Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0042373 (vascular disease)
 17,070 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Patients with homozygous familial hypercholesterolaemia (FH) caused by receptor-negative, low-density lipoprotein (LDL) receptor gene mutations have higher concentrations of LDL-cholesterol in plasma and earlier onset of cardiovascular disease (CVD) than patients homozygous for receptor-defective, LDL receptor mutations. In contrast, it is uncertain whether the severity of atherosclerotic disease differs in heterozygous FH caused by receptor-negative and receptor-defective mutations. The present authors investigated the influence of LDL receptor mutation type on the clinical phenotype in 31 patients with heterozygous FH caused by the receptor-negative, Trp23-stop mutation and in 31 patients heterozygous for the receptor defective Trp66-Gly mutation. Untreated levels of plasma LDL-cholesterol and calculated cholesterol-years score did not differ significantly between the two groups of patients. Detection of vascular disease was based on two approaches: (1) measurement of coronary calcification by spiral computed tomography (CT) scanning; and (2) ultrasonic measurement of carotid intima-media thickness (IMT). Age was significantly correlated to the presence of coronary calcification, but controlling for relevant cofactors, there was no evidence that the receptor-negative mutation caused more calcification than the receptor-defective mutation. Furthermore, carotid IMT was significantly influenced by plasma concentrations of Lp(a) and triglycerides, as well as by age, sex and smoking status, but again, there was no statistically significant effect of LDL receptor gene mutational type. The similarity in vascular phenotypes was probably caused by a similar life-long burden of LDL-cholesterol in the two groups of patients.
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PMID:LDL receptor mutation genotype and vascular disease phenotype in heterozygous familial hypercholesterolaemia. 1212 47

Coronary vascular disease is one facet of a generalized disturbance of vascular function present throughout the vascular tree. Dysfunction of the endothelium leads to thickening of the intima and media of the vessel wall of large and medium-sized muscular arteries and large elastic arteries, such as the aorta, carotid, and iliac arteries. Flow-mediated dilatation of the brachial artery is one of several tests used to assess dysfunction of the endothelium using high resolution ultrasound. Endothelial dysfunction has been demonstrated in children with heterozygous familial hypercholesterolemia, type 1 diabetes, morbid obesity, and homozygous homocystinuria and in the offspring of a parent with early coronary disease. High resolution ultrasound has also confirmed postmortem findings that atherogenesis has its beginnings in childhood and adolescence, with the demonstration of increased carotid artery intima-medial thickening in children with familial hypercholesterolemia, familial combined hyperlipidemia, and type 1 diabetes and in the offspring of a parent with early coronary disease. In combination with family history and traditional risk factors, ultrasound evaluation of brachial artery flow-mediated vasodilation and carotid artery intima-medial thickening could be used in a clinical setting to assess coronary risk in high risk pediatric patients.
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PMID:Clinical review 168: What vascular ultrasound testing has revealed about pediatric atherogenesis, and a potential clinical role for ultrasound in pediatric risk assessment. 1524 May 74

BACKGROUND: In Down syndrome patients several metabolic abnormalities have been reported, some involving the lipid metabolism. The level of LDL in plasma is the major determinant of the risk of vascular disease. There appear to be no studies on the LDL receptor in Down syndrome patients. METHODS: Flow cytometric methods for measuring the LDL receptor in peripheral blood mononuclear cells (PBMC) can identify patients with hypercholesterolemia. We applied this method in 19 old patients with Down syndrome and 23 healthy controls. RESULTS: Down syndrome patients had high levels of triglycerides and low levels of HDL, and high levels of CRP. We also found a down-regulation of LDL receptor expression. CONCLUSIONS: Down syndrome patients show no increase in the frequency of cardiovascular disease. The low incidence in cardiovascular disease despite the low level of HDL, high levels of CRP and reduction of LDL receptor expression lead to the conclusion that either these are not risk factors in these patients or that other risks factors - not yet identified - are considerably lower.
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PMID:LDL receptor expression on T lymphocytes in old patients with Down syndrome. 1570 98

Type 2 diabetes mellitus (DM) and the metabolic syndrome, both characterized by insulin resistance, are associated with an accelerated form of atherosclerotic vascular disease and poor outcomes following vascular interventions. These vascular effects are thought to stem from a heightened inflammatory environment and reduced bioavailability of nitric oxide (NO). To better understand this process, we characterized the vascular injury response in the obese Zucker rat by examining the expression of adhesion molecules, the recruitment of inflammatory cells, and the development of intimal hyperplasia. We also evaluated the ability of exogenous NO to inhibit the sequela of vascular injury in the metabolic syndrome. Obese and lean Zucker rats underwent carotid artery balloon injury. ICAM-1 and P-selectin expression were increased following injury in the obese animals compared with the lean rats. The obese rats also responded with increased macrophage infiltration of the vascular wall as well as increased neointima formation compared with their lean counterparts (intima/media = 0.91 vs. 0.52, P = 0.001). After adenovirus-mediated inducible NO synthase (iNOS) gene transfer, ICAM-1, P-selectin, inflammatory cell influx, and oxidized low-density lipoprotein (LDL) receptor expression were all markedly reduced versus injury alone. iNOS gene transfer also significantly inhibited proliferative activity (54% and 73%; P < 0.05) and neointima formation (53% and 67%; P < 0.05) in lean and obese animals, respectively. The vascular injury response in the face of obesity and the metabolic syndrome is associated with increased adhesion molecule expression, inflammatory cell infiltration, oxidized LDL receptor expression, and proliferation. iNOS gene transfer is able to effectively inhibit this heightened injury response and reduce neointima formation in this proinflammatory environment.
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PMID:Nitric oxide modulates vascular inflammation and intimal hyperplasia in insulin resistance and the metabolic syndrome. 1573 83

Mild hyperhomocysteinemia is considered an important risk factor for vascular disease. A common polymorphism (677C-->T) in the methylenetetrahydrofolate reductase (MTHFR) gene is associated with a decreased enzyme activity and consequent higher circulating levels of homocysteine. We hypothesized that the serum levels of homocysteine and/or the MTHFR polymorphism could influence the risk for coronary artery disease (CAD) in patients with heterozygous familial hypercholesterolemia (FH), who are genetically prone to atherosclerosis. We determined the MTHFR genotype and fasting total serum homocysteine level in 249 adult patients (103 males and 146 females) with heterozygous FH. MTHFR polymorphism was a major determinant of serum homocysteine in adult FH of both sexes. The logistic regression analysis showed that in FH patients a high level of homocysteine (> 12 micromol/l, corresponding to the upper quartile of serum distribution) was the most significant predictor of CAD (n=99) in all the groups considered (all CAD, previous myocardial infarction, myocardial infarction plus angiographically confirmed CAD). The adjusted odds ratio (OR (95% CI)) for the homocysteine-associated risk of CAD (upper quartile versus lower quartiles) was 3.27 (1.60-6.62) in males and females considered together, 5.67 (1.50-21.3) in males and 2.78 (1.17-6.62) in females. LDL cholesterol (upper quartile versus lower quartiles) and hypertension were the other variables independently associated with CAD. In both sexes MTHFR polymorphism was not an independent predictor of CAD. Plasma concentration of serum homocysteine, but not MTHFR genotype, is associated with an increased risk of CAD in male and female patients with heterozygous FH.
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PMID:Serum homocysteine, methylenetetrahydrofolate reductase gene polymorphism and cardiovascular disease in heterozygous familial hypercholesterolemia. 1577 50

The authors evaluated the lipid profile of children with a positive family history of coronary heart disease (CHD), cerebrovascular disease (CVD), or hyperlipidemia and compared them with controls in order to identify risk indicators for atherosclerosis. A group of 315 children (group A) aged more than 2 years old with a positive family history were evaluated for serum concentrations of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglycerides (TG), apolipoprotein B100 (ApoB100), apolipoprotein A1 (Apo A1), and lipoprotein (a) (Lp[a]). These values were compared with the levels of a control group of 214 children of comparable age (group B). The median age of children in groups A and B was 10.6 (range 2.3-16) and 9.8 (range 3-13.7) years of age, respectively. Among these children, 196 (52%), 47 (12.5%), and 72 (19.1%) had a positive family history of CHD (group A1), cerebrovascular disease (CVD) (group A2), and hypercholesterolemia (group A3), respectively. We identified 8 children with genetically determined dyslipidemia: 2 children with homozygous and 6 with heterozygous familial hypercholesterolemia. Children in group A3 had significantly higher concentrations of TC, TG, LDL-C, and ApoB100 and lower concentrations of Apo A1 compared with controls, while no significant differences were found in concentrations of lipid variables among children of group A1, A2, and A3. Significant differences were also noted in the concentrations of TC, LDL-C, and Lp(a) between children of group A1 and controls. Screening the progeny of young patients with CHD or familial hypercholesterolemia can identify children at excessive risk for future vascular disease.
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PMID:Lipid profile of children with a family history of coronary heart disease or hyperlipidemia: 9-year experience of an outpatient clinic for the prevention of cardiovascular diseases. 1607 21

Previously we showed L-4F, a novel apolipoprotein A-I (apoA-I) mimetic, improved vasodilation in 2 dissimilar models of vascular disease: hypercholesterolemic LDL receptor-null (Ldlr(-/-)) mice and transgenic sickle cell disease mice. Here we determine the mechanisms by which D-4F improves vasodilation and arterial wall thickness in hypercholesterolemic Ldlr(-/-) mice and Ldlr(-/-)/apoA-I null (apoA-I(-/-)), double-knockout mice. Ldlr(-/-) and Ldlr(-/-)/apoA-I(-/-) mice were fed Western diet (WD) with and without D-4F. Oral D-4F restored endothelium- and endothelial NO synthase (eNOS)-dependent vasodilation in direct relationship to duration of treatments and reduced wall thickness in as little as 2 weeks in vessels with preexisting disease in Ldlr(-/-) mice. D-4F had no effect on total or HDL cholesterol concentrations but reduced proinflammatory HDL levels. D-4F had no effect on plasma myeloperoxidase concentrations but reduced myeloperoxidase association with apoA-I as well as 3-nitrotyrosine in apoA-I. D-4F increased endothelium- and eNOS-dependent vasodilation in Ldlr(-/-)/apoA-I(-/-) mice but did not reduce wall thickness as it had in Ldlr(-/-) mice. Vascular endothelial cells were treated with 22(R)-hydroxycholesterol with and without L-4F. 22(R)-Hydroxycholesterol decreased NO (*NO) and increased superoxide anion (O2*-) production and increased ATP-binding cassette transporter-1 and collagen expression. L-4F restored *NO and O2*- balance, had little effect on ATP-binding cassette transporter-1 expression, but reduced collagen expression. These data demonstrate that although D-4F restores vascular endothelial cell and eNOS function to increase vasodilation, HDL containing apoA-I, or at least some critical concentration of the antiatherogenic lipoprotein, is required for D-4F to decrease vessel wall thickness.
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PMID:Effects of D-4F on vasodilation and vessel wall thickness in hypercholesterolemic LDL receptor-null and LDL receptor/apolipoprotein A-I double-knockout mice on Western diet. 1630 51

Autosomal-dominant hypercholesterolemia (ADH) has been identified as a major risk factor for coronary vascular disease (CVD) and is associated with mutations in the low-density lipoprotein receptor (LDLR) and the apolipoprotein B (APOB) gene. Since 1991 DNA samples from clinically diagnosed ADH patients have been routinely analyzed for the presence of LDLR and APOB gene mutations. As of 2001, 1,641 index patients (164 index patients per year) had been identified, while from 2001 onward a more sensitive, high-throughput system was used, resulting in the identification of 1,177 new index patients (average=294 index patients per year). Of these 1,177 index cases, 131 different causative genetic variants in the LDLR gene and six different causative mutations in the APOB gene were new for the Dutch population. Of these 131 mutations, 83 LDLR and four APOB gene mutations had not been reported before. The inclusion of all 2,818 index cases into the national screening program for familial hypercholesterolemia (FH) resulted in the identification of 7,079 relatives who carried a mutation that causes ADH. Screening of the LDLR and APOB genes in clinically diagnosed FH patients resulted in approximately 77% of the patients being identified as carriers of a causative mutation. The population of patients with ADH was divided into three genetically distinct groups: carriers of an LDLR mutation (FH), carriers of an APOB mutation (FDB), and non-LDLR/non-APOB patients (FH3). No differences were found with regard to untreated cholesterol levels, response to therapy, and onset of CVD. However, all groups were at an increased risk for CVD. Therefore, to ultimately identify all individuals with ADH, the identification of new genes and mutations in the genes that cause ADH is of crucial importance for the ongoing national program to identify patients with ADH by genetic cascade screening.
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PMID:Update of the molecular basis of familial hypercholesterolemia in The Netherlands. 1625 3

Heterozygous familial hypercholesterolemia (HeFH) is a monogenic disorder that affects about 1 in 500 people, with a higher prevalence in certain subpopulations such as people of Quebecois, Christian Lebanese and Dutch South Afrikaner extraction. HeFH is characterized by cholesterol deposits affecting the corneas, eyelids and extensor tendons; elevated plasma concentrations of low-density lipoprotein (LDL) cholesterol; and accelerated vascular disease, especially coronary artery disease (CAD). Although HeFH is genetically heterogeneous, it is most often caused by heterozygous mutations in the LDLR gene encoding the LDL receptor. We describe a man who was diagnosed with HeFH after he had a myocardial infarction at 33 years of age. By DNA sequence analysis, he was found to have a heterozygous splicing mutation in his LDLR gene. This discovery expanded the growing mutational spectrum in patients with HeFH in Ontario. Given that HeFH is a treatable cause of early vascular disease, it is important that this condition be recognized, diagnosed and treated in affected patients; but as yet, there is no consensus on the best approach. Diagnostic criteria based on family history and clinical presentation have been proposed for patients with suspected HeFH. Biochemical or molecular screening might be considered to detect new cases of HeFH in populations with a relatively high HeFH prevalence and a relatively small number of possible causative mutations. So far, however, the most cost-effective and efficient systematic strategy to detect previously undiagnosed cases of HeFH is still cascade testing: clinical and biochemical screening of close relatives of the proband patient diagnosed with HeFH. Pharmacologic treatment of HeFH is cost-effective.
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PMID:Heterozygous familial hypercholesterolemia: an underrecognized cause of early cardiovascular disease. 1660 62

Familial hypercholesterolaemia (FH) is a genetic disorder in which the concentration of serum cholesterol is elevated from birth and leads to premature coronary heart disease. FH is commonly caused by a mutation in the LDL receptor, but mutations in other genes can lead to a phenotype similar to FH. FH exhibits marked phenotypic variability due to genetic, metabolic and environmental factors. The presence of tendon xanthomata is the characteristic clinical sign seen in many patients with FH, but they may also have other non-specific signs of lipid disorders such as corneal arcus and xanthelasmata. Premature vascular disease is apparent in many patients. The wide variety of mutations and phenotypic variability have made it difficult to establish definite diagnostic criteria, but three sets of clinical criteria commonly used are the Simon Broome criteria, the Dutch Lipid Clinic criteria and the American criteria. FH screening fits the Wilson and Jungner recommendations for validity of a screening programme. Screening could be carried out on a population basis, in a clinical setting or by application to relatives of probands. This latter approach, termed cascade testing, appears to be the more cost-effective compared with population screening and can be carried out using clinical criteria or genetic testing, or by a combination of both methods. Clinicians need to be made more aware of the clinical features of FH and how to diagnose it in order to increase the index of suspicion and instigate appropriate treatment early, with the aim of preventing premature coronary heart disease.
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PMID:Diagnosis and screening for familial hypercholesterolaemia: finding the patients, finding the genes. 1713 75


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