Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0242339 (dyslipidemia)
 13,927 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Several large family studies are reviewed to identify results suggesting single gene traits contributing to the occurrence of hypertension in humans. Segregation analysis in families has suggested major gene effects for several highly heritable traits associated with hypertension. These include recessively segregating high sodium-lithium countertransport (major gene H2 = 34%), additively segregating low urinary kallikrein excretion (major gene H2 = 51%), and recessively segregating hyperinsulinemia (major gene H2 = 33%). In some families, hypertension and metabolic abnormalities (dyslipidemia, hyperinsulinemia, and obesity) seem to be related to several candidate genes studied but not conclusively proven (LPL deficiency mutations, dense LDL subfractions, or NIDDM with hyperinsulinemia). More recently, DNA markers have identified genes promoting hypertension. Glucocorticoid-remediable aldosteronism (GRA) promotes a rare but unusual form of hypertension that is unresponsive to ordinary medications but very responsive to glucocorticoid medications. GRA has been found in hypertensive persons with a specific mutation of the 11 beta-hydroxylase gene on chromosome 8q21. Many persons with essential hypertension carry a common "susceptibility gene" at the angiotensinogen locus (chromosome 1q4) identified using linkage studies in siblings, association studies, and in studies of preeclampsia and hypertension in pregnant women. These first two well-established genetic loci promoting human hypertension represent two ends of a broad spectrum. The rare "determinant" gene for GRA by itself seems to produce severe hypertension and early strokes. The angiotensinogen (AGT) "susceptibility" gene is very common (30% of Utah Caucasians) and seems to predispose to hypertension but probably requires other genetic and environmental influences to be fully expressed.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Evidence for single gene contributions to hypertension and lipid disturbances: definition, genetics, and clinical significance. 798 84

Dyslipidemia is a common feature of renal failure. It is primarily caused by delayed catabolism of lipoprotein particles. This is due to decreased activity of the key enzymes of delipidation of lipoprotein particles (LPL, HTGL) and of HDL remodeling (LCAT). In epidemiological studies no correlation has been found in dialysis patients between total lipids and atherosclerotic endpoints and a modest relation, at best, between more sophisticated apolipoprotein indices and vascular disease. Such lack of correlations are presumably explained by malnutrition as a confounding factor. Fascinating new observations in animal studies document that in various models of renal damage, development of glomerulosclerosis is accelerated by hyperlipoproteinemia, either endogenous hyperlipoproteinemia or hyperlipoproteinemia induced by feeding of fat. Conversely, correction of hyperlipoproteinemia mitigates development of glomerulosclerosis. Currently there is no firm evidence that the same is true in humans.
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PMID:[Dyslipoproteinemia: its importance in nephrology]. 814 62

The obese state has been recognized to accentuate the known risk factors for atherosclerotic disease as dyslipidemia, hypertension, glucose intolerance and insulin resistance. Among other risk factors, obesity is characterized by a series of lipid disturbances, such as hypercholesterolemia, high fasting (and postprandial) triglyceride levels, low HDL cholesterol, high apolipoprotein B, high small dense lipoprotein particles and alterations of serum and tissue LPL-activity. Although obesity is associated with such cluster of lipid abnormalities, these factors do not explain the complete process of atherogenesis in the obese subject. Other risk factors belonging to the polymetabolic syndrome-cluster, insulin resistance, hypertension, fibrinogen, add substantial but not full explanation to the atherothrombotic process. Over the last decade, a series of excellent studies have provided the background for a more indepth mechanism of atherosclerosis; the role of lipid peroxidation in particular has been one of the focuses of this current research. There exists a lot of evidence suggesting a major role for oxidized LDL and VLDL particles in the pathogenesis of atherosclerosis. Although obesity is characterized by dyslipidemia, less is known about the oxidation capacity of lipoproteins in obese subjects. We measured the oxidizability in vitro in 21 premenopausal women and compared them to 18 age-matched controls. The oxidizability of the non-HDL fraction is evaluated by measuring the fluorescence and thiobarbituric acid reactive substances (TBARS: MDA nM/mg non-HDL) at different time intervals of incubation. TBARS formation increased linearly with the increase of lipids both in non-obese and obese subjects.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Human obesity: from lipid abnormalities to lipid oxidation. 858 Oct 73

Familial combined hyperlipidemia, (FCHL) and dyslipidemia occurring in insulin resistant syndrome (IRS) share similar lipid abnormalities. Additionally insulin resistance is frequent in families affected by FCHL. The genetics of FCHL, an oligogenic disorder influenced by environmental factors is not established. Many genes that modulate dyslipidemia such as, LPL, apo E, the cluster A I-C III-A IV, have been identified. However the major gene which determines hypertriglyceridemia remains unknown. The community between HCF and insulin resistance syndrome might have:--either a metabolic origin: the increase in FFA which is a characteristic of IRS, capable to stimulate the hepatic production of triglycerides;--and/or a common genetic mechanism involving the alteration of many genes implied in the control of lipoprotein metabolism and insulin sensitivity.
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PMID:[Genetic factors in familial combined hyperlipidemia and insulin resistance syndrome associated with dyslipidemia]. 943 76

Heterozygous lipoprotein lipase deficiency (LPL+/-) is common and has been implicated in premature atherosclerosis in epidemiologic studies. However, in vitro data suggest that LPL deficiency in the vascular wall may be antiatherogenic. To address the role of LPL in atherosclerosis, LPL+/- mice in the C57BL/6J background were fed an atherogenic diet for 8 months. LPL+/- mice were more dyslipidemic than +/+ animals due to increased concentrations of non-HDL lipoproteins. There was no difference in aortic origin atherosclerosis between LPL+/- (n=56) and +/+ (n=55) mice. LPL+/- mice in the low density lipoprotein receptor knockout (LDLR-/-) background were fed the same atherogenic diet for 3 months. LPL+/-LDLR-/- mice were more dyslipidemic than LPL+/+LDLR-/- animals. There was no difference in atherosclerosis assayed for the entire aorta and no difference in aortic sterol content between LPL+/-LDLR-/- (n=28) and LPL+/+LDLR-/- (n=15) mice. LPL protein was detected in murine lesions in a consistent layered pattern. More luminal, lipid-laden macrophages generally did not stain for LPL, but deeper, lipid-poor macrophages as well as necrotic core regions contained immunoreactive LPL. LPL protein was more abundant in lesions from LPL+/+ LDLR-/- than LPL+/-LDLR-/- mice. After eating an atherogenic diet, LPL+/- as compared to LPL+/+ mice have more dyslipidemia, but no more atherosclerosis, and less LPL protein in atherosclerotic lesions. These data suggest that lipoprotein lipase deficiency in the vascular wall could prevent the retention of atherogenic lipoproteins.
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PMID:Effects of heterozygous lipoprotein lipase deficiency on diet-induced atherosclerosis in mice. 964 45

Familial hypertriglyceridemia has been suggested to be an autosomal dominant condition with age-dependent penetrance, but so far the underlying defective gene has not been elucidated. LPL gene and apolipoprotein A-I/C-III/A-IV gene cluster might be involved in familial clustering of hypertriglyceridemia. Heterozygous LPL deficiencies caused by several types of gene mutation are known to result in a partial defect in catabolism of VLDL, occurring mild to moderate hypertriglyceridemia. However, although the mutation of LPL gene results in reduced lipolytic activity, this type of dyslipidemia appears to manifest only if VLDL-TG production is also increased. These suggest that overproduction of VLDL-TG is a more important cause of hypertriglyceridemia than is the LPL deficiency. Moreover, families with a clustering of hypertriglyceridemia are known to be at increased risk of hyperinsulinemia due to impaired insulin sensitivity. Impaired insulin sensitivity and hyperinsulinemia are the major determinants of excessive VLDL-TG synthesis and dyslipidemia. Taken together, abnormally high production of VLDL-TG seemed to be the major factor in causing familial hypertriglyceridemia, but clearance capacity can play an important role in determining the severity of the TG elevation.
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PMID:[Primary hypertriglyceridemia]. 1063 13

Protease inhibitor-based highly active antiretroviral therapy (PI-HAART) has been implicated in dyslipidemia, peripheral insulin resistance, and abnormal adipose tissue deposition in human immunodeficiency virus (HIV) and acquired immunodeficiency syndrome, or AIDS. In vitro evidence indicates that some PIs reduce adipocyte lipoprotein (LPL) and hepatic lipase (HL) expression and activities. We examined whether LPL and HL activities are reduced in HIV-infected patients with dyslipidemia. Fasting serum lipids, glucoregulatory hormones, and postheparin LPL and HL activities, as well as whole body and regional adiposity, were measured in 19 HIV-seronegative controls, 9 HIV+ patients naive to all anti-HIV medications, 9 HIV+ patients naive to PIs, 9 HIV+ patients with prior PI experience but not currently receiving PIs, and 47 HIV+ patients receiving PI-HAART. The PI-HAART group had low LPL and HL activities. However, multiple linear regression analysis indicated that low postheparin LPL activity contributed only partially to HIV-dyslipidemia. Central adiposity and high C-peptide levels (an indicator of high insulin secretion) were stronger predictors of HIV-dyslipidemia. Low LPL and HL activities, by themselves, were insufficient to explain HIV-dyslipidemia because the PI-naive group had low LPL and HL activities but had normal adiposity, C-peptide levels, and serum lipid and lipoprotein levels. HDL-cholesterol was lower in PI-HAART and PI-naive groups than seronegative controls and was directly associated with LPL activity. These findings suggest that HIV-dyslipidemia is mediated primarily by factors that influence triglyceride and lipoprotein synthesis (e.g., central adiposity and hyperinsulinemia) and mediated only partially by factors that influence triglyceride clearance (e.g., lipase activity).
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PMID:Visceral adiposity, C-peptide levels, and low lipase activities predict HIV-dyslipidemia. 1283 64

Dyslipidaemia is common in patients with Type 2 diabetes and is held to be responsible for considerable CVD-related morbidity and mortality. Patients with Type 2 diabetes are at high risk from complications associated with atherosclerosis and should therefore receive preventive interventions. At the level of the adipocyte, impaired insulin action leads to increased rates of intracellular hydrolysis of triglycerides with the release of NEFA. The rise in NEFA provides substrate for the liver that, in the presence of impaired insulin action and relative insulin deficiency, is associated with complex alterations in plasma lipids: * Plasma VLDL levels are raised. (i). Increased VLDL levels are associated with post-prandial hyperlipidaemia that is compounded by impaired LPL activity. The latter may be independently associated with CAD. (ii). Remnant particles can deliver more cholesterol to macrophages than LDL-C particles. Thrombogenic alterations in the coagulation system also ensue from hypertriglyceridaemia. * Plasma HDL-C levels are reduced. (i). The reduction in cardioprotective HDL-C means a reduction of cholesterol efflux from the tissues--the first step in reverse cholesterol transport to the liver from peripheral tissues. (ii). The antioxidant and antiatherogenic activities of HDL-C are reduced when circulating levels are low. * LDL-C particles become small and dense. Small, dense LDL-C particles are held to be more atherogenic than their larger, buoyant counterparts because they (a) are more liable to oxidation and (b) may more readily adhere to and subsequently invade the arterial wall. The atherogenicity of LDL-C may also be enhanced by nonenzymatic glycation. Metabolic and lipid abnormalities can often be improved with lifestyle changes, including dietary modification, weight loss, smoking cessation and increased exercise. Although attainment of better glycaemic control may improve diabetic dyslipidaemia, pharmacological intervention is usually required. Several large-scale clinical trials, including 4S and more recently HPS, have clearly demonstrated the benefits of statins in reducing cardiovascular events. By virtue of their high absolute risk of CVD, many patients with Type 2 diabetes may achieve a greater risk reduction than their non-diabetic counterparts. For example, in 4S there was a 43% reduction in total mortality risk among patients with diabetes compared with 29% for non-diabetics and a reduced risk of MI by 55% vs. 32% for diabetic and non-diabetics, respectively. In the diabetic subgroup in HPS, there were reductions of approximately 25-30% in the risk of first major vascular events. More recently, the lipid-lowering arm of the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) was halted early because of a significant reduction in cardiovascular events compared with placebo. Surprisingly an analysis of subgroups failed to show significance among the diabetic population, although the sample size, shortened follow-up period and higher drop-in statin use among diabetics on placebo may have affected results. The Collaborative Atorvastatin Diabetes Study (CARDS), involving 2800 patients with Type 2 diabetes, was halted 2 years early in June 2003 because patients allocated atorvastatin had significant reductions in MI, stroke and surgical procedures compared with those receiving placebo. The UKPDS demonstrated that the appearance and progression of certain microvascular complications of Type 2 diabetes could be reduced by treatment directed at hyperglycaemia and hypertension. In addition, correction of dyslipidaemia in patients with diabetes is important in reducing the high toll from macrovascular disease. The subjects in the HPS had similar lipid profiles to the participants in UKPDS, suggesting that additional benefit would accrue from a therapeutic assault on the main cardiovascular risk factors simultaneously. We now have firm evidence that appropriate use of statins in patients with Type 2 diabetes can significantly reduce cardiovascular morbidity and mortality.
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PMID:Lipoprotein abnormalities and their consequences for patients with type 2 diabetes. 1498 18

Familial combined hyperlipidemia (FCHL) is the most common familial dyslipidemia, with a prevalence of 1-2% in the general population. A major locus for FCHL has been mapped to chromosome 1q21-q23 in Finnish, Chinese, German and US families. We studied seven extended Mexican families with 153 members, including 64 affected subjects. A total of 11 markers were genotyped, including D1S104 which has been linked to FCHL in other studies. Two point linkage analysis for the FCHL phenotype, and for the elevated triglyceride (TG) trait, allowing for heterogeneity, gave a maximum HLOD of 1.67 (alpha = 0.49) and 1.93 (alpha = 0.43) at D1S2768 (2.69 cM proximal to D1S104) respectively. Heterogeneity and non-parametric (NPL) multipoint analyses for the FCHL phenotype and the TG trait showed maximum HLODs of 1.27 (alpha = 0.46) and 1.64 (alpha = 0.38), and NPLs of 4.00 (P = 0.0001) and 3.68 (P = 0.0003) near D1S2768, respectively. In addition, analysis of four candidate genes putatively involved in the expression of FCHL showed no evidence of linkage for the LCAT gene or the APOA1/C3/A4/A5 gene cluster. However, we cannot exclude the participation of these genes, or the LIPC and LPL genes, as minor susceptibility loci in the expression of FCHL, or the TG or elevated total cholesterol (TC) traits in our families. In conclusion, our data confirm the involvement of a major susceptibility locus on chromosome 1q21-q23 in FCHL Mexican families, consistent with findings in other populations.
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PMID:Contribution of chromosome 1q21-q23 to familial combined hyperlipidemia in Mexican families. 1546 19

Lipoprotein lipase, HL, and endothelial lipase (EL) are proteoglycan-bound enzymes that regulate plasma lipoprotein levels through coordinated triglyceride (TG) lipase and phospholipase activity. We hypothesized that single nucleotide polymorphisms (SNPs) in lipase genes would have higher order impact on plasma lipoproteins beyond the influence of individual SNPs. In a sample of asymptomatic Caucasian subjects (n = 738), we used a two-stage approach, first identifying groups of subjects with similar multilocus lipase genotypes and then characterizing the relationships between genotype groups and plasma lipids. Using complementary methods, including a permutation test procedure and a mixed-effects modeling approach, we found a higher order interaction between four SNPs in three lipase genes (EL 2,237 3' untranslated region, EL Thr111Ile, HL -514C/T, and LPL HindIII) and plasma TG levels. Subjects who were heterozygous for all four lipase SNPs had significantly higher plasma TG levels beyond the effect of individual lipase SNPs and environmental factors, even after correcting for multiple comparisons. In conclusion, lipase genes had synergistic association with plasma TG beyond individual gene effects. Higher order multilocus genotype contributions to dyslipidemia and atherosclerotic cardiovascular disease need to be considered a priori because they may have an important effect even in the absence of significant main effects of the individual genes.
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PMID:Higher order lipase gene association with plasma triglycerides. 1596 89


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