Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A preponderance of dense low density lipoprotein (LDL) particles is associated with an increased risk of coronary heart disease. It has been shown that dense LDL levels can be modified by diet. We investigated the contribution of polymorphisms in the genes for apolipoprotein (apo) B, apo AIV, lipoprotein lipase (LPL) and cholesterol ester transfer protein (CETP) to variation in the changes in plasma concentrations of dense LDL between a high saturated and a high polyunsaturated fatty acid diet. A total of 46 freeliving individuals (19 men and 27 women) completed a crossover trial with two dietary interventions of 4 weeks each, a high saturated fat diet (providing 21% energy from saturated fat and 3% energy from polyunsaturated fat) and a high polyunsaturated fat diet (providing 11% energy as saturated fat and 10% energy as polyunsaturated fat). Overall, the change in dense LDL between the saturated and polyunsaturated fat period was 0.17+/-0.33 mmol/L and this change was similar in men and women. Of the polymorphisms studied only variation in the apo AIV gene causing the substitution of histidine for glutamine at position 360 (Q360H) was associated with significant differences in the change in dense LDL concentration. Apo AIV Q/H individuals (n=6) showed a three-fold greater change in dense LDL cholesterol unadjusted for Lp(a) levels than Q/Q individuals (0.46+/-0.27 versus 0.12+/-0.31 mmol/L, p=0.02). The greater decrease in dense LDL cholesterol with an increase in polyunsaturated fat seen in those with the apo AIV H360 variant, who represent roughly 10% of the general population, suggests that they may benefit most from a PUFA rich lipid lowering diet.
Atherosclerosis 2000 Apr
PMID:Genetic factors associated with response of LDL subfractions to change in the nature of dietary fat. 1072 89

Familial defective apolipoprotein B-100 (FDB) is a genetic disorder caused by a substitution of glutamine for arginine at residue 3500 of the apolipoprotein B-100 molecule. We have identified 23 heterozygotes and one homozygote for FDB (frequency 1:20) in a group of 510 patients with hypercholesterolemia. Mean age of the patients (18 females and 6 males) was 46 years. The diagnosis of FDB was based on point mutation PCR analysis of exon 26 of the apo B gene. Plasma lipids in heterozygous patients were: total cholesterol 8.76+/-1.2 mmol/l, triglycerides 1.42+/-0.5 mmol/l, HDL-cholesterol 1.43+/-0.3 mmol/l, LDL-cholesterol 6.69+/-1.2 mmol/l, apoB 1.69+/-0.4 g/l, Lp(a) 0.26+/-0.2 g/l. The most frequent apoE genotype was 3/3 (19 patients), apoE 3/4 genotype was found in 3 patients and one person had apoE 2/3. Xanthelasma palpebrarum was present in 4 patients and tendon xanthomas in 3 patients including the homozygote. Premature manifestation of coronary heart disease was revealed in 3 patients. Sixteen patients were treated with statins, a combination of statin and resin was used in 2 patients (including the homozygote), whereas six patients were treated with the diet only. We conclude that although the plasma lipid levels of total and LDL cholesterol in FDB patients are lower than in patients with familial hypercholesterolemia, the patients with FDB suffer from premature atherosclerosis. The therapeutic approach to FDB individuals and patients with familial hypercholesterolemia is very similar.
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PMID:Familial defective apolipoprotein B-100: a lesson from homozygous and heterozygous patients. 1098 82

Focal segmental glomerulosclerosis (FSGS) is an important cause of end-stage renal failure (ESRF) in children. Our previous studies have shown that Arab children in Israel have a worse prognosis compared with Jewish patients despite similar clinical presentation and management. Progression of proteinuric glomerular diseases has been associated with alterations in lipid metabolism, and similarities have been drawn between the mechanisms underlying atherosclerosis and glomerulosclerosis. Paraoxonase (PON) is a high-density lipoprotein (HDL)-associated enzyme involved in preventing the oxidation of low-density lipoprotein (LDL), and an association has been shown between two genetic polymorphisms in PON1 and the risk of coronary artery disease. The aim of this study was to determine the frequency of these genetic polymorphisms in PON1 in Arab and Jewish children with FSGS and to determine any association with severity of outcome. Forty-seven children (21 Arab and 26 Jewish) with biopsy-proven FSGS and 274 healthy controls of matching ethnic origin were studied. The glutamine (A)-192-arginine (B) and the methionine (M)-55-leucine (L) polymorphisms were analyzed. The frequency of the A allele was similar in patients and controls (0.68 versus 0.71), as was that of the L allele (0.63 versus 0.6). When subgroups were analyzed, the prevalence of the LL genotype in Arab patients was significantly greater than in Jewish patients (57.1% versus 26.9%, P: < 0.05) and Arab controls (57.1% versus 28.9%, P: < 0.03). A trend in association was found between homozygosity for the L allele and progression of renal disease in Arab children. Homozygosity for the L allele is a risk factor for developing FSGS in Arab children and may be associated with a worse prognosis.
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PMID:Genetic polymorphism in paraoxonase is a risk factor for childhood focal segmental glomerulosclerosis. 1109 50

Paraoxonase is an enzyme associated with the high-density lipoprotein (HDL) particle. It catalyses the hydrolysis of organophosphates and protects LDL from oxidative modification in vitro by hydrolyzing lipid peroxides, suggestive of a role for paraoxonase in the development of atherosclerosis. Two frequent mutations at the paraoxonase gene locus (PON1) underlie the leucine (Leu allele) --> methionine (Met allele) and the glutamine(Gln allele) --> arginine(Arg allele) aminoacid substitutions at residues 55 and 192, respectively. These polymorphisms have been associated with increased risk for cardiovascular disease (CVD) in several studies, while others have not found this association. Recently, another member of the PON gene family designated PON2 has been identified. While the PON2 gene product is expressed ubiquitously, its physiological role is unknown. A common polymorphism at codon 311 (Cys-->Ser) in the PON2 gene has been described. In our study we assessed the frequency and genotype distribution of the PON1 and PON2 polymorphisms in 197 patients with familial hypercholesterolemia (FH), to determine the possible association between these mutations and susceptibility for CVD. The FH cohort group was divided into subjects with (n=83) and without (n=114) definite clinical manifestations of CVD (FH-Symptomatic and FH-Asymptomatic respectively). The control population consisted of 201 healthy normolipidemic blood donors. All subjects in this study were of Caucasian background. Genotypes were identified by PCR based analysis. With regard to the PON1 polymorphisms 55 and 192, no different distributions of allele frequencies were found between the groups studied. However, we did show an association between the PON2 311 polymorphism and CVD. The frequencies of PON2 Ser311 carriers (Ser/Ser and Cys/Ser) between FH-Symptomatic and both FH-Asymptomatic and controls did show a significant difference (P=0.01 and P=0.02 respectively). In the FH-Symptomatic population, surprisingly, no subjects were homozygous for PON2 Cys311, whereas in the FH-Asymptomatic population nine persons (7.9%) and in the control group 12 persons (6.0%) were homozygous. Our data indicate that the common PON2 polymorphism is associated with clinical manifestations of CVD in FH patients. While PON2 Ser311 carriers seem to be at risk, subjects with the Cys/Cys311 genotype are likely to be protected against the development of premature CVD.
Atherosclerosis 2001 Feb 15
PMID:PON2 gene variants are associated with clinical manifestations of cardiovascular disease in familial hypercholesterolemia patients. 1125 65

Paraoxonase 1 (PON1) is an HDL-associated enzyme which protects HDL and LDL particles from lipid peroxidation. Its enzymatic serum activity varies 10-40-fold between individuals, and its biallelic gene polymorphism at codon 192 (glutamine-->arginine, Gln/Arg) has been associated with coronary artery disease in diabetic patients. To evaluate the role of this PON1 gene polymorphism in cerebrovascular disease, we determined the PON1 192 genotype in 149 patients with hemodynamically relevant extracranial artery stenosis and in 241 controls. The PON1 192 Gln/Arg genotype was determined using polymerase chain reaction followed by Alw I digestion and polyacrylamide gel electrophoresis. Among all subjects, there was no association between the PON1 192 Gln/Arg genotype and cerebrovascular disease (Odds ratio for Arg/Arg and Gln/Arg vs Gln/Gln 0.99, 95%-CI 0.70-1.39). In contrast, in the subgroup of type 2 diabetic patients the PON1 192 Arg allele conferred about twice the risk of cerebrovascular stenosis compared to those homozygous for the Gln allele (Odds ratio 2.00, 95%-CI 0.92-4.38). Our data indicate that in the general population the PON1 192 Gln/Arg gene polymorphism cannot be regarded as a major risk marker for cerebrovascular disease. The observed interaction with type 2 diabetes, however, is supporting the hypothesis that the effect of the PON1 192 Arg allele on atherosclerosis is modulated by other risk factors like diabetes.
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PMID:Paraoxonase 1 192 Gln/Arg gene polymorphism and cerebrovascular disease: interaction with type 2 diabetes. 1140 95

Hyperhomocysteinemia is an independent risk factor for atherosclerosis and vascular occlusive diseases. Measurements of total homocysteine (Hcy) require an accurate reproducible method. A high-performance liquid chromatographic (HPCL) method for evaluating plasma Hcy after reduction with 2-mercaptoethanol and precolumn derivatization with iodoacetic acid and o-phthaldialdehyde is described. The resultant derivatives were separated on reverse-phase column C18 in the isocratic HPCL mode with fluorimetric detection. The detection limit for Hcy is 0.8 mumol/liter. The concentration of Hcy after overnight fasting was increased significantly (p < 0.02) in the patients in comparison with the control (11.7 +/- 1.1 vs. 8.3 +/- 0.5 mumol/liter). The method can be used for measuring the concentrations of asparaginic acid, glutamic acid, cysteine, asparagine, serine, and glutamine.
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PMID:[Measurement of blood homocysteine by high performance liquid chromatography (HPLC)]. 1150 83

Urokinase plasminogen activator (uPA) has been implicated in the healing responses of injured arteries, but the importance of its various properties that influence smooth muscle cell (SMC) proliferation and migration in vivo is unclear. We used three recombinant (r-) forms of uPA, which differ markedly in their proteolytic activities and abilities to bind to the uPA receptor (uPAR), to determine, which property most influences the healing responses of balloon catheter injured rat carotid arteries. After injury, uPA and uPAR expression increased markedly throughout the period when medial SMCs were rapidly proliferating and migrating to form the neointima. Perivascular application of uPA neutralizing antibodies immediately after injury attenuated the healing response, significantly reducing neointima size and neointimal SMC numbers. Perivascular application of r-uPAwt (wild type uPA) or r-uPA/GDF (r-uPA with multiple mutations in its growth factor-like domain) doubled the size of the neointima. Four days after injury these two uPAs nearly doubled neointimal and medial SMC numbers in the vessels, and induced greater reductions in lumen size than injury alone. Proteolytically inactive r-uPA/H/Q (containing glutamine rather than histidine-204 in its catalytic site) did not affect neointima or lumen size. Also, in contrast to the actions of proteolytically active uPAs, tissue plasminogen activator (tPA) did not affect the rate of neointima development. We conclude that uPA is an important factor regulating the healing responses of balloon catheter injured arteries, and its proteolytic property, which cannot be mimicked by tPA, greatly influences SMC proliferation and early neointima formation.
Atherosclerosis 2001 Dec
PMID:Urokinase plasminogen activator augments cell proliferation and neointima formation in injured arteries via proteolytic mechanisms. 1173 Aug 9

Hepatic very-low-density lipoprotein particles (VLDL) containing full-length apolipoprotein B100 are metabolized in the blood stream to low-density lipoprotein (LDL) particles, whose elevated levels increase the risk of atherosclerosis. Statins and bile-acid sequestrants are effective LDL-lowering therapies for many patients. Development of alternative therapies remains important for patients with adverse reactions to conventional therapy, with defects in the LDL receptor-dependent lipoprotein uptake pathway and for intervention in children. Editing of apoB mRNA by the enzyme APOBEC-1 changes a glutamine codon to a stop codon, leading to the synthesis and secretion of apoB48-containing VLDL, which are rapidly cleared before they can be metabolized to LDL. Human liver does not edit apoB mRNA because it does not express APOBEC-1. Although initially promising, enthusiasm for apobec-1 gene therapy for hypercholesterolemia was blunted by the finding that uncontrolled transgenic expression of APOBEC-1 led to nonspecific editing of mRNAs and pathology. We demonstrate that APOBEC-1 fused to TAT entered primary hepatocytes, where it induced a transient increase in mRNA editing activity and enhanced synthesis and secretion of VLDL containing apoB48. Protein transduction of APOBEC-1 transiently stimulated high levels of apoB mRNA editing in a dose-dependent manner without loss of fidelity. These results suggested that apoB mRNA editing should be re-evaluated as a LDL-lowering therapeutic target in the new context of protein transduction therapy.
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PMID:Apolipoprotein B mRNA editing and the reduction in synthesis and secretion of the atherogenic risk factor, apolipoprotein B100 can be effectively targeted through TAT-mediated protein transduction. 1180 50

Several in vitro investigations showed that serum paraoxonase 1 (PON1) that is located on high-density lipoprotein reduces or prevents low-density lipoprotein (LDL) oxidation and therefore retards atherosclerosis. Accordingly, the well documented loss of PON1 activity in patients with overt diabetes mellitus was causally related to the development of micro- and macroangiopathy in the disease course. Because vascular complications start already in prediabetic states, e.g. impaired glucose tolerance (IGT), we investigated serum PON1 activities and circulating levels of oxidized LDL (oxLDL) in 125 IGT subjects, 75 patients with newly diagnosed diabetes mellitus type 2, and 403 individuals with normal glucose tolerance. Using three different substrates (paraoxon, phenylacetate, p-nitrophenylacetate) we found that PON1 activity is not significantly altered in IGT and diabetes mellitus subjects, respectively, when compared with normoglycemic controls. Both IGT subjects and diabetes mellitus patients had significantly increased levels of oxLDL in the circulation. However, serum PON1 activity variations and glutamine/arginine phenotype were not related to the levels of oxLDL. The data suggest that 1) PON1 activity loss is an event occurring later in the course of diabetes mellitus; and 2) PON1 does not affect oxidation of circulating LDL, at least in early diabetes mellitus.
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PMID:Lack of association between serum paraoxonase 1 activities and increased oxidized low-density lipoprotein levels in impaired glucose tolerance and newly diagnosed diabetes mellitus. 1267 62

The effect of a common apolipoprotein (apo) A-IV polymorphism (substitution of histidine for glutamine at position 360) on plasma lipid, lipoprotein cholesterol and lipoprotein(a) (Lp(a)) levels, and on low-density lipoprotein (LDL) particle size was examined by genotyping in 2322 Caucasian men and women (mean age: 48.9+/-10.1 years) participating in the Framingham Offspring Study (FOS). The relative frequencies of the apo A-IV-Gln (apo A-IV-1) and the apo A-IV-His (apo A-IV-2) alleles were 0.932 and 0.068, respectively, and were in Hardy-Weinberg equilibrium. No effect of the apo A-IV-2 genotype was observed on plasma triglyceride, total and lipoprotein cholesterol, and LDL particle size in either men or women after adjustment for age and body mass index. To avoid a possible interaction between the apo E genotype and the apo A-IV genotype, subgroup analyses were undertaken in 1,414 male and female subjects with the apo E3/3 genotype. Among women in this group there was a significant effect of the apo A-IV-2 allele on triglyceride levels (p=0.046). This effect was no longer significant after adjustment for age and BMI (p=0.074). No significant allele effect on other lipoprotein levels, including Lp(a), was noted in apo E3/3 men or women. We have also conducted a meta-analysis of our own data and of other studies found in the literature, indicating a significant lowering effect of apo A-IV-2 on plasma triglycerides, but no effects on other parameters. In conclusion, the apo A-IV-2 allele is associated with a modest reduction in plasma triglyceride levels in the general population.
Atherosclerosis 2005 Mar
PMID:Association of apo A-IV 360 (Gln --> His) polymorphism with plasma lipids and lipoproteins: the Framingham Offspring Study. 1572 Oct 24


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