑制剂 ,它是低密度脂蛋白受体相关蛋白 (LRP)主要的配体 ,并且能与Aβ结合并介导其降解和清除 ,说明它可能是另一个LOAD的易感基因。在 6 7名晚发性阿尔茨海默病人和 14 2名正常对照中比较了载脂蛋白E基因 (APOE)、TNF启动子区 (- 30 8A G)多态和A2M一 5bp核苷酸缺失 (I D)多态 (A2M 2 )与LOAD发病风险的关系。结果显示 ,APOEε4等位基因在AD病人组中显著高于对照组 (χ2=11 6 6 ,P <0 0 1) ,而TNF(- 30 8A G)多态和A2M缺失多态的基因型和等位基因在LOAD病人组和对照组中都无显著差别 (P >0 1)。按年龄和APOEε4等位基因分组同样无相关性 ,说明TNF 30 8A G位点的多态与A2M缺失不是中国人群的晚发性老年痴呆的风险因子     

Microsatellite polymorphism of the α1-antichymotrypsin gene locus associated with sporadic Alzheimer’s disease

A variant of the apolipoprotein E gene, APOE*4, is associated with both sporadic Alzheimer’s disease (AD) and a subset of familial AD and this association is stronger with early as opposed to late onset AD. Both APOE*4 and α₁-antichymotrypsin (ACT) will accelerate the rate of amyloid filament formation and are major constituents of the plaques associated with AD. We now show that a dinucleotide microsatellite allele in the 5′-flanking sequence of the ACT gene, designated A10, in association with APOE*4 significantly increases the risk of developing sporadic AD, which accounts for the majority of AD cases. Received: 15 May 1996 / Revised: 7 July 1996     

The association of a cystatin C gene polymorphism with late-onset Alzheimer's disease and vascular dementia

A polymorphism in the cystatin C (CST3) gene was suggested to associate with Alzheimer's disease (AD). In the present study we attempted to determine the association between CST3 polymorphism and AD or vascular dementia (VD), and whether such effects are dependent of the APOE4 allele. The polymorphisms of CST3 genotype were determined using polymerase chain reactions (PCR) followed by gel electrophoresis in 124 AD, 70 VD, and 115 control individuals. No statistical difference in CST3B allele frequencies was observed among all three groups. Associations between CST3B/B genotype and AD patients older than 75-year-old, or VD patients younger than 75-year-old were evident. The APOE4 allele alone significantly increased the odds for the developing AD, but not VD. A logistic regression analysis revealed that either CST3 or its interaction with APOE4 were not significant predictors of AD. However, a synergistic association of CST3 and APOE4 alleles was observed in predicting VD patients. These results suggest that CST3 might interact with APOE4 on conferring vascular pathologies.     

Genetic association between the apolipoprotein E (ApoE) gene alleles and various forms of Alzheimer's disease]

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.     

Apolipoprotein E-promoter single-nucleotide polymorphisms affect the phenotype of primary open-angle glaucoma and demonstrate interaction with the myocilin gene

Primary open-angle glaucoma (POAG) is an optic neuropathy that has a high worldwide prevalence and that shows strong evidence of complex inheritance. The myocilin (MYOC) gene is the only one that has thus far been shown to have mutations in patients with POAG. Apolipoprotein E (APOE) plays an essential role in lipid metabolism, and the APOE gene has been involved in neuronal degeneration that occurs in Alzheimer disease (AD). Here, we report that two APOE-promoter single-nucleotide polymorphisms (SNPs) previously associated with AD also modify the POAG phenotype. APOE(-219G) is associated with increased optic nerve damage, as reflected by increased cup:disk ratio and visual field alteration. In addition, APOE(-491T), interacting at a highly significant level with an SNP in the MYOC promoter, MYOC(-1000G), is associated with increased intraocular pressure (IOP) and with limited effectiveness of IOP-lowering treatments in patients with POAG. Together, these findings establish APOE as a potent modifier for POAG, which could explain the linkage to chromosome 19q previously observed by use of a genome scan for this condition and an increased frequency of glaucoma in patients with AD. The findings also shed new light on potential mechanisms of optic nerve damage and of IOP regulation in POAG.     

Mitochondrial DNA haplogroups and APOE4 allele are non-independent variables in sporadic Alzheimer's disease

Allele epsilon4 of the nuclear APOE gene is a leading genetic risk factor for sporadic Alzheimer's disease (AD). Moreover, an allele-specific effect of APOE isoforms on neuronal cell oxidative death is known. Because of the role of the mitochondrial genome (mtDNA) in oxidative phosphorylation and oxidative stress, an interaction between APOE polymorphism and mtDNA inherited variability in the genetic susceptibility to sporadic AD can be hypothesized. We have explored this hypothesis by analyzing mtDNA germline variants (mtDNA haplogroups) in a sample of AD patients (213 subjects) genotyped for APOE and classified as APOE epsilon4 carriers and non-carriers. We found that the frequency distribution of mtDNA haplogroups is different between epsilon4 carriers and non-carriers (P=0.018), thus showing non-random association between APOE and mtDNA polymorphisms. The same analysis, carried out in two samples of healthy subjects (179 age-matched and 210 individuals aged more than 100 years), showed independence between epsilon4 allele and mtDNA haplogroups. Therefore, the APOE/mtDNA interaction is restricted to AD and may affect susceptibility to the disease. In particular, some mtDNA haplogroups (K and U) seem to neutralize the harmful effect of the APOE epsilon4 allele, lowering the epsilon4 odds ratio from statistically significant to non-significant values.     

Parkinson's disease and apolipoprotein E: possible association with dementia but not age at onset

Idiopathic Parkinson's disease (PD) is an age-dependent, neurodegenerative condition frequently associated with dementia. Although it is predominantly a sporadic disease, 20-30% of cases are familial, suggesting a complex mode of inheritance. Apolipoprotein E (APOE) allele epsilon4 has been associated with familial and sporadic late-onset senile dementia of the Alzheimer's type. To investigate the role of this gene in the development of dementia associated with PD and age at onset of PD, we evaluated the frequency of APOE gene polymorphism in a sample of PD patients with (n=118) and without (n=167) a family history, as well as matched normal controls (n=96). The PD sample was categorized according to age at onset and presence or absence of dementia. Kaplan-Meier survival analysis was used to plot genotype-specific age at onset distribution curves. Allele frequencies of APOE in PD patients with and without a family history and normal controls were not significantly different. APOE genotypes were also similar between the groups. However, the frequencies of epsilon4 allele and epsilon4/- genotype in the PD group with dementia were more than twofold higher than in normal controls, and the differences were statistically significant. There were no differences in the allele and genotype frequencies of the APOE gene between PD groups with different age at onset. The familial PD had significantly earlier age at onset than sporadic PD (Log-rank test, P=0.027). The age at onset distribution curves for different genotype groups were similar, and their differences were not statistically significant (P=0.38). After the Bonferroni's correction for multiple tests, the positive results are not significant at the P<0.05 level. We conclude that APOE does not play an important role in susceptibility to PD or age at onset of PD, but may play a role in dementia associated with PD in our sample.     

Evidence for major gene inheritance of Alzheimer disease in families of patients with and without apolipoprotein E epsilon 4.

Apolipoprotein E (APOE) genotype is the single most important determinant to the common form of Alzheimer disease (AD) yet identified. Several studies show that family history of AD is not entirely accounted for by APOE genotype. Also, there is evidence for an interaction between APOE genotype and gender. We carried out a complex segregation analysis in 636 nuclear families of consecutively ascertained and rigorously diagnosed probands in the Multi-Institutional Research in Alzheimer Genetic Epidemiology study in order to derive models of disease transmission which account for the influences of APOE genotype of the proband and gender. In the total group of families, models postulating sporadic occurrence, no major gene effect, random environmental transmission, and Mendelian inheritance were rejected. Transmission of AD in families of probands with at least one epsilon 4 allele best fit a dominant model. Moreover, single gene inheritance best explained clustering of the disorder in families of probands lacking epsilon 4, but a more complex genetic model or multiple genetic models may ultimately account for risk in this group of families. Our results also suggest that susceptibility to AD differs between men and women regardless of the proband's APOE status. Assuming a dominant model, AD appears to be completely penetrant in women, whereas only 62%-65% of men with predisposing genotypes develop AD. However, parameter estimates from the arbitrary major gene model suggests that AD is expressed dominantly in women and additively in men. These observations, taken together with epidemiologic data, are consistent with the hypothesis of an interaction between genes and other biological factors affecting disease susceptibility.     

SNPing away at complex diseases: analysis of single-nucleotide polymorphisms around APOE in Alzheimer disease

There has been great interest in the prospects of using single-nucleotide polymorphisms (SNPs) in the search for complex disease genes, and several initiatives devoted to the identification and mapping of SNPs throughout the human genome are currently underway. However, actual data investigating the use of SNPs for identification of complex disease genes are scarce. To begin to look at issues surrounding the use of SNPs in complex disease studies, we have initiated a collaborative SNP mapping study around APOE, the well-established susceptibility gene for late-onset Alzheimer disease (AD). Sixty SNPs in a 1.5-Mb region surrounding APOE were genotyped in samples of unrelated cases of AD, in controls, and in families with AD. Standard tests were conducted to look for association of SNP alleles with AD, in cases and controls. We also used family-based association analyses, including recently developed methods to look for haplotype association. Evidence of association (P相似文献   

Oxidative damage and protection by antioxidants in the frontal cortex of Alzheimer's disease is related to the apolipoprotein E genotype.

A great number of epidemiological studies have demonstrated that the frequency of the epsilon4 allele of the apolipoprotein E gene (APOE) is markedly higher in sporadic and in familial late onset Alzheimer disease (AD). In the frontal cortex of AD patients, oxidative damage is elevated. We address the hypothesis that the APOE genotype and reactive oxygen-mediated damage are linked in the frontal cortex of AD patients. We have related the APOE genotype to the levels of lipid oxidation (LPO) and to the antioxidant status, in frontal cortex tissues from age-matched control and AD cases with different APOE genotypes. LPO levels were significantly elevated in tissues from Alzheimer's cases which are homozygous for the epsilon4 allele of APOE, compared to AD epsilon3/epsilon3 cases and controls. Activities of enzymatic antioxidants, such as catalase and glutathione peroxidase (GSH-PX), were also higher in AD cases with at least one epsilon4 allele of APOE, while superoxide dismutase (SOD) activity was unchanged. In the frontal cortex, the concentration of apoE protein was not different between controls and AD cases, and was genotype independent. The Ginkgo biloba extract (EGb 761), the neurosteroid dehydroepiandrosterone (DHEA) and human recombinant apoE3 (hapoE3rec) were able to protect control, AD epsilon3/epsilon3 and epsilon3/epsilon4 cases against hydrogen peroxide/iron-induced LPO, while hapoE4rec was completely ineffective. Moreover, EGb 761 and DHEA had no effect in homozygous epsilon4 cases. These results demonstrate that oxidative stress-induced injury and protection by antioxidants in the frontal cortex of AD cases are related to the APOE genotype.     

Apolipoprotein-E dependent role for the FAS receptor in early onset Alzheimer's disease: finding of a positive association for a polymorphism in the TNFRSF6 gene

The TNFRSF6 gene encodes FAS, a cell-surface receptor involved in apoptosis initiation. Elevated levels of FAS have been reported in the brains of Alzheimer's disease (AD) patients. We have tested a G/A polymorphism at position -670 in the TNFRSF6 gene for association with non-familial, early onset Alzheimer's disease (EOAD) by using dynamic allele-specific hybridization. In an initial set of Scottish EOAD cases (n=78) and controls (n=152), we found that, for individuals carrying one or two APOE4 alleles, the homozygous GG-genotype was enriched in the patients (26.7% versus 10.9% in controls). A second study was conducted on an independent set of Scottish individuals (87 EOAD, 358 controls). In this material, the TNFRSF6 GG-genotype frequency was elevated in patients regardless of APOE4 status (28.7% versus 15.1%) and was even more enriched in APOE4 carriers (35.9% versus 15.3%). A combination of the two sample sets (165 cases, 510 controls) gave a significant disease association for the TNFRSF6 GG-genotype that was irrespective of APOE4 (P=0.0020) and that was almost completely attributable to the enrichment present within the set of APOE4 carriers (P=0.0016). This represents an odds ratio of 8.71 for GG-homozygotes carrying at least one APOE4 allele compared with other TNFRSF6 genotypes in APOE4 non-carriers. The TNFRSF6 variation was further explored in Scottish late-onset Alzheimer's disease (n=159) but no associations were found. These results imply that TNFRSF6, in interaction with APOE4, is a genetic risk factor for sporadic EOAD. Hence, the AD risk contributed by APOE4 could be mechanistically related to a pathway in common with FAS-mediated apoptosis.     

Analysis of the association of allelic variants of apolypoprotein E and interleukin 1 beta genes with multiple sclerosis in ethnic Tatars

Multiple sclerosis (MS) is a multifactorial disease of the central nervous system. The apolipoprotein E (APOE) and interleukin 1 beta (IL1B) genes are considered to be candidate genes of MS. The aim of the study was to examine the hypothesis of the importance of APOE and IL1B gene polymorphisms in MS development in ethnic Tatars. DNA samples isolated by phenol-chloroform extraction from peripheral blood of 383 ethnic Tatars (120 MS patients and 263 healthy donors) were studied. 112C/R and 158R/C APOE gene polymorphisms as well as -511T/C IL1B gene polymorphism were analyzed by polymerase chain reaction (PCR) followed by PCR product digestion by endonuclease. Odds ratio (OR) values were used for evaluation of the relative risk of alleles and(or) genotype combinations. It has been shown that APOE*2/*3 genotype is associated with low risk of the disease development (OR = 0.20) in women. A combined effect of APOE and IL1B allelic variants has been discovered indicating the increased risk of the disease development in the carriers of APOE*4 and IL1B*T/*T alleles (OR = 4.76).     

A genome-wide association study of Alzheimer’s disease using random forests and enrichment analysis

Alzheimer??s disease (AD) is a serious neurodegenerative disorder and its cause remains largely elusive. In past years, genome-wide association (GWA) studies have provided an effective means for AD research. However, the univariate method that is commonly used in GWA studies cannot effectively detect the biological mechanisms associated with this disease. In this study, we propose a new strategy for the GWA analysis of AD that combines random forests with enrichment analysis. First, backward feature selection using random forests was performed on a GWA dataset of AD patients carrying the apolipoprotein gene (APOE?4) and 1058 susceptible single nucleotide polymorphisms (SNPs) were detected, including several known AD-associated SNPs. Next, the susceptible SNPs were investigated by enrichment analysis and significantly-associated gene functional annotations, such as ??alternative splicing??, ??glycoprotein??, and ??neuron development??, were successfully discovered, indicating that these biological mechanisms play important roles in the development of AD in APOE?4 carriers. These findings may provide insights into the pathogenesis of AD and helpful guidance for further studies. Furthermore, this strategy can easily be modified and applied to GWA studies of other complex diseases.     

In search of genes involved in neurodegenerative disorders

Dissecting the genetics of Alzheimer's disease (AD) and Parkinson's disease (PD) has contributed significantly to our understanding of the pathogenesis of neurodegeneration in these two complex disorders. For AD, three highly penetrant genes (amyloid precursor protein (APP, PSEN1 and PSEN2) and one susceptibility gene (APOE) have been identified. For PD, seven genes (SNCA, Parkin, UCHL1, NR4A2, DJ1, PINK1 and LRRK2) have been found. These genes explain only a small proportion of AD and PD patients and are mostly associated with an early onset presentation of the disease. APOE remains the only common gene, which increases the risk of both rare early and late onset AD. The ongoing challenge is to unravel the genetics of the most frequent forms of these complex disorders. In the present paper, we briefly review the state of the art in the genetics of AD and PD. We also discuss the prospects of finding new genes associated with common forms of these diseases in light of two hypotheses concerning the genetic variation of complex diseases: common disease/common variants and common disease/rare variants.     

Apolipoprotein E: risk factor for Alzheimer disease.

The apolipoprotein E gene (APOE) has three common alleles (epsilon 2, epsilon 3, and epsilon 4) that determine six genotypes in the general population. In this study, we examined 77 patients with late-onset Alzheimer disease (AD), along with an equal number of age- and sex-matched controls, for an association with the APOE-epsilon 4 allele. We show that the frequency of this allele among AD patients was significantly higher than that among the control population (.351 vs. .130, P = .000006). The genotype frequencies also differed between the two groups (P = .0002), with the APOE-epsilon 4/epsilon 3 genotype being the most common in the AD group and the APOE-epsilon 3/epsilon 3 being the most common in the control group. In the AD group, homozygosity for epsilon 4 was found in nine individuals, whereas none was found in the control group. The odds ratio for AD, when associated with one or two epsilon 4 alleles, was 4.6 (95% confidence interval [CI] 1.9-12.3), while the odds ratio for AD, when associated with heterozygosity for APOE-epsilon 4, was 3.6 (95% CI 1.5-9.8). Finally, the median age at onset among the AD patients decreased from 83 to 78 to 74 years as the number of APOE-epsilon 4 alleles increased from 0 to 1 to 2, respectively (test for trend, P = .001). Our data, which are in agreement with recent reports, suggest that the APOE-epsilon 4 allele is associated with AD and that this allelic variant may be an important risk factor for susceptibility to AD in the general population.     

Interaction between genes and environment in neurodegenerative diseases

Alzheimer's disease (AD) and Parkinson's disease (PD) are highly prevalent disorders that account for a large part of the global burden of neurodegenerative diseases. Most AD and PD cases occur sporadically and it is generally agreed that they could arise through interactions among genetic and environmental factors. Candidate genes involved in the metabolism of xenobiotics, neurodegeneration and functioning of dopaminergic neurons were found to be associated with PD. Some of these genes interact with environmental factors that could modify PD risk. Thus, we found that the inverse association between smoking and the risk of PD depended on a polymorphism of the iNOS (inducible NO synthase) gene. We also found that the cytochrome P450 2D6 gene could have a modifying effect on the risk of PD among persons exposed to pesticides. Both interactions have biological plausibility supported by laboratory studies and could contribute to better understand the aetiology of PD. A single susceptibility gene has been identified in sporadic AD. The epsilon4 allele of epsilon polymorphism of the apolipoprotein E gene (APOE) is strongly associated with AD, the risk of AD being multiplied by 5 in persons carrying two epsilon4 alleles. The mechanism of the association between APOE and AD is poorly understood. A few interactions between the epsilon polymorphism and possible risk factors for AD have been described. However, these interactions had no biological plausibility and were likely due to chance.     

Apolipoprotein B, apolipoprotein E, and angiotensin-converting enzyme polymorphisms in 2 Italian populations at different risk for coronary artery disease and comparison of allele frequencies among European populations

Polymorphisms at the apolipoprotein B (APOB XbaI, EcoRI, insertion-deletion), apolipoprotein E (APOE), and angiotensin-converting enzyme (ACE) loci are thought to be involved in susceptibility to coronary artery disease (CAD) and myocardial infarction. The aim of this study was to determine whether the allele distribution of the APOB, APOE, and ACE polymorphisms is different in 2 Italian regions with higher (northern Italy) and lower (Sardinia) CAD occurrence. The frequencies of the APOB and APOE alleles that are considered CAD risk factors were higher in northern Italy (APOB X- = 0.655; APOB R- = 0.198; APOB insertion = 0.757; APOE*4 = 0.110) than in Sardinia (APOB X- = 0.568; APOB R- = 0.159; APOB insertion = 0.680; APOE*4 = 0.052), although only APOE allele frequencies differed significantly (p = 0.001). ACE deletion allele frequencies in the 2 geographic areas showed an opposite pattern (northern Italy = 0.658; Sardinia = 0.721). Furthermore, we investigated the impact of APOB and APOE polymorphisms on interindividual variation in total cholesterol level in the 2 Italian samples, which differ in dietary habits. Only APOE phenotypes showed different mean levels of total cholesterol; the association was significant only in northern Italy (p = 0.04), where continental dietary habits and higher mean cholesterol levels prevail. These results support the suggestion that the cholesterol increasing effect of APOE*4 is environmentally mediated. Analysis of allele distributions among European populations, with remarkable differences in CAD prevalence, revealed a constant positive relationship between APOE*4 allele frequency and CAD incidence. The highest frequencies of APOB X- and R- were observed in Finland, where the incidence of CAD is high, and there is a partial agreement between APOB R- frequency and CAD occurrence across Europe, while APOB insertion and ACE deletion alleles are evenly distributed among European populations.