Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The common polymorphism at codon 311 (C311S) of paraoxonase 2 gene (PON2) was investigated in 165 patients with sporadic late-onset Alzheimer's disease (LOAD) and 174 controls in Chinese. The PON2*C allele frequency was significantly increased in the patients as compared with controls. However, no significant difference was observed after stratification of apolipoprotein E (ApoE) epsilon4 allele. These results suggested that the PON2 polymorphism might be a risk factor for LOAD independent of ApoE epsilon4 status in Chinese.
Brain Res Mol Brain Res 2004 Jan 05
PMID:Possible association between Cys311Ser polymorphism of paraoxonase 2 gene and late-onset Alzheimer's disease in Chinese. 1474 12

The research of Alzheimer's disease (AD) genetics has been extremely prolific over the past decade, and currently more than 10 genes are reported to show either positive or negative evidence for disease association per month. Here, we review all 90 studies from 2003 reporting a total of 127 association findings between candidate genes and AD. While most positive results were largely contradictory, we identified three loci-on chromosomes 6p21, 10q24, 11q23-that yielded positive results in three or more independent studies, in addition to the well-established AD association with the gene encoding apolipoprotein E (APOE). Based on these data, we suggest that it may be prudent for investigators to pay closer attention to issues such as power, replicability and haplotype structure prior to initial publication. This should serve to greatly decrease the likelihood of false positive and false negative findings reported in future years.
Hum Mol Genet 2004 Apr 01
PMID:Alzheimer's disease: one disorder, too many genes? 1476 23

After the identification of the apolipoprotein E gene isoform (APOE-epsilon4) as a risk factor for late-onset Alzheimer's disease (LOAD), the search for other polymorphisms associated with AD has been undertaken by many groups of investigators around the world. These studies have shown controversial results in many populations. More recently, a single nucleotide polymorphism in the promoter region of the brain-derived neurotrophin factor (BDNF) was found to be a risk factor for AD in two independent population studies. Here we report the analysis of this polymorphism in a group of 188 LOAD Brazilian patients compared to matched normal controls. A strong association between the APOE-epsilon4 polymorphism and LOAD was observed, but there was no significant association between this BNDF polymorphism and affected patients. The possibility that other polymorphisms or mutations in this gene play a role in the development of AD cannot be ruled out. However, the results of the present study suggest that in opposition to the two reported studies, this polymorphism does not seem to be implicated in LOAD Brazilian patients. It also shows the importance of replication studies in different populations, as susceptibility loci might differ in different ethnic groups; this will have important implications in future treatments with pharmacological agents.
J Mol Neurosci 2004
PMID:Lack of association between the brain-derived neurotrophin factor (C-270T) polymorphism and late-onset Alzheimer's disease (LOAD) in Brazilian patients. 1499 20

Given that a substantial proportion of individuals with coronary artery disease (CAD) also have type 2 diabetes, it is important to identify genes that confer susceptibility to CAD independently in subjects with type 2 diabetes and in those without this condition. A large-scale association study was performed to identify genes that confer susceptibility to CAD in either the absence or presence of type 2 diabetes. The study population comprised 5207 unrelated Japanese individuals, including 3085 subjects with CAD and 2122 controls. Among all subjects, 1704 individuals had type 2 diabetes and 3503 individuals did not have this condition. The genotypes for 33 polymorphisms of 27 candidate genes were determined with a fluorescence- or colorimetry-based allele-specific DNA primer-probe assay system. Multivariate logistic regression analysis with adjustment for age, body mass index, and the prevalence of smoking, hypertension, hypercholesterolemia, and hyperuricemia revealed that the following polymorphisms were significantly (P < 0.005) associated with CAD: the 1019C -->T of the connexin 37 gene for men with type 2 diabetes; the 2445G -->A in the fatty acid-binding protein 2 gene for women with this condition; the -863C-->A in the tumor necrosis factor-alpha gene, the -219G-->T in the apolipoprotein E gene, the 1019C-->T in the connexin 37 gene for men without type 2 diabetes; and the -482C-->T in the apolipoprotein C-III gene for women without this condition. Genotyping of these polymorphisms may prove informative for assessment of the genetic risk for CAD in the absence or presence of type 2 diabetes.
Mol Genet Metab 2004 Apr
PMID:Genetic risk for coronary artery disease in individuals with or without type 2 diabetes. 1505 15

Estrogens reduce adipose tissue mass in both humans and animals. The molecular mechanisms for this effect are, however, not well characterized. We took a gene expression profiling approach to study the direct effects of estrogen on mouse white adipose tissue (WAT). Female ovariectomized mice were treated for 10, 24 and 48 h with 17beta-estradiol or vehicle. RNA was extracted from gonadal fat and hybridized to Affymetrix MG-U74Av2 arrays. 17beta-Estradiol was shown to decrease mRNA expression of liver X receptor (LXR) alpha after 10 h of treatment compared with the vehicle control. The expression of several LXRalpha target genes, such as sterol regulatory element-binding protein 1c, apolipoprotein E, phospholipid transfer protein, ATP-binding cassette A1 and ATP-binding cassette G1, was similarly decreased. We furthermore identified a 1.5 kb LXRalpha promoter fragment that is negatively regulated by estrogen. Several genes involved in lipogenesis and lipolysis were identified as novel targets that could mediate estrogenic effects on adipose tissue. Finally, we show that ERalpha is the main estrogen receptor expressed in mouse white adipose tissue (WAT) with mRNA levels several hundred times higher than those of ERbeta mRNA.
J Mol Endocrinol 2004 Jun
PMID:Gene expression profiling identifies liver X receptor alpha as an estrogen-regulated gene in mouse adipose tissue. 1517 19

The risk of developing Alzheimer's disease (AD) is tied most closely to age and appears to follow Gompertzian kinetics. However, specific genetic factors are also linked closely to AD, and the apolipoprotein E (APOE) genotype accounts for as much of 50% of the attributable risk for AD in many populations. This paper reviews the onset, diagnosis, and epidemiology of AD, specifically with regard to the APOE genotype and the interaction of the genotype with age.
J Mol Neurosci 2004
PMID:APOE genotype effects on Alzheimer's disease onset and epidemiology. 1518 Dec 44

There is now a large body of evidence suggesting that apolipoprotein E (apoE) genotype is the single most important genetic risk factor for the most common (sporadic) form of Alzheimer's disease. Yet in proportion to the total number of investigations in this field, relatively few groups are studying the contribution of this cholesterol-binding protein to disease risk and severity. Of those that are, a major focus is on the impact of apoE on amyloid-related mechanisms of disease. I argue here that apoE should be considered a major culprit in its own right, not simply in a supporting role. The argument is based on several lines of evidence, including the fact that apoE is associated with both plaques and tangles, the overwhelming evidence for genetic risk of the disease attributed to apoE, increasing evidence that apoE might also modify risk of other nonamyloidogenic neurological diseases, neurotoxicity attributed to apoE and/or proteolytic fragments of apoE, negative consequences of transgenic expression of apoE4 in mice, and genetic evidence for polymorphisms that increase both apoE expression and disease risk, regardless of isoform.
J Mol Neurosci 2004
PMID:Apolipoprotein E is a prime suspect, not just an accomplice, in Alzheimer's disease. 1518 Dec 46

Abnormalities in the processing of amyloid precursor protein to amyloid-beta (Abeta) are causal factors, and the presence of the epsilon4 allele of apolipoprotein E (apoE) is the primary risk factor for Alzheimer's disease (AD). Based, at least in part, on these genetics, the potential structural and functional interactions between these two proteins are the focus of our research. To understand the nature of the physical interactions between apoE and Abeta, we initially utilized gel-shift assays to demonstrate that native apoE2 and E3 (associated with lipid particles) form an SDS-stable complex with Abeta that is more abundant than the apoE4:Abeta complex. We further demonstrated that exogenous apoE3 but not E4 prevents Abeta-induced neurotoxicity by a process that requires apoE receptors. In addition, both exogenous apoE3 and E4 prevent Abeta-induced, glial-mediated inflammation, also via a process that requires apoE receptors. These functional effects all occur at a molar ratio of apoE to Abeta of 1:30. Because the biological activities for both apoE and Abeta are profoundly influenced by their isoform and conformation, respectively, we further investigated the idea that apoE3 and E4 differentially interact with particular aggregation species of Abeta1-42. Our overall hypothesis is that apoE has two general functions in relation to Abeta. First, apoE interacts with oligomeric Abeta via an apoE receptor-mediated process to inhibit neurotoxicity and neuroinflammation (apoE3 > apoE4) a process possibly related to binding and clearance of apoE3:oligomer complexes. Second, apoE facilitates the deposition of Abeta as amyloid (apoE4 > apoE3). We will continue to investigate the effect of apoE isoform and Abeta conformation on the structural and functional interactions between these two proteins in relation to the pathogenesis of AD.
J Mol Neurosci 2004
PMID:ApoE and Abeta1-42 interactions: effects of isoform and conformation on structure and function. 1518 Dec 52

The epsilon4 allele of apolipoprotein E APOE is a risk factor for Alzheimer's disease (AD) and cerebral amyloid angiopathy (CAA), and the epsilon2 allele is associated with a decreased risk for AD. There is strong evidence to suggest that a major, if not the main, mechanism underlying the link between apoE and both AD and CAA is related to the ability of apoE to interact with the amyloid-beta (Abeta) peptide and influence its clearance, aggregation, and conformation. In addition to a number of in vitro studies supporting this concept, in vivo studies with amyloid precursor protein (APP) transgenic mice indicate that apoE and a related molecule, clusterin (also called apolipoprotein J), have profound effects on the onset of Abeta deposition, as well as the local toxicity associated with Abeta deposits both in the brain parenchyma and in cerebral blood vessels. Taken together, these studies suggest that altering the expression of apoE and clusterin in the brain or the interactions between these molecules and Abeta would alter AD pathogenesis and provide new therapeutic avenues for prevention or treatment of CAA and AD.
J Mol Neurosci 2004
PMID:In vivo effects of ApoE and clusterin on amyloid-beta metabolism and neuropathology. 1518 Dec 53

Human apolipoprotein E is the most important supplier of the cholesterol precursor for steroid hormone production in steroidogenic tissues and therefore could play a role in the regulation of steroid hormone function and influence human reproduction. This hypothesis has been confirmed by studies describing a differential fertility associated with common apolipoprotein (APOE) genotypes in two European populations. In the present investigation the impact of APOE genetic variation on fertility was studied in two Ecuadorian populations, African-Ecuadorians (57 women) and Cayapa Indians (27 women). In addition some biodemographic variables concerning women's fertility were investigated (124 African-Ecuadorian women; 40 Cayapa women) to better understand the APOE-fertility relationships in these pre-industrial populations. General fertility rates in both populations were very high (6.5 and 6.2 for the African-Ecuadorians and for the Cayapa respectively). When considering only women near the end of reproductive life (>/=40 years), a more marked difference was observed between the two groups (9.1 versus 7.7, P=0.09). In both communities, the highest number of children was found to be associated with the e*4/e*3 genotype; the e*4/e*3 genotype frequency (0.50) in the African-Ecuadorian women with 9-17 children was about three times that of the women with 0-8 children (0.14) (P=0.02). The present findings are at variance with those observed in European populations, where e*3/e*3 was the genotype associated with the highest reproductive efficiency. A possible explanation for this inconsistency could be due to the different functional properties associated with the e*3 and e*4 alleles and to genotype interactions with environmental factors including reproductive strategies.
Mol Hum Reprod 2004 Aug
PMID:Apolipoprotein E polymorphism and fertility: a study in pre-industrial populations. 1522 Apr 65


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