Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Abeta peptides are thought to be centrally involved in Alzheimer's disease (AD) pathogenesis, although Abeta's pathophysiological mechanisms remain to be elucidated. We previously showed that soluble beta-amyloid1-40 (Abeta) and Abeta1-42 exhibit vasoactive properties, and are able to promote vasoconstriction in rat aortae induced by an endogenous vasoconstrictor, endothelin-1. It is well established that the APOE epsilon4 allele confers risk for both familial and sporadic AD, as well as for hypertension. We now report that physiologic amounts (10 nM) of specific human recombinant apoE isoforms are vasoactive (E4 > E3, and not E2) in isolated rat aortae. In order to investigate if various apoE isoforms could modulate Abeta vasoactivity, we co-incubated Abeta1-40 with various isoforms of apoE in our tissue bath system. Our results show that, while none of the APOE isoforms are able to affect the maximum constriction induced by Abeta; the apoE E4 isoform synergistically enhances the rate of vasoconstriction induced by Abeta. Our data suggest that apoE may promote hypertension and contribute to AD pathogenesis via enhancement of vasoconstriction, and support a link between hypertension, cerebral amyloid angiopathy and AD.
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PMID:Isoform-specific vasoconstriction induced by apolipoprotein E and modulation of this effect by Alzheimer's beta-amyloid peptide. 985 6

There is growing debate over the utility of multiple locus association analyses in the identification of genomic regions harboring sequence variants that influence common complex traits such as hypertension and diabetes. Much of this debate concerns the manner in which one can use the genotypic information from individuals gathered in simple sampling frameworks, such as the case/control designs, to actually assess the association between alleles in a particular genomic region and a trait. In this paper we describe methods for testing associations between estimated haplotype frequencies derived from multilocus genotype data and disease endpoints assuming a simple case/control sampling design. These proposed methods overcome the lack of phase information usually associated with samples of unrelated individuals and provide a comprehensive way of assessing the relationship between sequence or multiple-site variation and traits and diseases within populations. We applied the proposed methods in a study of the relationship between polymorphisms within the APOE gene region and Alzheimer's disease. Cases and controls for this study were collected from the United States and France. Our results confirm the known association between the APOE locus and Alzheimer's disease, even when the epsilon 4 polymorphism is not contained in the tested haplotypes. This suggests that, in certain situations, haplotype information and linkage disequilibrium-induced associations between polymorphic loci that neighbor loci harboring functional sequence variants can be exploited to identify disease-predisposing alleles in large, freely mixing populations via estimated haplotype frequency methods.
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PMID:Genetic analysis of case/control data using estimated haplotype frequencies: application to APOE locus variation and Alzheimer's disease. 1115 23

This article reviews the current status of our knowledge of lipoproteins, nutrition, and coronary heart disease (CHD). Special emphasis is placed on CHD risk assessment, dietary intervention studies, diet-gene interactions, and current dietary guidelines and the contributions of my laboratory to these areas. CHD remains a major cause of death and disability, and risk factors include age, sex, hypertension, smoking, diabetes, elevated serum LDL cholesterol, and low HDL cholesterol. Emerging independent risk factors include elevated serum concentrations of lipoprotein(a), remnant lipoproteins, and homocysteine. The cornerstone of CHD prevention is lifestyle modification. Dietary intervention studies support the concepts that restricting saturated fat and cholesterol and increasing the intake of essential fatty acids, especially n - 3 fatty acids, reduces CHD risk. The variability in LDL-cholesterol response to diet is large, related in part to APOE and APOA4 genotype. The use of antioxidants in intervention studies has not been shown to reduce CHD risk. Compliance with dietary recommendations remains a major problem, and directly altering the food supply may be the most effective way to ensure compliance. The available data indicate that the recommendation to use fats, oils, and sugars sparingly for CHD prevention should be modified to a recommendation to use animal, dairy, and hydrogenated fats; tropical oils; egg yolks; and sugars sparingly and to increase the use of vegetables, fruit, and whole grains.
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PMID:Lipoproteins, nutrition, and heart disease. 1181 9

Recent evidence indicates that different vascular risk factors are present in Alzheimer's disease (AD) and other prevalent dementia types probably contributing to deterioration of cerebrovascular function, thus enhancing neurodegeneration and premature neuronal death due to a reduction in brain perfusion. Brain blood flow shows a reduced velocity and increased pulsatility (PI) and resistance indices (RI) in different types of dementia and in diabetes and hypertension, as well. High levels of diastolic blood pressure correlate with diminished brain blood flow and elevated PI and RI, accompanied by cognitive deterioration. Nitric oxide (NO) levels are found increased in the sera and brain tissue of AD patients. Vascular risk factors (hyperglycemia, LDL-cholesterol, triglycerides, hypertension) and altered brain hemodynamic parameters correlate with APOE genotypes of which APOE-4/4 carriers represent the AD population with the highest cerebrovascular risk. In addition, the genomic profiles of patients with dementia integrating AD-related genes (APOE, PS1, PS2, cFOS) in a mini-tetragenic haplotype significantly differ from controls with an absolute genetic variation of about 50%-60%. Cerebrovascular dysfunction is a factor common to most types of dementia; however, genetic variation among different dementia types might be determinant for the activation of early vascular events inducing or accelerating neurodegeneration. In this regard, cerebrovascular dysfunction should be considered a potential therapeutic target in dementia.
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PMID:Cerebrovascular risk factors in Alzheimer's disease: brain hemodynamics and pharmacogenomic implications. 1450 10

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

The predominating theory on the pathophysiology of Alzheimer's disease (AD) concerns the mis-metabolism of amyloid precursor protein (APP). As a result of this mis-metabolism, there is an increased production of the 42 amino acid form of beta-amyloid (Abeta42) that rapidly will form oligomers that initiates a cascade of events leading to the accumulation of amyloid plaques. Commonly recognised as vascular factors, hypertension, hypercholesterolemia and diabetes and the inheritance of the epsilon4 allele of the APOE gene, are also risk factors for AD. These risks have been found to promote the production of Abeta42. An association between cholesterol and the development of AD was suggested in the early 1990s and ever since, an increasing amount of research has confirmed that there is a link between cholesterol and the development of AD. A high cholesterol levels in mid-life is a risk for AD and statins, i.e., cholesterol-lowering drugs, reduce this risk. Statins may not only inhibit enzymes involved in the endogenous synthesis of cholesterol but also affect enzymes involved in Abeta metabolism, i.e., alpha-secretase and beta-secretase. This normalises the breakdown of APP thereby promoting the non-amyloidogenic pathway. In this review, investigations focusing on cholesterol and Alzheimer's disease are presented.
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PMID:Cholesterol and Alzheimer's disease--is there a relation? 1633 84

High fat diets and sedentary lifestyles are becoming major concerns for Western countries. They have led to a growing incidence of obesity, dyslipidemia, high blood pressure, and a condition known as the insulin-resistance syndrome or metabolic syndrome. These health conditions are well known to develop along with, or be precursors to atherosclerosis, cardiovascular disease, and diabetes. Recent studies have found that most of these disorders can also be linked to an increased risk of Alzheimer's disease (AD). To complicate matters, possession of one or more apolipoprotein E epsilon4 (APOE epsilon4) alleles further increases the risk or severity of many of these conditions, including AD. ApoE has roles in cholesterol metabolism and Abeta clearance, both of which are thought to be significant in AD pathogenesis. The apparent inadequacies of ApoE epsilon4 in these roles may explain the increased risk of AD in subjects carrying one or more APOE epsilon4 alleles. This review describes some of the physiological and biochemical changes that the above conditions cause, and how they are related to the risk of AD. A diversity of topics is covered, including cholesterol metabolism, glucose regulation, diabetes, insulin, ApoE function, amyloid precursor protein metabolism, and in particular their relevance to AD. It can be seen that abnormal lipid, cholesterol and glucose metabolism are consistently indicated as central in the pathophysiology, and possibly the pathogenesis of AD. As diagnosis of mild cognitive impairment and early AD are becoming more reliable, and as evidence is accumulating that health conditions such as diabetes, obesity, and coronary artery disease are risk factors for AD, appropriate changes to diets and lifestyles will likely reduce AD risk, and also improve the prognosis for people already suffering from such conditions.
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PMID:Apolipoprotein E, cholesterol metabolism, diabetes, and the convergence of risk factors for Alzheimer's disease and cardiovascular disease. 1678 33

The aim of the present study was to assess the genetic risk for atherothrombotic cerebral infarction (ACI) in men and women separately as well as in individuals with or without conventional risk factors for atherosclerosis and thereby to contribute to the personalized prevention of ACI. The study population comprised 2705 unrelated Japanese individuals (1244 men, 1461 women), including 636 subjects (372 men, 264 women) with ACI. Subjects with ACI and controls either had or did not have conventional risk factors for atherosclerosis, including hypertension, hypercholesterolemia, and diabetes mellitus. The genotypes for 202 polymorphisms of 152 candidate genes were determined by a method that combines polymerase chain reaction and sequence-specific oligonucleotide probes with suspension array technology. Multivariable logistic regression analysis and a stepwise forward selection procedure revealed that 11 different polymorphisms were significantly (P < 0.005) associated with ACI in women or men or in individuals with or without hyper-tension, hypercholesterolemia, or diabetes mellitus: the 584C-->T polymorphism of LIPG, 5665G-->T of EDN1, and G-->A of CCL11 in women; 677C-->T of MTHFR, 1323C-->T of ITGB2, 3932T-->C of APOE, and -231A-->G of EDNRA in men; -572 G -->C of IL6 in hypertensive individuals; -403G-->A of CCL5 and G-->A of COMT in individuals with hypercholesterolemia; and 3932T--> C of APOE and A-->G of TNFSF4 in diabetic individuals. Polymorphisms associated with ACI may thus differ between women and men as well as among individuals with different risk factors. Stratification of subjects on the basis of sex or conventional risk factors for atherosclerosis may therefore be important in order to achieve the personalized prevention of ACI with the use of genetic information.
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PMID:Genetic risk for atherothrombotic cerebral infarction in individuals stratified by sex or conventional risk factors for atherosclerosis. 1701 17

Echocardiographic measures of cardiac target organ damage, including left ventricular mass and relative wall thickness, are powerful predictors of heart disease morbidity and mortality. The aim of this study is to investigate whether single nucleotide polymorphisms in candidate genes for hypertension and heart disease have effects on quantitative measures of hypertensive cardiac target organ damage, independent of their actions on blood pressure levels, in a cohort of hypertensive black sibships. To detect replication of genetic effects across samples, this study took advantage of the affected sibling pair design and created 2 samples, each with 448 unrelated individuals. As part of the Genetic Epidemiology Network of Arteriopathy Study, subjects were screened using 2D echocardiography, and 395 single nucleotide polymorphisms in 80 candidate genes were genotyped. Linear regression was used to test for single nucleotide polymorphisms significantly associated with left ventricular mass index (g/m(2.7)) or relative wall thickness after adjusting for associated covariates. Significant single nucleotide polymorphisms were subsequently tested for consistent directionality in genotype-phenotype relationships across samples. Three single nucleotide polymorphisms, 1 each in the APOE, SCN7A, and SLC20A1 genes, were significantly associated in both samples with left ventricular mass index and had replicate genotype-phenotype relationships. One in the ADRB1 gene was significantly associated with relative wall thickness with replicate effects in both samples. We identified genetic variation that significantly influences left ventricular traits with replicable effects in a cohort of hypertensive, black siblings.
Hypertension 2007 May
PMID:Genetic variations associated with echocardiographic left ventricular traits in hypertensive blacks. 1733 38

Type 2 diabetes is a risk factor for late-onset Alzheimer's disease (AD), and studies suggest that pathogenic effects of diabetes and insulin resistance may be associated with non-APOE4 AD. Therefore, we examined association of the APOE4 allele with diabetes in an AD population. Retrospective and cross-sectional clinical and APOE-genotype data on 465 cases with probable or definite AD previously ascertained by the National Institute of Mental Health Genetics Initiative were analyzed by regression analysis. Dependent variables included presence of APOE4 alleles and AD onset age. Diabetes was the independent variable and covariates included gender, hypertension, and other potentially confounding variables. We also examined for interactions involving weight status as overweight and obesity are independent risk factors for insulin resistance, diabetes and AD. Prevalence of diabetes was 13% among AD cases without an APOE4 allele and 5-6% among AD cases with one or two APOE4 alleles. Odds ratio for diabetes was 0.26 [95% CI: 0.09-0.73; P = 0.011] by APOE4 status after adjusting for all covariates. Diabetes did not associate with AD onset age. Among other independent variables included in the model, APOE4 and diuretic medication treatment were associated with AD onset age. In a subset of cases with body mass index determinations, overweight also exhibited an inverse association with APOE4 and associated with decreased non-APOE4 AD onset age. Pathogenic mechanisms associated with diabetes and overweight are enriched in AD cases without an APOE4 allele.
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PMID:Diabetes and overweight associate with non-APOE4 genotype in an Alzheimer's disease population. 1818 40


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