The --491 TT apolipoprotein E promoter polymorphism is associated with reduced risk for sporadic Alzheimer's disease

Homozygosity for the A allele of the -491 A/T apolipoprotein E (APOE) promoter polymorphism has recently been reported to be associated with sporadic Alzheimer's disease (AD). Two hundred and fifty one patients with AD and an equal number of controls derived from the same region in a Spanish population, were genotyped for -491 A/T and epsilon2/epsilon3/epsilon4 APOE polymorphisms. We did not detect an elevated -491 AA genotype frequency when comparing AD cases to controls. In contrast, persons homozygous for the T allele were at a significantly reduced risk of AD (odds ratio of 0.10, P=0.006). Multiple logistic regression analysis indicated that the -491 TT polymorphism added information on the risk of AD which was independent of that of the APOE epsilon4 allele.     

The CDC2 I-G-T haplotype associated with the APOE epsilon4 allele increases the risk of sporadic Alzheimer's disease in Sicily

The cell division cycle 2 (CDC2) gene is a candidate susceptibility gene for Alzheimer's disease (AD). We investigated the CDC2 genotype, and allele and haplotype frequencies in AD patients and matched controls, distinguishing between apolipoprotein E (APOE) epsilon4 allele carriers and non-carriers. APOE epsilon4 is an established predictor of AD risk. APOE and CDC2 genotypes were examined in 109 sporadic AD patients and in 110 healthy age- and sex-matched controls from Sicily. The epsilon4 allele of APOE was predictive of AD risk in our study group (odds ratio: 5.37, 95% CI 2.77-10.41; P<0.0001). Genotype and allele frequencies of the three tested CDC2 polymorphisms (Ex6+7I/D, Ex7-15 G>A, Ex7-14 T>A) were not significantly different between AD patients and controls. However, a significant different distribution of a specific CDC2 haplotype (I-G-T) was found between AD patients and controls when analyzing APOE epsilon4-positive subjects (P=0.0288). Moreover, the combined presence of the I-G-T haplotype and the epsilon4 allele almost doubled the risk of AD (odds ratio: 10.09, 95% CI 3.88-26.25; P<0.0001) compared to carriers of epsilon4 alone. This study suggests that the I-G-T haplotype of the CDC2 gene increases the risk of AD in APOE epsilon4 carriers.     

Apolipoprotein E polymorphism and stroke in a population from eastern Turkey

Human apolipoprotein E (apo E) alleles are polymorphic with significantly different frequencies among different ethnic groups and have been associated with increased risk of coronary heart disease, and postulated as a major genetic susceptibility locus for Alzheimer's disease. Studies undertaken in different populations have shown different association patterns between apo E genotype and stroke. The aim of this study was to determine the risk of apo E genotype in stroke patients living in the eastern part of Turkey. The apo E genotypes and allele frequencies of 229 individuals from the same geographic area were determined by polymerase chain reaction and restriction fragment length polymorphism, of which 103 were patients with a documented history of stroke without other apparent dementia and 126 age-matched healthy subjects as a control group. A reduced E3/4 genotype frequency was found in subjects with stroke and the E2/3 genotype frequency was elevated in patients with previous stroke. There was no association between apo E epsilon4 allele and stroke. The APOE alleles had divergent effects in this population. Association between APOE (the gene) alleles and stroke in this population may be altered due to interaction with other genetic effects. The effects of APOE alleles and genotypes require further study in different populations.     

细胞间黏附分子1基因K469E多态性与冠状动脉粥样硬化性心脏病的关联研究

目的研究中国汉族人群中细胞间黏附分子1（intercellular adhesion moleculel，ICAM1）基因K469E多态性与冠状动脉粥样硬化性心脏病（简称冠心病）的关联。方法采用聚合酶链反应．限制性片段长度多态性方法检测了173例冠心病患者和141名对照的ICAM1基因K469E基因型和等位基因的分布。结果基因型频率符合Hardy-Weinberg平衡。冠心病组的KK基因型的频率显著高于对照组（64．2％比48．9％，P〈0．01），同样，冠心病组K等位基因的频率显著高于对照组（79．2％比69．9％，P〈0．01）。经Logistic回归分析排除年龄，性别，和冠心病其它危险因素的影响后，KK纯合子患冠心病的危险性是KE和EE基因型的2．35倍（95％CI：1．03-5．36，P〈0．05）。结论ICAM1基因K469E多态性与中国汉族人冠心病的危险性相关，其中K等位基因可能是冠心病的遗传危险因素。     

Influence of the apolipoprotein E epsilon4 allele on human embryonic development

Human apolipoprotein E (apoE) exists in three major isoforms encoded by distinct alleles (APOE epsilon2, epsilon3 and epsilon4) and has important functions in nerve development and repair. Inheritance of the 4 allele is a major risk factor for the development of Alzheimer's disease. To investigate the role of APOE polymorphisms in embryonic development, we analyzed the APOE genotypes of 81 spontaneously aborted embryos and 110 adult controls using a solid-phase minisequencing technique. The epsilon4 allele was significantly less frequent in the spontaneous abortion group than in the control group (P=0.009), while the frequency of epsilon3 was significantly increased (P=0.005), suggesting that epsilon4 may have protective effects during embryogenesis. These protective effects might counterbalance the deleterious age-related effects of the epsilon4 allele in natural selection.     

Apolipoprotein E gene promoter (–219G/T) polymorphism is associated with premature coronary heart disease

The relationship of two apolipoprotein (apo) E gene polymorphisms and coronary heart disease (CHD) was investigated in 118 Finnish families with premature CHD and in 110 healthy control subjects. Affected siblings and probands with premature CHD had higher frequencies of the T allele of the -219G/T promoter polymorphism and the epsilon 4 allele (genotypes epsilon 4/3 or epsilon 4/4) of the apo epsilon 2/epsilon 3/ epsilon 4 polymorphism than those of healthy control subjects. Additionally, when the two apo E gene polymorphisms were combined, affected siblings and probands had a higher frequency of the -219T allele and the epsilon 4 allele combinations than did healthy controls. The -219T and the epsilon 4 alleles both separately and together were associated with higher levels of 2-h glucose in an oral glucose tolerance test. These results indicate that the two polymorphisms of the apo E gene have similar effects on the risk of coronary atherosclerosis in families with premature CHD. This risk was not explained by the effect of apo E gene polymorphisms on cholesterol metabolism, but their effect on cardiovascular risk factor clustering with insulin resistance may be of importance. We conclude that in addition to the epsilon 4 allele, also the -219G/T promoter polymorphism of the apo E gene is associated with early onset CHD.     

Apolipoprotein E genotype in Korean schizophrenic patients.

The apolipoprotein E (APOE) epsilon4 allele is a known risk factor for the development of Alzheimer's disease, however, an association of the APOE genotype with schizophrenia is controversial. We investigated the association in 60 Korean schizophrenic patients and 60 healthy controls. APOE genotypes were identified by reverse hybridization-based line probe assay. There were significant differences in the distribution of APOE genotypes between schizophrenic patients and controls. APOE epsilon2 and epsilon3 allele frequencies in schizophrenic patients were significantly different from those in controls. Our results suggest that APOE alleles seem to be operative in the pathogenesis of schizophrenic disorders.     

Association of apolipoprotein E genotypes with serum lipid profiles in a healthy population of Taiwan

Apolipoprotein E (apoE, protein; APOE, gene) plays a major role in lipoprotein metabolism and lipid transport. Many investigators have described associations between apoE genotypes, coronary artery disease (CAD), and other risk factors. The aim of this study was to investigate the association between apoE genotypes and serum lipid profiles in a healthy population of 220 volunteers at Kaohsiung in Taiwan. Other CAD risk factors such as serum levels of apolipoprotein A-I (apoA-I), apolipoprotein B, (apoB), homocysteine (Hcy), folate, and vitamin B12 were also measured. ApoE genotypes were determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). In the study population, the frequency of apoE allele epsilon3 was greatest (85.2%); the frequency of epsilon2 was 8.4%; and that of epsilon4 was 6.4%. The serum apoA-1/apoB ratio showed significant difference among the 3 apoE genotype groups (p 0.0001); the apoA-1/apoB ratio was 1.9 +/- 0.1 (mean +/- SD) in the epsilon2 group, vs 1.4 +/- 0.04 and 1.5 +/- 0.12 in the epsilon3 and epsilon4 groups, respectively. No significant associations were found between APOE alleles and the serum levels of the various lipids or other CHD risk factors.     

APOE-related mortality: effect of dementia, cardiovascular disease and gender

Allele-frequency comparisons between younger and older populations suggest an effect of apolipoprotein E gene (APOE) on mortality, not consistently confirmed by longitudinal data. Our aim was to assess the effect of APOE on survival taking into account the possible contribution of Alzheimer's disease, other dementias, ischemic heart- and cerebrovascular disease (IHCD). In a community-based longitudinal study, the Kungsholmen Project, 75+ year-old individuals (n=1094) were examined, and followed for 18 years. An increased mortality-risk of 22% in those with the epsilon4 allele was detected; whereas a 28% decreased mortality-risk was detected in those with the epsilon2 allele compared to those with the epsilon3epsilon3 genotype. IHCD adjustment did not change the mortality-risk in those with the epsilon4 allele or the epsilon2 allele. Dementia accounted for the majority of the increased mortality-risk associated with the epsilon4 allele, but the protective effect of the epsilon2 allele remained. Both effects of the epsilon4 allele and the epsilon2 allele were strongly modified by gender. A 49% elevated risk for death in men was related to the epsilon4 allele, and a 36% decreased mortality-risk was found in women with the epsilon2 allele. These findings suggest different roles for the APOE alleles in survival by gender in old age.     

结合珠蛋白基因1/2多态性与中国人冠心病易感性的关联研究

目的 通过分析冠心病患者及冠脉正常组中结合珠蛋白(haptoglobin,HP)基因1/2多态性分布,初步探讨HP基因1/2多态性与冠心病易感性的关系.方法 经冠脉造影确诊冠心病组189例,冠脉正常对照组242名;采用聚合酶链反应-限制性片段长度多态性技术检测所有受试者HP基因型.结果 冠心病组HP基因型分布与对照组相比差异有统计学意义(P=0.002),表现为HP2-2基因型在冠心病组的频率明显高于对照组(0.54vs.0.35,P=0.000),单因素分析显著增加冠心病的风险(OR=2.166,95%CI:1.467～3.196),HP2等位基因的频率也明显高于对照组(0.74 vs.0.61).同时,多因素Logistic回归分析表明HP2-2基因型是冠心病的独立危险因素(P=0.002;OR=2.101,95%CI:1.311～3.367).结论 HP2-2基因型与冠心病的发生相关,可能是冠心病发病的独立危险因子;HP2等位基因可能是中国人冠心病的易感基因.

Abstract：

Objective To assess the association of haptoglobin (HP)1/2 polymorphism with coronary heart disease (CHD) in Chinese Hans. Methods One hundred and eighty-nine CHD patients and 242 healthy controls confirmed with angiography were recruited. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method was utilized to genotype the HP1 and HP2 alleles and genotype frequencies in cases and controls were compared. Results The frequency of HP2-2 genotype was significantly higher in CHDs than in controls (0. 54 vs. 0.35, P=0.000). The HP2-2 genotype significantly increased the risk for CHD in univariable analysis (OR= 2. 165, 95% CI: 1. 467-3. 196). Multifactor Logistic regression analysis indicated that HP2-2 genotype is an independent risk factor to CHD (P=0.002;OR=2. 101, 95% CI: 1. 311-3. 367). Similarly, the HP2 allele frequency in the CHD group was significantly higher than that in the control subjects (0.74 vs. 0. 61, P= 0. 000). Conclusion The HP2-2genotype is associated with CHD in Chinese. HP2-2 genotype may be an independent risk factor to CHD,and HP2 allele may be a genetic susceptibility factor to CHD in Chinese.     

Memory performance and the apolipoprotein E polymorphism in a community sample of middle-aged adults

The apolipoprotein E genotype (APOE) is an established risk factor for Alzheimer disease, with the age-at-onset occurring earlier in individuals having at least one APOE epsilon 4 allele, relative to the APOE epsilon 3 or APOE epsilon 2 isoforms. Moreover, nondemented older adults with the APOE epsilon 4 allele also show diminished cognitive performance, particularly on tests of learning and memory, and an accelerated decline in memory performance with increasing age. The current investigation extends the study of the APOE epsilon 4 allele and cognitive performance to healthy, middle-aged adults. A community sample of 220 non-Hispanic Caucasian men and women, aged 24-60 (average age = 46), were genotyped for the APOE polymorphism and completed a battery of neuropsychological tests. Multivariate analyses were conducted on measures of verbal learning and memory (e. g., learning a list of words and recalling them 30 min later), visual memory (e.g., reproducing a previously copied figure from memory), and attention span (e.g., repeating long lists of digits), after adjustments for age, and estimated IQ. Results indicated that performance on learning and memory tasks was significantly poorer in adults having any APOE epsilon 4 allele, relative to adults with APOE epsilon 2 and epsilon 3 genotypes (P <.01). Attention span did not differ by genotype. These findings, the first in a sample of middle-aged adults, suggest that the APOE polymorphism is a marker for age-related decline in memory (detectable prior to overt, clinical manifestations of memory loss), and/or a marker for individual differences in memory ability across the life span. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:707-711, 2000.     

囊泡相关膜蛋白8基因多态性与冠状动脉粥样硬化性心脏病的相关性研究

目的 研究囊泡相关膜蛋白8(synaptobrevins/vesicle-associated membrane proteins 8,VAMP8)基因rs1010多态性在中国汉族人群中的分布及与冠状动脉粥样硬化性心脏病(简称冠心病)的相关性.方法 采用聚合酶链反应-限制性片段长度多态性技术,对汉族185例冠心病患者及149名正常人VAMP8 rs1010基因多态性,基因型及等位基因频率分布进行研究.结果 研究人群中存在VAMP8 rs1010基因多态性,基因型符合Hardy-Weinberg平衡,冠心病患者A等位基因频率显著高于对照组(67.3%VS 53.0%,P<0.05).Logistic回归分析得出:VAMP8基因(AA+AG)基因型是冠心病的独立危险因素,(AA+AG)基因型比GG基因型的比数比为1.969,95%可信区间为1.032～3.755.结论 VAMP8 rs1010基因多态性与冠心病有关,A等位基因可能是汉族人群冠心病的遗传危险因素.     

No association between alpha-1-antichymotrypsin polymorphism and Alzheimer's disease in Koreans

To examine the possible involvement of the alpha-1-antichymotrypsin gene (ACT) polymorphism in the manifestation of Alzheimer's disease (AD), we analyzed genotypes of the ACT and apolipoprotein E gene (APOE) among 110 Korean patients with probable AD and 209 nondemented controls. No significant difference was obtained in genotypic (chi(2)=1.98, df=2, P>0.1) and allelic frequencies (chi(2)=1.61, df=1, P>0.1) of ACT between the AD and control groups. No overexpression of the ACT A/A genotype and ACT A allele was found when we analyzed the late-onset AD patients and the early-onset AD patients, separately. Then we stratified the ACT genotypes based on the presence or absence of the APOE epsilon4 allele to evaluate the possible interaction between them. In the APOE epsilon4-negative subjects, although the ACT A allele tended to be overexpressed in the AD group, the differences in the frequencies of the ACT A allele (chi(2)=2.79, df=1, P>0.1) and ACT A/A genotype (chi(2)=0.16, df=1, P>0.1) were not statistically significant. No significant overrepresentations of the ACT A allele (chi(2)=0.02, df=1, P>0.1) and ACT A/A genotype (chi(2)=0.17, df=1, P>0.1) were found in the APOE epsilon4-positive subjects, either. In addition, the status of the ACT genotype did not influence the age-at-onset of AD (F=0.03, df=2, P>0.1). Therefore, the ACT polymorphism does not contribute to the development of AD independently or interactively with the APOE epsilon4 allele in Koreans.     

Pronounced impact of Th1/E47cs mutation compared with -491 AT mutation on neural APOE gene expression and risk of developing Alzheimer's disease

Possession of the apolipoprotein E (APOE) epsilon4 allele is the most frequently associated genetic susceptibility factor for Alzheimer's disease (AD). Recently, new polymorphisms in the regulatory region of the APOE gene have been described. We analysed the effects of three of these mutations (-491 AT, -427 CT and Th1/E47cs) on disease risk in a large case-control study, and tested their impacts on APOE allelic expression in brain tissues. The Th1/E47cs T allele was associated with an increased risk of occurrence of AD, while the -491 T allele was associated with a decreased risk, independently of the APOE epsilon2/epsilon3/epsilon4 polymorphism effect. However, the impact of the Th1/E47cs mutation was the strongest. The -427 CT polymorphism was not associated with the disease. In AD subjects heterozygous for the epsilon4 allele, analysis of allelic expression showed that the relative expression levels of the epsilon4 allele were higher than those of the corresponding controls. Consistent with epidemiological data, the relative level of expression of the epsilon4 allele was modified accordingly to the presence or absence of the two main promoter polymorphisms, indicating, in vivo, the deleterious effect of the Th1/E47cs T allele and the protective effect of the -491 T allele in population. These data indicate that in addition to the qualitative effect of the APOE epsilon2/epsilon3/epsilon4 polymorphisms on the AD occurrence, the quantitative variation of expression of these alleles due to functional APOE promoter mutations, is a key determinant of AD development.      

L-选择素基因多态性与冠状动脉粥样硬化性心脏病易感性的相关性研究

目的探讨L-选择素基因P213S多态性是否与冠状动脉粥样硬化性心脏病有关联。方法采用病例-对照研究，对212例经冠状动脉造影确诊的冠心病患者和230名正常对照者进行研究。应用聚合酶链反应限制性片段长度多态性（polymemse chain reaction-restriction fragment length polymorphism，PCRRFLP）技术测定L-选择素基因多态性。结果冠心病组213P等位基因频率明显高于对照组（77．59％vs69．35％，P=0．006）。PP纯合子患冠心病的风险是SS纯合子的2．70倍（95％CI：1．07～6．81），且经Logistic回归分析校正性别、年龄、体重指数、血清总胆固醇、甘油三酯、高密度脂蛋白-胆固醇和低密度脂蛋白-胆固醇等相关因素之后，差异仍具有统计学意义。根据冠状动脉造影结果进一步对冠心病患者进行分组后分析，发现L-广选择素基因P213S多态性与病变血管支数及疾病程度无相关性。结论L-广选择素213P等位基因可能与我国汉族人冠心病的易感性相关联。     

No association between the intronic presenilin 1 polymorphism and Alzheimer's disease in the Chinese population

Wragg et al. [1996: Lancet 347:509-512] recorded an association between the intron-based presenilin 1 (PS1) genotype 1/1 and late-onset Alzheimer's disease (AD). This study was performed to determine if there is a similar association in the Chinese population. Ninety-one AD cases, 50 multiinfarct dementia (MID) patients, and 73 age-matched normal controls were recruited. Genotyping of PS1 and apolipoprotein E (APOE) was performed by the methods of polymerase chain reaction and restriction fragment length polymorphism. In AD, MID, and normal controls PS1 allele 1 frequency was 0.6703, 0.5600, and 0.6301, respectively; PS1 allele 2 frequency was 0.3297, 0.4400, and 0.3699, respectively. No association was detected between these diseases and any PS1 allele or genotype. There was only a nearly significant negative association between MID and PS1 genotype 1/1 in the subgroup population bearing APOE allele E4 (odds ratio = 0.2753, P = 0.0776). Our results do not support the conclusion that the intronic PS1 polymorphism is associated with Alzheimer's disease.     

Utility of the predictors of coronary heart disease mortality in a longitudinal study of elderly Finnish men aged 65 to 84 years is dependent on context defined by Apo E genotype and area of residence

A common assumption underlying most genetic studies is that individuals with different genotypes respond similarly to exposure to internal (epigenetic and background genotype effects) and external (ecological) environments. Here we evaluate whether this assumption is true in individuals with different genotypes of the gene coding for the apolipoprotein E (Apo E) molecule, an important determinant of the metabolic fate of plasma lipids and lipoproteins. We addressed whether the utility of known risk factors of coronary heart disease (CHD) in the prediction of CHD death in a 5-year follow-up is the same for the two most common Apo E genotypes, epsilon3/3 and epsilon4/3, in two cohorts of elderly Finnish men (age at baseline: 65-84 years), one in Eastern and the other in Southwestern Finland. The CHD mortality rate was higher in the epsilon4/3 than in the epsilon3/3 genotype in both cohorts (11.1 versus 7.8%, Pr = 0.281 in the Eastern cohort and 19.6 versus 8.2%, Pr = 0.002 in the Southwestern cohort). In the Eastern cohort, serum high density lipoprotein (HDL) cholesterol level was identified as a strong predictor of CHD death in the epsilon3/3 genotype (beta = -2.155, Pr = 0.019). In the Southwestern cohort, age (beta = 0.139, Pr = 0.006), body mass index (BMI) (beta = 0.149, Pr = 0.016), and serum total cholesterol level (beta = 0.453, Pr = 0.051) were identified as strong predictors in the epsilon3/3 genotype, as were smoking (beta = 0.236, Pr = 0.008) and BMI (beta = -0.124, Pr = 0.057) in the epsilon4/3 genotype. The latter observation indicates that in Southwestern Finland the probability of CHD death decreases with increasing BMI in elderly men with the epsilon4/3 genotype, while in their counterparts with the epsilon3/3 genotype the risk increases with increasing BMI. This difference was statistically significant (Pr = 0.002). These observations clearly argue against the assumption that individuals with different genotypes respond similarly to exposures to internal and/or external environments. These observations are consistent with a complex pathobiology of CHD involving biochemical and physiological agents that are under the influence of interactions between genetic and environmental factors. Information about these interactions is necessary for developing a more precise risk assessment and ultimately to improve public health and clinical strategies to prevent this devastating disease both at the individual and population levels.     

Independent association of an APOE gene promoter polymorphism with increased risk of myocardial infarction and decreased APOE plasma concentrations-the ECTIM study

Apolipoprotein E (APOE) is a major protein in lipid metabolism existing in three common isoforms: APOE2, -3 and -4. The varepsilon4 allele of the APOE gene ( APOE ) coding for the APOE4 isoform is associated with an increased risk of myocardial infarction (MI) and of Alzheimer's disease (AD). Recently, several polymorphisms in the APOE regulatory region have been reported. Some of these have been associated with AD and modified APOE allelic mRNA expression in AD brains. Here, we have investigated whether three of these promoter polymorphisms (-491AT, -427CT and -219GT) can also modify cardiovascular risk. The hypothesis was tested in a large multicentre case-control study of MI, the ECTIM Study, on 567 cases and 678 controls. Among the three APOE promoter polymorphisms tested, only the-219T allele was associated with a significantly increased risk of MI (OR = 1.29, 95% CI: 1.09-1.52, P < 0.003) and the effect was shown to be independent of the presence of the other mutations, including the APOE epsilon2/epsilon3/epsilon4 polymorphism. Moreover, the-219T allele greatly decreased the APOE plasma concentrations in a dose-dependent manner ( P < 0.008). These data indicate that the-219GT polymorphism of the APOE regulatory region emerges as a new genetic susceptibility risk factor for MI and constitutes another common risk factor for both neurodegenerative and cardiovascular diseases.     

载脂蛋白E基因多态性与早发冠心病的关系及其对血脂的影响

目的 研究载脂蛋白E（apolipoprotein E,apoE)基因多态性与早发冠心病（coronary heart disease,CHD)的相关关系及其对血脂水平的影响。方法 应用聚合酶链反应－限制性片段长度多态性（polymerase chain reaction-restricted fragment hength polymorphism,PCR-RFLP)基因分析方法,测定52例早发CHD、161例迟发CHD患者和180名对照者的apoE基因型;血脂水平按常规方法测定。结果 发现的5种apoE基因型,分别为E3／3、E4／4、E3／2、E4／3及E4／2。早发CHD组和迟发CHD组apoE4/3基因型和ε4等位基因频率均高于对照组（P＜0．01）;进一步对两组CHD患者的apoE多态性进行分析,发现早发组ε4等位基因频率较迟发组为高（P＜0．05）。apoE各等位基因型之间,TC和LDL－C水平之间存在统计学差异（P＜0．05）。结论 apoE基因多态性与早发CHD的发生发展有关并影响血脂的水平。