Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0038454 (stroke)
 147,016 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The mechanism linking the APOE4 gene with increased susceptibility for Alzheimer's disease (AD) and poorer outcomes following closed head injury and stroke is unknown. One potential link is activation of the innate immune system in the CNS. Our previously published data demonstrated that apolipoprotein E regulates production of nitric oxide, a critical cytoactive factor released by immune active macrophages. To determine if immune regulation is different in the presence of apolipoprotein E4 compared to apolipoprotein E3, we have measured NO production by peritoneal and CNS macrophages (microglia) cultured from transgenic mice that only express the human apoE4 or apoE3 protein isoform. Significantly more NO was produced in APOE4 mice compared to APOE3 transgenic mice that only express human apoE3 protein. Similarly, monocyte derived macrophages from humans carrying APOE4 gene alleles also produce significantly greater NO than those individuals with APOE3. The mechanism for this isoform-specific difference in NO production is not known and multiple sites in the NO production pathway may be affected. Expression of inducible nitric oxide synthase (iNOS) mRNA and protein are not significantly different between the APOE3 and APOE4 mice, suggesting that induction of iNOS is not a primary cause of the increased NO production in APOE4 animals. One alternative regulatory mechanism that demonstrates isoform specificity is arginine transport, which is greater in microglia from APOE4 transgenic mice compared to microglia from APOE3 mice. Increased transport is consistent with an increased production of NO and may reflect a direct or indirect effect of the APOE genotype on microglial arginine uptake and microglial activation in general. Overall, greater NO production in APOE4 carriers where characteristically high levels of oxidative/nitrosative stress are found in diseases such as AD provides a mechanism that potentially explains the genetic association between APOE4 and human diseases.
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PMID:APOE and the regulation of microglial nitric oxide production: a link between genetic risk and oxidative stress. 1239 81

We have tried, with only partial success, to confirm findings in a recently reported study in this journal on the relationship of APOE genotype to mortality in community representative Hispanics (n = 659), Whites (n = 272), and African-Americans (n = 450), aged 65 and over, living in Northern Manhattan, New York. That study found that using proportional hazards models adjusted for sex and lipid levels, Hispanics and Whites with the E2/E3 genotype, but not African-Americans, had the lowest mortality risk. Those under age 75 had risks comparable to those over age 75, suggesting minimal survivor bias. Nearly 50% of the mortality risk associated with the APOE genotype appeared to act through heart disease, diabetes, and stroke. The current study of African-Americans (n = 1,083) and Whites (n = 915) aged 71 and over living in the more rural Southeastern US, found no protective effect of the E2/E3 genotype for either African-Americans or Whites. Among younger Whites (age 71-75), point estimates suggested that the E2/E3 genotype might be protective, but at a nonsignificant level; self-reported African-American race, but not genotype, was a risk factor for mortality in this age group. Neither lipid level nor health condition attenuated the effect of APOE genotype. Differences in findings may reflect issues of sampling, age, the relative distribution of the APOE alleles, or some other factor. Until such time as studies use truly representative samples and include younger ages, findings in this area must be treated with caution.
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PMID:Mortality and apolipoprotein E in African-American, and White elders: an attempted replication. 1274 52

The literature on the association between apolipoprotein E (ApoE) and mortality across ethnic and age groups has been inconsistent. No studies have looked at this association in developing countries. We used data from the Indianapolis-Ibadan Dementia study to examine this association between APOE and mortality in 354 African-Americans from Indianapolis and 968 Yoruba from Ibadan, Nigeria. Participants were followed up to 9.5 years for Indianapolis and 8.7 years for Ibadan. Subjects from both sites were divided into 2 groups based upon age at baseline. A Cox proportional hazards regression model adjusting for age at baseline, education, hypertension, smoking history and gender in addition to time-dependent covariates of cancer, diabetes, heart disease, stroke, and dementia was fit for each cohort and age group. Having ApoE epsilon4 alleles significantly increased mortality risk in Indianapolis subjects under age 75 (hazard ratio: 2.00; 95% CI: 1.19-3.35; p = 0.0089). No association was found in Indianapolis subjects 75 and older (hazard ratio: 0.71; 95% CI: 0.45-1.10; p = 0.1238), Ibadan subjects under 75 (hazard ratio: 1.04; 95% CI: 0.78 to 1.40; p = 0.7782), or Ibadan subjects over 75 (hazard ratio: 1.21; 95% CI: 0.83 to 1.75; p = 0.3274).
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PMID:Apolipoprotein E and mortality in African-Americans and Yoruba. 1464 29

Ischaemic stroke is the most common form of stroke and is caused by atherosclerosis in most patients. Several genetic determinants contribute to stroke risk. Of these, carotid intimal-medial wall thickness (IMT) is particularly relevant, because it is a surrogate measure of subclinical atherosclerosis and a strong predictor of future ischaemic stroke. Studies of twins, siblings, and families have provided significant evidence for heritability, but the genes involved have not been identified. Some researchers have reported that IMT is high in people with functional variants of genes related to matrix deposition (MMP3), inflammation (interleukin 6), and lipid metabolism (hepatic lipase, APOE, CETP, and PON1). In this review, we assess the robustness of these associations and examine whether there is any evidence of risk modification by factors, such as smoking.
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PMID:Genetic risk factors for stroke and carotid atherosclerosis: insights into pathophysiology from candidate gene approaches. 1503 35

It is unclear how the APOE genotype contributes to the incidence of vascular diseases and dementia. In a population-based sample (n = 6,852) with complete follow-up, APOE was weakly associated with myocardial infarction and not related with stroke. In the absence of epsilon4, the incidence of dementia would be 25.8% lower; in the absence of epsilon2/epsilon3, 2.8% higher. Risk estimates of dementia, specified for age, sex, and APOE, are provided for counseling. APOE is not strongly related to vascular diseases, but contributes substantially to dementia incidence.
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PMID:The impact of APOE on myocardial infarction, stroke, and dementia: the Rotterdam Study. 1507 25

Numerous studies have demonstrated that increased C-reactive protein (CRP) levels predict coronary heart disease, stroke, peripheral vascular disease, and diabetes, and are associated with features of the metabolic syndrome. Only three previous studies have investigated the heritability of CRP levels, primarily in samples of Caucasian families. The purpose of the present study was to estimate the magnitude of genetic influences on CRP levels, and to examine potential associations between variation in the APOE gene and CRP levels, using a sample of 562 individual Japanese Americans from 68 extended kindreds. In general, correlation coefficients between first-degree relatives for CRP were approximately 0.2, and spouse correlations did not differ from zero, consistent with genetic influences. Heritability estimates were approximately 0.3 (p < 0.01), even with adjustment for factors known to influence CRP levels. A significant relationship was seen between unadjusted CRP levels and APOE genotypes (p = 0.02), with the highest mean CRP level among epsilon2 carriers (1.20 mg/L), and nearly the same mean levels among epsilon3/epsilon3 subjects and epsilon4 carriers (0.72 and 0.74 mg/L, respectively). However, this relationship was diminished with adjustment for covariates (p = 0.07). These results demonstrate the presence of both genetic and environmental effects on CRP levels among Asian Americans, and additional studies are needed to determine if the APOE gene contributes to these genetic influences.
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PMID:Heritability of C-reactive protein and association with apolipoprotein E genotypes in Japanese Americans. 1518 Jun 98

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.
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PMID:Apolipoprotein E polymorphism and stroke in a population from eastern Turkey. 1537 Jan 97

The apolipoprotein E ( APOE ) gene in humans contains two single-base polymorphisms in exon 4, which result in three common alleles, conventionally named epsilon2 , epsilon3 and epsilon4 . Numerous studies have shown an important association between the epsilon4 variant and an increased risk of Alzheimer's disease; other data suggest a possible linkage of APOE genetic heterogeneity with lipid profile and an increased risk of atherothrombotic stroke and coronary heart disease. APOE genotyping is therefore an increasingly common assay in laboratory medicine. The most widely used technique for APOE genotyping is based upon restriction isotyping, i.e., amplification of the fragment of exon 4 containing the most common sequence variations, followed by enzymatic digestion of the amplicon and fragments analysis by gel electrophoresis. We developed a novel, reliable and fast method that exploits the sensitivity and specificity of denaturing high-performance liquid chromatography in detecting single-nucleotide polymorphisms. We show that, in most cases, with a single chromatographic separation it is possible to correctly identify the six different APOE allelic patterns, without any manipulation after the polymerase chain reaction amplification. When compared to restriction isotyping, our method is much faster, less labor intensive and similarly inexpensive.
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PMID:Apolipoprotein E haplotyping by denaturing high-performance liquid chromatography. 1589 73

The association of APOE genotypes with cerebral microbleeds (CMBs) was examined on the basis of the location of CMBs in 414 patients who were admitted primarily because of stroke. With respect to possession of the epsilon2 or epsilon4 allele, the adjusted odds ratio was 1.94 (1.05 to 3.58) for lobar CMBs but 1.21 (0.69 to 2.11) for nonlobar CMBs. This suggests that the pathogenesis of CMBs may differ depending on their location.
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PMID:APOE epsilon2/epsilon4 polymorphism and cerebral microbleeds on gradient-echo MRI. 1627 40

Apolipoprotein E (apoE, protein; APOE, gene) is the major lipid-transport protein in the brain and plays an important role in modulating the outcome and regenerative processes after acute brain injury. The aim of the present study was to determine if gene transfer of the epsilon3 form of APOE improves outcome in a murine model of transient focal cerebral ischaemia. Mice received an intrastriatal injection of vehicle, a second-generation adenoviral vector containing the green fluorescent protein gene (Ad-GFP) or a vector containing the APOE epsilon3 gene (Ad-APOE) 3 days before 60 mins focal ischaemia. Green fluorescent protein expression was observed in cells throughout the striatum and subcortical white matter indicating successful gene transfer and expression. ApoE levels in the brain were significantly increased after Ad-APOE compared with Ad-GFP or vehicle treatment. Ad-APOE treatment reduced the volume of ischaemic damage by 50% compared with Ad-GFP or vehicle treatment (13+/-3 versus 29+/-4 versus 27+/-5 mm(3)). The extent of postischaemic apoE immunoreactivity was enhanced in Ad-APOE compared with Ad-GFP or vehicle treated mice. These results show the ability of APOE gene transfer to markedly improve outcome after cerebral ischaemia and suggest that modulating apoE levels may be a potential strategy in human stroke therapy.
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PMID:APOE epsilon3 gene transfer attenuates brain damage after experimental stroke. 1680 48


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