Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0018799 (heart disease)
 34,133 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The National Cholesterol Education Program (NCEP) recommends that dietary total fat, saturated fat, and cholesterol intake be reduced to < or = 30% of calories, < 10% of calories, and < 300 mg/d, respectively (step 1 diet), in the general population to reduce plasma low-density lipoprotein cholesterol (LDL-C) levels and heart disease risk. We examined the LDL-C-lowering response to such a diet (26% fat, 8% saturated fat, and 201 mg/d cholesterol) compared with an average American diet (39% fat, 15% saturated fat, and 435 mg cholesterol/d) in 153 subjects using diet periods of 4 through 24 weeks for each diet phase. The mean LDL-C reduction was 13% in men (n = 93) and 7% in postmenopausal women (n = 60). The effect of apolipoprotein (apo) A-IV phenotype on responsiveness was examined. LDL-C lowering in men was significantly (P < .005) less (7%) for 17 apoA-IV (1/2) subjects than for 76 apoA-IV (1/1) subjects (16%). In women, 7% lowering was observed in both 12 apoA-IV (1/2) subjects and 48 apoA-IV (1/1) subjects. ApoA-IV phenotype had a significant effect on plasma high-density lipoprotein cholesterol levels during both dietary periods; women carrying the apoA-IV-2 allele had higher levels than those homozygous for the apoA-IV-1 allele. The opposite was true for triglyceride levels, but only during the period when the subjects consumed the high-fat, high-cholesterol diet.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:ApoA-IV phenotype affects diet-induced plasma LDL cholesterol lowering. 819 78

A pedigree of a large family with high prevalence of heart disease is subjected to association and sib-pair linkage analysis to investigate the role of 5 candidate genes in the regulation of lipoprotein metabolism and the development of coronary artery disease. At the 5% nominal significance level, the apolipoprotein B locus (APOB) was found to be linked to high-density lipoprotein cholesterol level (HDL-C), low-density lipoprotein cholesterol level (LDL-C), the ratio HDL-C/LDL-C, and apolipoprotein AI level times this ratio (apoAI x LDL-C/HDL-C). APOB (PvuII) was strongly associated with apolipoprotein B levels (apoB) (P = 0.006) and the VNTR region of the APOB locus showed highly significant association between allele 7 and low triglyceride levels (P = 0.004). No significant linkage results were found with cholesterol ester transfer protein (CETP). At the 1% nominal significance level, CETP [TaqI(B)] showed significant association with LDL-C, apoB, and HDL-C/LDL-C. There was significant linkage of lipoprotein lipase (LPL) with very-low-density lipoprotein cholesterol and the ratio apoAI/HDL-C, and strong association results between LPL (HindIII) and triglyceride levels (P = 0.005). At the 5% nominal significance level, haptoglobin (HPA) was associated with HDL-C, HDL-C/LDL-C, apoAI/HDL-C and apoAI x LDL-C/HDL-C. The apolipoprotein AI locus did not show any significant linkages or associations. The study thus indicated that genetic variation of APOB, LPL, CETP, and lecithin cholesterol acyl transferase (which is linked to HPA and CETP) may play an important role in the regulation of lipoprotein metabolism and could contribute to the risk of coronary artery disease.
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PMID:Genetic contributions to quantitative lipoprotein traits associated with coronary artery disease: analysis of a large pedigree from the Bogalusa Heart Study. 827 86

We studied several risk factors in relation to parental cardiovascular heart disease: total cholesterol, triglycerides, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, apolipoprotein (apo) A-I, apo B, and lipoprotein(a) [Lp(a)] were determined in 322 serum samples (43 from subjects with and 279 without parental cardiovascular heart disease). The distribution of Lp(a) concentrations in our young population was similar to that of other white populations, i.e., markedly skewed, with higher frequencies at low values. As compared with children whose parents did not report cardiovascular heart disease, those with affected parents had a higher mean Lp(a) (0.23 vs 0.18 g/L; P < 0.05). Moreover, 42% of the children with parental cardiovascular heart disease, but only 19% of those with no parental cardiovascular heart disease, exhibited Lp(a) values > 0.30 g/L. These results suggest not only that Lp(a) is an important risk factor for cardiovascular heart disease, but also that Lp(a) is more strongly related to the risk of cardiovascular heart disease than are HDL- and LDL-cholesterol and apo A-I and B.
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PMID:Relation of lipoprotein(a) in 11- to 19-year-old adolescents to parental cardiovascular heart disease. 844 60

Cigarette smoking alters the pattern of endogenous steroid levels. We examined this phenomenon in two separate male groups. Group A consisted of 189 dyslipidemic men participating in the Helsinki Heart Study and group B of 100 men including patients with heart disease and healthy controls. The subjects in the latter group underwent ACTH-testing. In group A, smokers had significantly higher basal androstenedione and dehydroepiandrosterone sulfate (DHEAS) levels and androstenedione/cortisol ratios than nonsmokers. Mean concentrations of cortisol, dehydroepiandrosterone (DHEA), androstanediol glucuronide, testosterone, and sex-hormone binding globulin (SHBG) did not differ between smokers and nonsmokers. In group B, smokers had lower high density lipoprotein (HDL)-cholesterol and apolipoprotein AI and higher triglyceride levels than nonsmokers. Basal androstenedione and ACTH stimulated androstenedione and DHEA concentrations were higher in smokers. No significant differences were found in basal insulin, SHBG, estrone, estradiol, testosterone, free testosterone, and dihydrotestosterone concentrations between smokers and nonsmokers. These results suggest that smoking decreases the activity of either 21- or 11 beta-hydroxylase in the adrenal cortex, which results in increased secretion of adrenal androgens.
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PMID:Cigarette smoking is associated with elevated adrenal androgen response to adrenocorticotropin. 866 73

The apolipoprotein E genotype and cortical senile plaque (SP) and cortical and hippocampal neurofibrillary tangle (NFT) densities were determined in non-demented individuals and neuropathologically confirmed AD patients. The non-demented population was further subdivided according to presence or absence of pathologically established critical coronary artery disease (cCAD), hypertension (HyperT), or neither (non-heart disease; non-HD). The apolipoprotein E4 (APOE4) allele incidence and dose frequencies were increased in the AD, cCAD and HyperT groups compared to the non-HD controls. The mean number of SP and NFT was significantly increased with the presence of the APOE4 allele within the entire population. After grouping the non-demented subjects according to cardiac status, SP but not NFT density was increased among those individuals with the APOE4 genotype. In HyperT, the increased density of SP also correlated to the APOE4 allele dose frequency. The density of SP and NFT was increased in all regions of AD brain compared to all other non-demented groups, but no significant difference was found between AD patients with or without an APOE4 allele. These two AD groups were age-matched, but could not be matched for disease duration. The data suggest a relationship between heart disease, APOE4 genotype and the presence of SP regardless of cognitive status.
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PMID:Increased density of senile plaques (SP), but not neurofibrillary tangles (NFT), in non-demented individuals with the apolipoprotein E4 allele: comparison to confirmed Alzheimer's disease patients. 879 Dec 46

Fibrinogen is an important risk factor for atherosclerosis, stroke and cardiovascular heart disease (CHD). This risk is increased when associated with a high serum cholesterol. Furthermore, it is also believed that not only fibrinogen concentration, but also the quality of fibrin networks may be an important risk factor for the development of CHD. CHD and stroke as a result of atherosclerosis, plus the related problems of hyperinsulinaemia, hyperlipidaemia and hypertension are strongly related to diet. The "western" diet, defined by low fibre and high fat, sucrose and animal protein intakes, appears to be a major factor leading to death. It has been established that the water-soluble dietary fibre, pectin, significantly decrease the concentration of serum cholesterol levels. Evidence is also accumulating that a diet rich in fibre may protect against diseases associated with raised clotting factors. This investigation studied the possible effects of pectin on fibrinogen levels and fibrin network architecture. Two groups of 10 male hyperlipidaemic volunteers each, received a pectin supplement (15 g/day) or placebo (15 g/day) for 4 weeks. Lipid and fibrin network structure variables were measured at baseline and the end of supplementation. Pectin supplementation caused significant decreases in total cholesterol, low-density lipoprotein cholesterol, apolipoprotein A & B and lipoprotein (a). Significant changes in the characteristics of fibrin networks developed in the plasma of the pectin supplemented group indicated that networks were more permeable and had lower tensile strength. These network structures are believed to be less atherogenic. It is suspected that pectin modified network characteristics by a combination of its effects on metabolism and altered fibrin conversion. This confirms the therapeutic possibilities of dietary intervention. Furthermore, this study also showed that changes in plasma fibrinogen need not be present to induce alterations in fibrin network architecture.
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PMID:Dietary pectin influences fibrin network structure in hypercholesterolaemic subjects. 917 40

Apolipoprotein (apo) E plays an important role in lipid metabolism, and the major isoforms of apoE (apoE2, apoE3, and apoE4) have significantly different metabolic effects. Apolipoprotein E4 is associated with a higher risk of both heart disease and Alzheimer's disease (AD). Patients homozygous for apolipoprotein E2 are predisposed to type III hyperlipoproteinemia, and apoE2 may be protective against AD. Structure/function studies have proved to be a useful tool in understanding how the different apoE isoforms result in different pathological consequences. As these studies continue, it is essential to have a reliable method to produce large quantities of apoE and mutants of apoE. We describe here a method of apoE production in Escherichia coli strain BL21(DE3). The cDNA from apoE isoforms was inserted into a pET32a vector with a T7 promoter and a fusion partner (thioredoxin). The T7 promoter results in high expression of an easily purified His-tagged fusion protein. A thrombin recognition site was positioned in the expression vector so that only two novel amino acids (Gly-Ser) are added to the amino terminus of apoE following the removal of thioredoxin. Approximately 20 mg of apoE is obtained from a 1-liter culture. The major isoforms of apoE produced with this system were extensively characterized for their ability to bind the low-density lipoprotein (LDL) receptor, for their characteristic lipid association preferences, and for their stability as measured by guanidine denaturation. The recombinant proteins behaved identically to plasma-derived apoE isoforms.
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PMID:Functional characterization of apolipoprotein E isoforms overexpressed in Escherichia coli. 1041 18

Altered plasma levels of lipids and lipoproteins, obesity, hypertension, and diabetes are major risk factors for atherosclerotic cardiovascular disease. To identify genes that affect these traits and disorders, we looked for association between markers in candidate genes (apolipoprotein AII (apo AII), apolipoprotein AI-CIII-AIV gene cluster (apo AI-CIII-AIV), apolipoprotein E (apo E), cholesteryl ester transfer protein (CETP), cholesterol 7alpha-hydroxylase (CYP7a), hepatic lipase (HL), and microsomal triglyceride transfer protein (MTP)) and known risk factors (triglycerides (Tg), total cholesterol (TC), apolipoprotein AI (apo AI), apolipoprotein AII (apo AII), apolipoprotein B (apo B), body mass index (BMI), blood pressure (BP), leptin, and fasting blood sugar (FBS) levels.) A total of 1,102 individuals from the Pacific island of Kosrae were genotyped for the following markers: Apo AII/MspI, Apo CIII/SstI, Apo AI/XmnI, Apo E/HhaI, CETP/TaqIB, CYP7a/BsaI, HL/DraI, and MTP/HhpI. After testing for population stratification, family-based association analysis was carried out. Novel associations found were: 1) the apo AII/MspI with apo AI and BP levels, 2) the CYP7a/BsaI with apo AI and BMI levels. We also confirmed the following associations: 1) the apo AII/MspI with Tg level; 2) the apo CIII/SstI with Tg, TC, and apo B levels; 3) the Apo E/HhaI E2, E3, and E4 alleles with TC, apo AI, and apo B levels; and 4) the CETP/TaqIB with apo AI level. We further confirmed the connection between the apo AII gene and Tg level by a nonparametric linkage analysis. We therefore conclude that many of these candidate genes may play a significant role in susceptibility to heart disease.
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PMID:Candidate genes involved in cardiovascular risk factors by a family-based association study on the island of Kosrae, Federated States of Micronesia. 1211 31

Apolipoproteins A-I and A-II form the major protein constituents of high-density lipid particles (HDL), the concentration of which is inversely correlated with the frequency of heart disease in humans. Although the physiological role of apolipoprotein A-II is unclear, evidence for its involvement in free fatty acid metabolism in mice has recently been obtained. Currently, the best characterized activity of apolipoprotein A-II is its potent antagonism of the anti-atherogenic and anti-inflammatory activities of apolipoprotein A-I, probably due to its competition with the latter for lipid acyl side chains in HDL. Many interactions of apolipoprotein A-I with enzymes and proteins involved in reverse cholesterol transport and HDL maturation are mediated by lipid-bound protein. The structural bases of interaction with lipids are expected to be common to exchangeable apolipoproteins and attributable to amphipathic alpha-helices present in each of them. Thus, characterization of apolipoprotein-lipid interactions in any apolipoprotein is likely to provide information that is applicable to the entire class. We report structures of human apolipoprotein A-II and its complex with beta-octyl glucoside, a widely used lipid surrogate. The former shows that disulfide-linked dimers of apolipoprotein A-II form amphipathic alpha-helices which aggregate into tetramers. Dramatic changes, observed in the presence of beta-octyl glucoside, might provide clues to the structural basis for its antagonism of apolipoprotein A-I. Additionally, excursions of individual molecules of apolipoprotein A-II from a common helical architecture in both structures indicate that lipid-bound apolipoproteins are likely to have an ensemble of related conformations. These structures provide the first experimental paradigm for description of apolipoprotein-lipid interactions at the atomic level.
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PMID:Structures of apolipoprotein A-II and a lipid-surrogate complex provide insights into apolipoprotein-lipid interactions. 3040 70

Human apolipoprotein (apo) E exists as one of three major isoforms, E2, E3 or E4. Individuals carrying the epsilon 4 allele have an increased risk of heart disease and premature onset of Alzheimer's disease. To investigate the molecular basis for this phenomenon, the N-terminal domain of apoE3, apoE2 and apoE4 were expressed in bacteria, isolated and employed in lipid binding and stability studies. Far UV circular dichroism spectroscopy in buffer at pH 7 revealed a similar amount of alpha-helix secondary structure for the three isoforms. By contrast, differences were noted in apoE-NT isoform-specific transformation of bilayer vesicles of dimyristoylphosphatidylglycerol (DMPG) into discoidal complexes. ApoE4-NT induced transformation was most rapid, followed by apoE3-NT and apoE2-NT. To determine if differences in the rate of apoE-NT induced DMPG vesicle transformation is due to isoform-specific differences in helix bundle stability, guanidine HCl denaturation studies were conducted. The results revealed that apoE2-NT was the most stable, followed by apoE3-NT and apoE4-NT, establishing an inverse correlation between helix bundle stability and DMPG vesicle transformation rate at pH 7. When the zwitterionic dimyristoylphosphatidylcholine (DMPC) was employed as the model lipid surface, interaction of apoE-NT isoforms with the lipid substrate was slow. However, upon lowering the pH from 7 to 3, a dramatic increase in the rate of DMPC vesicle transformation rate was observed for each isoform. To evaluate if the increased DMPC vesicle transformation rates observed at low pH is due to pH-dependent alterations in helix bundle stability, guanidine HCl denaturation studies were performed. ApoE2-NT and apoE3-NT displayed increased resistance to denaturation as a function of decreasing pH, while apoE4-NT showed no change in stability. Studies with the fluorescent probe, 8-anilino-1-naphthalene sulfonic acid, indicated an increase in apoE hydrophobic surface exposure upon decreasing the pH to 3.0. Taken together, the data indicate that changes in the stability of secondary structure elements in apoE-NT isoforms are not responsible for pH-induced increases in lipid binding activity. It is likely that pH-induced disruption of inter-helical tertiary contacts may promote helix bundle conformational changes that present the hydrophobic interior of the protein to potential lipid surface binding sites.
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PMID:Lipid binding ability of human apolipoprotein E N-terminal domain isoforms: correlation with protein stability? 1264 85


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