Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0020473 (hyperlipidemia)
 15,891 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Familial hypercholesterolemia is an inherited disease in humans that is associated with coronary artery disease and is caused by a deficiency of the receptor that mediates the internalization of low density lipoprotein (LDL). We have used an animal model for familial hypercholesterolemia, the Watanabe heritable hyperlipidemic (WHHL) rabbit, to design a therapeutic approach for this disease, which attempts to correct the hepatic defect in LDL receptor expression. Hepatocytes were harvested from WHHL rabbits, plated in primary cultures, and exposed to recombinant retroviruses capable of efficiently transferring a functional human LDL receptor gene. Genetically modified cells were harvested and infused into the portal vein of WHHL recipients, who were analyzed for metabolic consequences of human LDL receptor expression. Each animal exhibited a statistically significant decrease in total serum cholesterol 2-6 days after transplantation, with an eventual return to pretreatment levels. Proviral DNA sequences and virus-directed transcripts were detected in liver tissue 24 hr after transplantation. In situ hybridization demonstrated provirus expression in a small population of hepatocytes distributed in periportal sections of the liver. This study illustrates the potential of somatic gene therapy in ameliorating hyperlipidemia associated with familial hypercholesterolemia.
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PMID:Temporary amelioration of hyperlipidemia in low density lipoprotein receptor-deficient rabbits transplanted with genetically modified hepatocytes. 223 51

Hyperlipidemia and hypertension are risk factors for cardiovascular diseases. To obtain insight into intracellular mechanisms underlying these phenomenon, the influence of low density lipoprotein (LDL) on the intracellular free calcium concentration, the intracellular pH, the calcium influx as well as proliferation rate of cultured vascular smooth muscle cells was studied. 1-15 micrograms/ml of LDL increased dose-dependently the concentration of intracellular free calcium and led to biphasic pH-shifts. 3-7 micrograms/ml of LDL augmented thymidine incorporation into cell DNA by 70% and enhanced calcium influx by 80%. LDL (1-15 micrograms/ml) clearly increased contractile response of aortic rings. The findings indicate that low concentrations of LDL may contribute to the pathogenesis of cardiovascular diseases by enhancing cell proliferation and vasoconstriction via changing intracellular calcium and intracellular pH.
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PMID:Induction of cell proliferation and vasoconstriction by low density lipoprotein. 234 38

Hyperlipidemia and hypertension play important roles in the pathogenesis of atherosclerosis. To investigate the underlying intracellular mechanisms, we studied the effect of various concentrations of low density lipoprotein from normolipidemic subjects on concentrations of free intracellular calcium, intracellular pH, DNA synthesis, and vascular tone in vascular smooth muscle cells and rings from rat aortas. Low density lipoprotein in the range of 1-15 micrograms/ml induced a dose-dependent increase of concentration of free intracellular calcium and a biphasic change of the intracellular pH. Similar concentrations of low density lipoprotein led to an enhanced DNA synthesis. Furthermore, cumulative addition of 1-15 micrograms/ml low density lipoprotein produced a dose-dependent increase in contractile tension of thoracic aortic rings from rats. The maximal low density lipoprotein-induced contractile response was approximately 70% of that induced by 40 mM KCl. These findings indicate that low concentrations of low density lipoprotein occurring, for example, in the extravascular fluid might contribute to the pathogenesis of cardiovascular diseases by enhancing cell proliferation and vasoconstriction by changing intracellular calcium and intracellular pH.
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PMID:Novel cellular activities for low density lipoprotein in vascular smooth muscle cells. 235 25

In the United Kingdom, about 5% of patients with familial hypercholesterolemia (FH) have a detectable deletion or rearrangement of part of the LDL-receptor gene, which results in the detection of shorter or abnormally sized fragments of the LDL-receptor gene in a Southern blot hybridization. This gene deletion can be used for following the inheritance of the defective gene and for diagnosis in the families of these individuals. In the families of the remaining patients, diagnosis may be possible using linked restriction fragment length polymorphisms (RFLPs) detected with the LDL-receptor probe. There are now 10 common RFLPs of the LDL-receptor gene, with variable sites in the 3' half of the gene. Over 80% of patients are heterozygous for at least one of these RFLPs, and, therefore, RFLPs are potentially informative for DNA diagnosis. For a fetus at risk of homozygous FH, antenatal diagnosis may also be possible using these methods. However, family studies require samples to be available from affected or unaffected relatives of the patient, and this limits the applicability of the tests. For some mutations, the base-pair change causing the defect in the LDL receptor itself creates or destroys a site for a restriction enzyme. Such "mutation-specific" RFLPs could be used for population screening, but, so far, such use has only been reported for the FH mutation common in Lebanon. In the future, it may be possible to develop mutation-specific oligonucleotide probes for the diagnosis of FH. These would be appropriate for screening populations or patients with hyperlipidemia. This information may also be useful if different mutations require different therapeutic strategies.
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PMID:Gene probes in diagnosis of familial hypercholesterolemia. 256 21

Two patients with marked elevation of plasma and very low density lipoprotein (VLDL) lipids were investigated to establish the molecular basis of their hyperlipidaemia. In one the demonstration of the apolipoprotein E 2/2 phenotype substantiated the diagnosis of type III hyperlipidaemia. In the other the E4/3 phenotype excluded this diagnosis. In both cases oligonucleotide probing of amplified DNA and isoelectric focusing (IEF) of apo VLDL identified the correct apolipoprotein E phenotype as defined by peptide mapping and IEF of purified apolipoprotein E after modification with iodoacetic acid. Probing of amplified DNA clearly distinguishes the three common variants of apolipoprotein E (E2, E3, E4) and facilitates the diagnosis of type III hyperlipidaemia.
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PMID:Apolipoprotein E variation in patients with hyperlipidaemia: DNA and protein phenotyping. 234 20

We report a common DNA polymorphism of the apolipoprotein E (apoE) gene detected with the enzyme HpaI. In an individual who is heterozygous for the polymorphism, two hybridising fragments of DNA, one of 50 kb (the H1 allele) and one of 20 kb (the H2 allele) are detected. In 54 controls the frequency of the rare allele is 0.38 (PIC value 0.36). We have also studied the frequency of the polymorphism in normolipidaemic and hyperlipidaemic individuals whose apo E protein typing is known. In 39 individuals with type III hyperlipidaemia and the apo E phenotype E2E2, the frequency of the H2 allele is 0.97. In contrast, the frequency of the H2 allele in normolipidaemic individuals with the E2E2 phenotype is closer to that found in the general population. Possible explanations for this are discussed.
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PMID:A common restriction fragment length polymorphism of the human apolipoprotein E gene and its relationship to type III hyperlipidaemia. 288 78

We have studied the frequency of DNA polymorphisms in and around the apolipoprotein A-1 (Apo-A1) and apolipoprotein CIII (Apo-CIII) gene loci in 53 persons of Caucasian descent with genetic hyperlipidemias. Three restriction-fragment-length polymorphisms (RFLPs) have previously been located 5' and 3' to the Apo-A1 gene and in the Apo-CIII gene and were detected after digestion with XmnI, PstI, and SstI, respectively, and hybridization with a 2.2-kb fragment of the Apo-A1 gene. These RFLPs are in linkage equilibrium. The rare variant sites for XmnI (X2) and SstI (S2) were more frequent in familial combined hyperlipidemia (FCH) than in controls and persons with other genetic hyperlipidemias. When considered as a haplotype, this difference was significant (P less than .03). The findings in this study suggest that the previously reported association between S2 and hypertriglyceridemia may be accounted for, in part, by inclusion of numerous patients with FCH. Our data provide further evidence that these RFLPs around and within the Apo-A1/Apo-CIII genes do not participate in unmasking clinical expression in persons with familial dysbetalipoproteinemia.
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PMID:DNA polymorphisms in and around the Apo-A1-CIII genes and genetic hyperlipidemias. 288 93

A variety of DNA markers for apolipoprotein genes were examined among patients with angiocardiographically proven heart disease and among a variety of normal individuals with various lipid values. An increased frequency of an apoAI-CIII SstI RFLP and an apoB minisatellite (allele 5) was found among patients with CHD. Higher levels of cholesterol were found among carriers of the rare apoB TaqI and the common apoCII TaqI variants, whereas higher levels of triglycerides were found in carriers of the common apoAII MspI and the rare apoB XbaI variants. Lower levels of HDL were found among carriers of the common apoAII MspI and the rare apoB PvuII variants. The biological significance of these results and those of other investigators for the pathogenesis of CHD and hyperlipidemia is suggestive but not yet fully clarified. Additional genetic epidemiologic studies and family investigations will be required. Currently used statistical methodology may lead to false inferences regarding the genetic equilibrium or disequilibrium status of closely linked DNA variants. Conclusions regarding the presence of genetic equilibrium if closely linked flanking markers are in disequilibrium may be faulty.
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PMID:Molecular genetics of apolipoproteins and coronary heart disease. 288 66

The 3' end of the apo B gene is highly polymorphic. Two point mutations in the coding sequence of the gene create EcoRI (E+, E-) and XbaI (X+, X-) RFLPs. The two loci are in random association and the frequency of the four haplotypes, E+X+, E+X-, E-X+ and E-X- in the normolipidaemic population are 0.68, 0.30, 0.02 and 0.00, respectively. Although the polymorphic nucleotide underlying the EcoRI RFLP creates an amino acid substitution in the apo B protein (Glu----Lys) in a region close to a putative LDL-receptor recognition site(s), we find no statistically significant difference in the frequency of the apo BGlu and apo BLys alleles in hyperlipidaemic patients (familial hypercholesterolaemia, type IIA with no tendon xanthomas, IIB and probably IV) and the normolipidaemic population. In contrast, we confirm previous findings, that the X+ allele is in linkage disequilibrium with a genetic locus that predisposes to the development of higher fasting plasma triglyceride levels than the X- allele. We have characterized a highly polymorphic region immediately 3' to the apo B gene. At least 5 alleles of this locus exist in the population and our family studies show it should be an extremely informative locus to use in studies where polymorphic or mutant apo B alleles are suspected to underly certain forms of familial hyperlipidaemia. DNA sequence analysis of this highly polymorphic locus shows that the variation is entirely attributable to the number of times the simple repeating sequence 5'-TTTATAATTAAAATATTTATAATTAAATAT-3' is present.
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PMID:Characterization of genetic markers in the 3' end of the apo B gene and their use in family and population studies. 289 57

In the UK, about 5% of patients with familial hypercholesterolaemia have a detectable deletion or rearrangement of part of the LDL-receptor gene. This results in the detection of shorter or abnormal sized fragments of the LDL-receptor gene in a Southern blot hybridization. This can be used to follow the inheritance of the defective gene, and for diagnosis in the families of these individuals. In the families of the rest of the patients, diagnosis may be possible using linked restriction fragment length polymorphisms (RFLPs) detected with the LDL-receptor probe. There are now ten common RFLPs of the LDL-receptor gene, with variable sites in the 3' half of the gene. Over 80% of patients are heterozygous for at least one of these RFLPs, and therefore potentially informative for DNA diagnosis. For a foetus at risk of homozygous familial hypercholesterolaemia, antenatal diagnosis may also be possible using these methods. However, family studies require samples to be available from affected or unaffected relatives of the patient, and this limits the applicability of the tests. For some mutations, the base pair change causing the defect in the LDL-receptor itself creates or destroys a site for a restriction enzyme. Such 'mutation-specific' RFLPs could be used for population screening, but so far have only been reported for the familial hypercholesterolaemia mutation that is common in Lebanon. In the future it may be possible to develop mutation-specific oligonucleotide probes for the diagnosis of familial hypercholesterolaemia. These would be appropriate for population screening or screening patients with hyperlipidaemia. This information may be useful if different mutations require different therapeutic strategies.
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PMID:The use of recombinant DNA techniques for the diagnosis of familial hypercholesterolaemia. 290 68


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