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)

Homocysteine is a metabolite of methionine that may be remethylated by enzymes requiring folate and cobalamin (vitamin B12) to again form methionine or catabolized by the pyridoxine (vitamin B6) dependent enzyme, cystathionine beta synthase (CBS) to form cysteine (fig. 1) [1]. Homocysteine exists as a combination of various free and protein bound forms, but the total amount is what is usually measured and may be reported as homocyst(e)ine [2]. The biological plausibility that elevated homocysteine might lead to vascular disease noted in 1969 by McCully [3]. He reported that a child with abnormal cobalamin metabolism and hyperhomocysteinemia had arterial lesions similar to those seen in children with severe hyperhomocysteinemia from CBS deficiency. These findings led to the idea that moderate elevations in homocysteine, even those still within the so-called normal range, might also lead to vascular pathology through a variety of mechanisms including atherosclerosis and thrombosis [4].
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PMID:Homocysteine as a risk factor for ischemic stroke: an epidemiological story in evolution. 970 30

Hyperhomocysteinemia is a condition which, in the absence of kidney disease, indicates a disrupted sulfur amino acid metabolism, either because of vitamin deficiency (folate, B12 and B6) or a genetic defect. Epidemiologic evidence suggests that mild hyperhomocysteinemia is associated with increased risk of arteriosclerotic disease and stroke. The relationship between hyperhomocysteinemia and thrombosis has been investigated in 10 studies involving a total of 1200 patients and 1200 controls. Eight of these studies demonstrated positive association with odds ratios that ranged from two to 13. This association was enhanced by including a methionine loading test. There is some evidence which suggests that hyperhomocysteinemia and activated protein C resistance have synergistic effect on the onset of thrombotic disease. Recent studies with animal models for mild hyperhomocysteinemia provided encouraging results in the understanding of the mechanism that underlies this relationship between mild elevations of plasma homocysteine and vascular disease. These animal models pointed to the possibility that the effect of elevated homocysteine is multifactorial, affecting both the vascular wall structure and the blood coagulation system.
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PMID:Relationship between homocysteine and thrombotic disease. 970 66

Vascular disease is a serious public health problem in the industrialized world, and is a frequent cause of death among the adult population of Brazil. Mild hyperhomocysteinemia has been identified as a risk factor for arterial disease, venous thrombosis, and neural tube defects. Individuals homozygous for the thermolabile variant of methylenetetrahydrofolate reductase (MTHFR-T) are found in 5-15% of the general population and have significantly elevated plasma homocysteine levels which represent one of the genetic risk factors for vascular diseases. We have analyzed the prevalence of individuals homozygous for the MTHFR-T in 327 subjects representing the three distinct ethnic groups in Brazil. The prevalence of homozygotes for the mutated allele MTHFR-T was high among persons of Caucasian descent (10%) and considerably lower among Black (1.45%) and Indians persons populations (1.2%). These data suggest that screening for the MTHFR-T allele should help in identifying individuals with a high risk of vascular disease among populations with a heterogeneous background.
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PMID:Prevalence of the mutation C677 --> T in the methylene tetrahydrofolate reductase gene among distinct ethnic groups in Brazil. 971 34

A common mutation in methylenetetrahydrofolate reductase (MTHFR), C677T, results in a thermolabile variant with reduced activity. Homozygous mutant individuals (approximately 10% of North Americans) are predisposed to mild hyperhomocysteinemia, when their folate status is low. This genetic-nutrient interactive effect is believed to increase the risk for neural tube defects and vascular disease. In this communication, we characterize a second common variant in MTHFR (A1298C), an E to A substitution. Homozygosity was observed in approximately 10% of Canadian individuals. This polymorphism was associated with decreased enzyme activity; homozygotes had approximately 60% of control activity in lymphocytes. Heterozygotes for both the C677T and the A1298C mutation, approximately 15% of individuals, had 50-60% of control activity, a value that was lower than that seen in single heterozygotes for the C677T variant. No individuals were homozygous for both mutations. Additional studies of the A1298C mutation, in the absence and presence of the C677T mutation, are warranted, to adequately address the role of this new genetic variant in complex traits. A silent genetic variant, T1317C, was identified in the same exon. It was relatively infrequent (allele frequency 5%) in our study group, but was quite common in a small sample of African individuals (allele frequency 39%).
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PMID:A second genetic polymorphism in methylenetetrahydrofolate reductase (MTHFR) associated with decreased enzyme activity. 1060 82

This article presents the research of the Nijmegen homocysteine team on birth defects and vascular disease. Hyperhomocysteinemia was found in women who gave birth to offspring with neural tube defects (NTDs) and other birth defects and in women with vascular disease. Elevated homocysteine levels in the blood plasma can be explained by lack of B vitamins (folic acid), mutation of the 5,10-methylenetetrahydrofolate reductase (MTHFR) genes, or both. Genetic mutations were found on the first chromosome (677 C T and 1298 A-C) and can explain up to 50% of the protective effect of folic acid against NTDs. The inborn error of methionine-homocysteine metabolism was also found in cases with recurrent early pregnancy loss, schisis, congenital heart defects, and vascular problems such as placental abruption, infarcts, and fetal growth retardation. One of the most exciting medical findings of recent years is that folic acid can prevent NTDs. This might also hold true for other birth defects and vascular disease.
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PMID:Open or closed? A world of difference: a history of homocysteine research. 973 77

Hyperhomocysteinemia is an independent risk factor for atherothrombotic disease. The mechanism by which homocysteine induces atherosclerosis and thrombosis is not fully understood. Data on arterial histology in humans with homocystinuria and mild hyperhomocysteinemia are limited. In vitro studies as well as studies in animals and humans indicate that hyperhomocysteinemia induces dysfunction of the vascular endothelium, with loss of endothelium-dependent vasodilation and endothelial antithrombotic properties, and proliferation of vascular smooth muscle cells, which are key processes in current models of atherogenesis and thrombosis. One of the hypotheses is that homocysteine can lead to cellular dysfunction through a mechanism involving oxidative damage but future studies in humans are needed to confirm this. Studies in hyperhomocysteinemic vascular patients have shown that endothelial antithrombotic properties appear to be more severely impaired than in similar patients with normohomocysteinemia. Furthermore, impaired endothelium-dependent vasodilation has been observed in clinically healthy hyperhomocysteinemic subjects in whom no abnormalities were found in endothelial antithrombotic properties. Future studies involving homocysteine-lowering treatment in hyperhomocysteinemic patients with vascular disease and in clinically healthy hyperhomocysteinemic subjects are necessary to investigate the mechanisms by which homocysteine causes atherothrombotic disorders in humans.
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PMID:Hyperhomocysteinemia and atherothrombotic disease. 976 55

A variety of signs and symptoms constituting the uraemic syndrome may be related to the retention and accumulation of uraemic toxins. Several identified (and yet unidentified) uraemic toxins of low molecular weight are removed at least in part by dialysis therapy resulting in marked improvement of multiple organ dysfunctions and clinical symptoms. However, many abnormalities persist due to the high protein binding of several uraemic toxins or their high molecular weight associated with inadequate dialysis clearance. Moreover, carbamoylation of amino acids and proteins in uraemia as well as metabolic acidosis contribute to the functional and metabolic abnormalities of the uraemic state. Uraemia interferes with the function of polymor-phonuclear leukocytes by deranging their cellular biochemistry and biology. P-cresol and several newly identified granulocyte inhibitory proteins are responsible for reduced chemotaxis, oxidative activity, intracellular killing of bacteria, and glucose consumption by polymorphonuclear leukocytes. Hyperhomocysteinaemia is an independent risk factor for vascular disease in end-stage renal disease patients. Uraemic toxins interfere with calcitriol synthesis and concentration or activity of the calcitriol receptor. Advanced glycolysation end-products (AGEs) accumulate as a result of impaired renal excretion. AGE peptides may represent a modern-day version of "middle molecule" toxicity or uraemia. Of potential clinical importance are pentosidine-, imidazolone- and carboxymethyllysine-modifications of beta 2-microglobulin with respect to the development of uraemia associated amyloidosis. Several uraemic toxins also affect nitric oxide pathway. Particularly, dimethyl-L-arginine (ADMA) is a potent inhibitor of nitric oxide synthesis. Parathyroid hormone satisfies the strict criteria of an uraemic toxin. Many uraemic symptoms can be attributed to the excess of parathyroid hormone in patients with chronic renal failure. Finally, recent investigations indicate, that one or more dialyzable uraemic toxin(s) suppress(es) appetite and may contribute to malnutrition in uraemia.
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PMID:Genesis of the uraemic syndrome: role of uraemic toxins. 978 69

Even mild hyperhomocysteinemia is associated with premature vascular disease. Despite the growing evidence that plasma homocysteine is a cardiovascular risk factor, the mechanism behind the vascular injuries is still unknown. Information about the metabolism of homocysteine is, therefore, essential for an understanding of its role in atherogenesis. In the present study we have, therefore, investigated the export mechanism of homocysteine. In HeLa cell lines the release of homocysteine was found to be a continuous process, which was increased in the presence of copper ions. High cell density led to a lowered release of homocysteine, probably due to a more extensive metabolism of the intracellular homocysteine. It was also found that HeLa cells were able to take up extracellularly released homocysteine and use it in the cellular metabolism. The ratio between intracellular homocysteine and the total amount of homocysteine is a measure of the ability of the cell to export the intracellularly produced homocysteine. The ratio also reflects the reuse of extracellular homocysteine. Under basal conditions, endothelial cells exported most of the intracellularly produced homocysteine and exhibited a very low concentration of homocysteine intracellularly, low reusage of exported homocysteine and consequently a low ratio in comparison with HeLa and hepatoma cell lines. After addition of homocysteine, all cell lines exhibited similar ratios. Thus, the intracellular homocysteine concentration in endothelial cells is more influenced by the extracellular concentration of homocysteine than is the intracellular concentration in HeLa and hepatoma cells. It may be speculated that this phenomenon could be associated with an increased sensitivity of endothelial cells to homocysteine and explain the association between hyperhomocysteinemia and vascular disease.
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PMID:Higher export rate of homocysteine in a human endothelial cell line than in other human cell lines. 982 69

Hyperhomocysteinemia, a risk factor for vascular disease, is related to vitamin B12, vitamin B6, and especially folate deficiency, or to genetic factors such as mutations in methylenetetrahydrofolate reductase (MTHFR), an enzyme involved in the remethylation pathway of homocysteine to methionine. Recently, a C677 --> T mutation identified in the MTHFR gene was found to be frequently associated with decreased MTHFR activity and an elevated plasma homocysteine concentration. Since hyperhomocysteinemia seems to be determined by both genetic and environmental factors, we studied the interactions between MTHFR (phenotype and genotype) and folate status, including methyltetrahydrofolate (methylTHF), the product of MTHFR, on the homocysteine concentration in 52 healthy subjects, (28 women and 24 men; mean age, 32.7 years). MTHFR activity seems to be dependent on folate status, as shown by a lower activity in folate-deficient subjects and a return to normal values after supplementation with folic acid, and also by a decreased enzymatic activity on phytohemagglutinin (PHA)-stimulated lymphocytes grown in a folic acid-deficient medium. Conversely, the C677 --> T mutation seems to influence folate metabolism. Subjects who were homozygous for this mutation (+/+) had significantly higher plasma homocysteine and lower plasma folate and total and methylfolate levels in red blood cells (RBCs) than heterozygous (+/-) and normal (-/-) subjects. The ratio of RBC methylfolate to RBC total folate was, respectively, 0.27 in +/+, 0.66 in +/-, and 0.71 in -/-. This mutation seems to have an impact on methylTHF generation. These data illustrate the interactions between nutritional and genetic factors.
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PMID:Plasma homocysteine levels related to interactions between folate status and methylenetetrahydrofolate reductase: a study in 52 healthy subjects. 982 23

Studies of symptomatic patients have identified hyperhomocysteinemia as an independent risk factor for vascular disease. In case-control studies, a point mutation (C677T) in the gene encoding 5,10-methylenetetrahydrofolate reductase (MTHFR) has also been linked to an increased risk of vascular disease through its effect on homocysteinemia. Our aim was to extend these observations to asymptomatic subjects by studying the influence of both homocysteinemia and its mutation on carotid artery geometry. We examined 144 subjects free of atherosclerotic lesions. Fasting homocysteinemia was measured by high-performance liquid chromatography with fluorometric detection. MTHFR genotype was analyzed by polymerase chain reaction followed by HinfI digestion. Carotid artery geometry was characterized by internal diameter and intima-media thickness, as assessed by a high-resolution echo-tracking system. Subjects in the upper homocysteine tertile had a greater carotid internal diameter than did subjects in the middle and lower tertiles (6516+/-770 versus 6206+/-641 and 5985+/-558 microm, respectively; P<0.001). Subjects homozygous for the mutation had a smaller carotid artery internal diameter than did subjects heterozygous or homozygous for the wild-type allele (5846+/-785 versus 6345+/-673 and 6199+/-671 microm, respectively; P<0.05). Homocysteinemia was not significantly increased in subjects homozygous for the mutation. In multivariate regression analysis, homocysteinemia was independently and positively associated with lumen diameter (P=0.0008) and wall thickness (P=0.020). Conversely, homozygosity for the mutation was negatively associated with internal diameter (P=0.009). These preliminary data suggest that mildly elevated homocysteinemia and homozygosity for the MTHFR C677T mutation are associated with opposite preclinical modifications of carotid artery geometry. If confirmed, these results may have important implications for new treatment strategies for vascular disease before the onset of clinical manifestations.
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PMID:Opposite effects of plasma homocysteine and the methylenetetrahydrofolate reductase C677T mutation on carotid artery geometry in asymptomatic adults. 984 74


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