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)

It is presently unclear whether polymorphic variations in the oxidized low-density lipoprotein receptor 1 (OLR1), or low-density lipoprotein receptor-related protein 1 (LRP1), genes act as risk factors for Alzheimer's disease (AD). In the present study, we have investigated the extent of amyloid beta protein (Abeta) deposition as cerebral amyloid angiopathy (CAA) or senile plaques (SP) in relationship to OLR1 +1071 and +1073 polymorphisms and LRP1 C766T polymorphism in patients with AD There was an increased Abeta40 load as CAA, but not as SP, in frontal cortex of AD patients carrying OLR1+1073 CC genotype, compared to those with CT, TT or CT+TT genotypes, but only in those individuals without apolipoprotein (APOE) epsilon4 allele. No differences in total Abeta or Abeta42 load as CAA or SP between OLR1+1073 genotypes was seen, nor were there any differences between OLR1+1071 and LRP1 genotypes for any measure of Abeta. Present data suggests that homozygosity for the C allele for OLR1+1073 polymorphism, selectively in individuals without APOE epsilon4 allele, may impair clearance of Abeta, and particularly Abeta40, from the brain across the blood-brain barrier, leading to its 'diversion' into perivascular drainage channels, thereby increasing the severity of CAA in such persons.
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PMID:A 3'-UTR polymorphism in the oxidized LDL receptor 1 gene increases Abeta40 load as cerebral amyloid angiopathy in Alzheimer's disease. 1632 15

Hyperhomocysteinemia, a risk factor for cardiovascular disease, is caused by nutritional or genetic disturbances in homocysteine metabolism. A polymorphism in methylenetetrahydrofolate reductase (MTHFR) is the most common genetic cause of mild hyperhomocysteinemia. To examine mechanisms by which an elevation in plasma homocysteine leads to vascular disease, we first performed microarray analyses in livers of Mthfr-deficient mice and identified differentially expressed genes that are involved in lipid and cholesterol metabolism. Microarrays and RT-PCR showed decreased mRNA for apolipoprotein A (ApoA)-IV and for ApoA-I and increased mRNA for cholesterol 7alpha hydroxylase (Cyp7A1) in Mthfr(+/-) mice compared with Mthfr(+/+) mice. Western blotting revealed that ApoA-I protein levels in liver and plasma of Mthfr(+/-) mice were 52% and 62% of levels in the respective tissues of Mthfr(+/+) mice. We also performed Western analysis for plasma ApoA-I protein levels in 60 males with coronary artery disease and identified a significant (P<0.01) negative correlation (-0.33) between ApoA-I and plasma homocysteine levels. This cohort also displayed a negative correlation (-0.24, P=0.06) between high-density lipoprotein cholesterol and plasma homocysteine. Treatment of HepG2 cells with supraphysiological levels of 5 mmol/L homocysteine reduced peroxisome proliferator-activated receptor (PPAR) alpha and ApoA-I protein levels and decreased ApoA-I promoter activity. Transfection with a PPARalpha construct upregulated ApoA-I and MTHFR. Our results suggest that hyperhomocysteinemia may increase risk of atherosclerosis by decreasing expression of ApoA-I and increasing expression of CYP7A1.
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PMID:Elevated homocysteine reduces apolipoprotein A-I expression in hyperhomocysteinemic mice and in males with coronary artery disease. 1651 70

There is abundant evidence that the risk of atherosclerotic vascular disease is directly related to plasma cholesterol levels. Accordingly, all of the national and transnational screening and therapeutic guidelines are based on total or LDL cholesterol. This presumes that cholesterol is the most important lipoprotein-related proatherogenic risk variable. On the contrary, risk appears to be more directly related to the number of circulating atherogenic particles that contact and enter the arterial wall than to the measured concentration of cholesterol in these lipoprotein fractions. Each of the atherogenic lipoprotein particles contains a single molecule of apolipoprotein (apo) B and therefore the concentration of apo B provides a direct measure of the number of circulating atherogenic lipoproteins. Evidence from fundamental, epidemiological and clinical trial studies indicates that apo B is superior to any of the cholesterol indices to recognize those at increased risk of vascular disease and to judge the adequacy of lipid-lowering therapy. On the basis of this evidence, we believe that apo B should be included in all guidelines as an indicator of cardiovascular risk. In addition, the present target adopted by the Canadian guideline groups of an apo B <90 mg dL(-1) in high-risk patients should be reassessed in the light of the new clinical trial results and a new ultra-low target of <80 mg dL(-1) be considered. The evidence also indicates that the apo B/apo A-I ratio is superior to any of the conventional cholesterol ratios in patients without symptomatic vascular disease or diabetes to evaluate the lipoprotein-related risk of vascular disease.
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PMID:Apo B versus cholesterol in estimating cardiovascular risk and in guiding therapy: report of the thirty-person/ten-country panel. 1647 2

Middle-age Down's syndrome patients develop dementia with antomicopathological changes that are characteristic for Alzheimer's disease. Cerebral amyolid angiopathy (CAA) most commonly manifests itself as a lobar intracerebral haemorrhage that tends to recur. Multiple haemorrhages may occur simultaneously. CAA is frequently associated with Alzheimer's disease, however the relationship between CCA and Down's syndrome is poorly know. Although there are established clinical criteria for the diagnosis of CAA related to lobar intracerebral haemorrhage, definitive CAA needs anatomicopathologial confirmation. This paper presents the case of a male with Down's syndrome and recurrent lobar intracerebral haemorrhage. An autopsy showed lesions in leptomeningeal and cortical arteries which are characteristic of CAA in addition to anatomicopathological changes of Alzheimer s disease that were mostly seen in entorhinal cortex and hippocampus. The paper also discusses the pathological association between beta-amyloid protein, apolipoprotein alleles, CAA, Alzheimer's disease and Down's syndrome.
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PMID:[Cerebral amyloid angiopathy, recurrent intracerebral haemorrhages and Down's syndrome]. 1710 27

This article reviews the evidence showing that apolipoprotein (apo) B and A-1 are superior to the conventional cholesterol indices as analytes in laboratory practice, indices of the lipoprotein-related risk for vascular disease, and measures of the adequacy of low-density lipoprotein-lowering therapy.
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PMID:Apolipoprotein A1 and B. 1711 Feb 37

Neocortical neuritic plaques (NP) and neurofibrillary tangles (NFT) are hallmarks of Alzheimer's disease (AD) and usually, both are present. The Honolulu-Asia Aging Study autopsy series includes a significant number of individuals with only one neocortical AD lesion type. These could represent an early phase of the AD process. If so, such individuals would be expected to share other clinical and pathological features of AD. We compared frequency of apolipoprotein epsilon E4 (APOE4) allele, average Braak stage, and burden of cerebral amyloid angiopathy (CAA) among the two single lesion type groups, a group without AD lesions, and groups with high and low frequencies of both AD lesions. Single AD lesion groups shared only the characteristics associated with their unique lesion type with the combined AD lesion group and did not have higher prevalence of dementia than the no AD lesion group. Only the NP+NFT group showed a "dose-response" relationship with greater probability of dementia with higher neocortical frequencies of either AD lesion. The single neocortical AD lesion groups do not appear to represent early AD.
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PMID:Characterization of Japanese-American men with a single neocortical AD lesion type. 1749 84

Apolipoprotein A-IV (apoA-IV) is a 376-amino acid exchangeable apolipoprotein made in the small intestine of humans. Although it has many proposed roles in vascular disease, satiety, and chylomicron metabolism, there is no known structural basis for these functions. The ability to associate with lipids may be a key step in apoA-IV functionality. We recently identified a single amino acid, Phe(334), which seems to inhibit the lipid binding capability of apoA-IV. We also found that an intact N terminus was necessary for increased lipid binding of Phe(334) mutants. Here, we identify Trp(12) and Phe(15) as the N-terminal amino acids required for the fast lipid binding seen with the F334A mutant. Furthermore, we found that individual disruption of putative amphipathic alpha-helices 3-11 had little effect on lipid binding, suggesting that the N terminus of apoA-IV may be the operational site for initial lipid binding. We also provide three independent pieces of experimental evidence supporting a direct intramolecular interaction between sequences near amino acids 12/15 and 334. This interaction could represent a unique "switch" mechanism by which apoA-IV changes lipid avidity in vivo.
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PMID:Modulation of apolipoprotein A-IV lipid binding by an interaction between the N and C termini. 1768 71

The relationships among lipoprotein metabolism, genetic vascular factors, vascular disease, and Alzheimer's disease suggest that the examination of centenarian populations in relation to certain genes or lipoprotein metabolism provide insights into human longevity. The findings on the higher frequency of the apolipoprotein E epsilon4 allele in middle-aged subjects than in centenarians were substantially confirmed. On the contrary, recent findings did not confirm previous data on increased prevalence of the high-risk angiotensin I converting enzyme D allele in French centenarians. The variability in the strength of association between angiotensin I converting enzyme polymorphism and longevity could be related to regional differences in angiotensin I converting enzyme D allele frequency in Europe recently showed, as also recently reported for apolipoprotein Eepsilon2 and epsilon4 allele in centenarians. Indeed some studies of lipoprotein profiles in centenarians have also had contradictory outcomes, with evidence of lower serum levels of high-density lipoprotein cholesterol, with higher high-density lipoprotein 2 cholesterol subfraction, larger high-density lipoprotein and low-density lipoprotein particle sizes, and higher lipoprotein(a) concentration in centenarians, which is apparently disadvantageous for human longevity. Elevated lipoprotein(a) serum levels, increasing the risk for cerebrovascular disease, may play a role in determining clinical Alzheimer's disease, but lipoprotein(a) elevation in centenarians, in the absence of other coronary artery disease risk factors, appears as a positive survival factor. In different populations, there are significant trends in the reduction of serum apolipoprotein E levels from apolipoprotein E epsilon2- to epsilon4-carriers and significant differences in serum apolipoprotein E levels with respect to age in epsilon4-carriers but only after adjustment for high-density lipoprotein cholesterol. While further studies are needed to confirm the possible role of apolipoprotein E concentration as putative longevity factor this paper provides an overview of many of the investigated vascular factors with respect to longevity.
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PMID:Lipoproteins, vascular-related genetic factors, and human longevity. 1799 Sep 70

The levels of pro- and antiatherogenic lipoproteins are the most important risk factors for vascular disease, and there is now compelling evidence that the apolipoprotein (apo) B/apoA-I ratio is a better index of the likelihood of vascular events than any of the corresponding cholesterol indices: the total cholesterol/high-density lipoprotein cholesterol (HDL-C) ratio, non-HDL-C/HDL-C ratio, or low-density lipoprotein cholesterol (LDL-C)/HDL-C ratio. But are there any restrictions on the application of the apoB/apoA-I ratio to clinical practice? This article suggests that the answer is yes. Based on the available biologic and epidemiologic data, the relation between risk and apoB is continuous, whereas at the extremes of HDL concentration in plasma the relation to risk is not certain. Moreover, LDL plays a causal role in atherogenesis whereas HDL plays a contingent role. Appreciating these distinctions should allow appropriate use of the apoB/apoA-I ratio as a simple, single, summary index of the lipoprotein-related risk of vascular disease.
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PMID:The strengths and limitations of the apoB/apoA-I ratio to predict the risk of vascular disease: a Hegelian analysis. 1817 52

Our purpose was to evaluate associations of single nucleotide polymorphisms (SNPs) at the low density lipoprotein (LDL) receptor (LDLR C44857T, minor allele frequency (MAF) 0.26, and A44964G, MAF 0.25, both in the untranslated region) and HMG-CoA reductase (HMGCR i18 T>G, MAF 0.019) gene loci with baseline lipid values, statin-induced LDL-cholesterol (C) lowering response, and incident coronary heart disease (CHD) and cardiovascular disease (CVD) on trial. Our population consisted of 5804 elderly men and women with vascular disease or one or more vascular disease risk factors, who were randomly allocated to pravastatin or placebo. Other risk factors and apolipoprotein (apo) E phenotype were controlled for in the analysis. Despite a prior report, no relationships with the HMGCR SNP were noted. For the LDLR SNPs C44857T and A44964G we noted significant associations of the rare alleles with baseline LDL-C and triglyceride levels, a modest association of the C44857T with LDL-C lowering to pravastatin in men, and significant associations with incident CHD and CVD of both SNPs, especially in men on pravastatin. Our data indicate that genetic variation at the LDLR locus can affect baseline lipids, response to pravastatin, and CVD risk in subjects placed on statin treatment.
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PMID:Genetic variation at the LDL receptor and HMG-CoA reductase gene loci, lipid levels, statin response, and cardiovascular disease incidence in PROSPER. 1826 33


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