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

A 49 year-old hypercholesterolemic male with marked electrocardiographic ST segment depression on exercise testing was found to have an apo E E3/3 phenotype by isoelectric focusing, but an APOE E4/3 genotype using HhaI restriction isotyping. DNA sequence analysis of the proband's APOE gene found a G-->C point mutation at codon 251. This predicted a change in the amino acid encoded by codon 251, from arginine to glycine. The mutation occurred on an allele that encoded arginine at position 112 and this variant was named APOE R112; R251G. The R251G change altered a recognition site for the endonuclease StuI and was the basis for a restriction isotyping method to rapidly screen for this mutation. In relatives of the proband, APOE R112; R251G was consistently found in subjects with both hyperlipidemia and atherosclerosis. Apo E R112; R251G-containing very low density lipoproteins bound normally to macrophages in vitro. However, the proband had an abnormal post-prandial lipoprotein response to a dietary fat challenge. The association of APOE R112; R251G with abnormal phenotypes suggests that the amino acid change in the carboxy-terminal, perhaps in combination with the common amino acid polymorphism at codon 112, has a functional impact upon lipoprotein metabolism in members of this family.
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PMID:Apolipoprotein E R112; R251G: a carboxy-terminal variant found in patients with hyperlipidemia and coronary heart disease. 936 Jun 38

Microvascular abnormalities caused by endothelial dysfunction seem to be responsible for the myocardial ischemia in patients with cardiac syndrome X (CSX). Nitric oxide is a key mediator of endothelial function and is synthesized by endothelial nitric oxide synthase (eNOS). We investigated if the 3 potential polymorphisms of the eNOS gene (VNTR in intron 4, T786C polymorphism in the promoter region, and G894T polymorphism in exon 7) are independent risk factors for CSX. Sixty-nine patients with CSX and 73 healthy controls were studied. Genotypes were determined through polymerase chain reaction with or without restriction endonuclease digestions. Genotype distribution was significantly different between patients with CSX and controls for intron 4aa (allele for 4 repeats of 27 bp), intron 4aa genotype frequency being 3.2% and 6.8%, respectively. The presence of intron 4a is 3.2 (odds ratio) times protective (95% confidence interval, 1.5-6.8) for the risk of CSX disease. The protective effect of intron 4a polymorphism also holds after adjustment for age and sex and when the study group is limited to those without hypertension and hyperlipidemia. No significant difference was observed in genotype distribution of G894T and T786C polymorphism between patients with CSX and controls. In conclusion, intron 4aa genotype of eNOS gene is protective for CSX. No association was found between promoter and exon 7 polymorphisms of eNOS gene and CSX.
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PMID:Intron 4 VNTR polymorphism of eNOS gene is protective for cardiac syndrome X. 1990 45

Atherosclerosis (AS) is a disease induced by multiple factors, including genetic and environmental elements. The aim of the present study is to investigate the comprehensive effects of high cholesterol, high methionine diet, and apolipoprotein E deficiency (ApoE(-/-)) on the pathogenesis of AS. ApoE(-/-) mice were fed with high cholesterol and methionine diet for 15 weeks to induce hyperlipidemia and hyperhomocysteinemia. The methylation levels of genomic DNA (gDNA) and B1 repetitive elements in aortic tissues were measured by both methylation-dependent restriction analysis and nested methylation-specific polymerase chain reaction (PCR). Methylation sequence-bias pattern was assayed by DNA methyl-accepting capacity with restriction endonuclease digestion. The mRNA expression of DNA methyltransferase-1, 3 (DNMT1, 3) was detected by real-time PCR. The concentrations of S-adenosylmethionine (SAM) and S-adenosylhomocysteine (SAH) were determined by high-performance liquid chromatography. The results showed hypomethylation of gDNA and B1 repetitive elements. The mRNA expression of DNMT1 was reduced. The levels of SAM, SAH, and SAM/SAH ratio were increased. The atherosclerotic lesion areas strongly correlated with the risk factors. The distribution of DNA demethylation was preferred to non-CpG islands, which may suggest the major impact of hypomethylation on DNA integrity and genomic instability. Overall, our data unequivocally showed that the comprehensive role of high cholesterol, high methionine diet, and ApoE(-/-) is not uniformly consistent with the role of a single risk factor. The DNA methylation pattern in AS is quite complex and depends on genetic background and many involved risk factors.
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PMID:The comprehensive effects of hyperlipidemia and hyperhomocysteinemia on pathogenesis of atherosclerosis and DNA hypomethylation in ApoE-/- mice. 2301 35

The rat is a time-honored traditional experimental model animal, but its use is limited due to the difficulty of genetic modification. Although engineered endonucleases enable us to manipulate the rat genome, it is not known whether the newly identified endonuclease Cpf1 system is applicable to rats. Here we report the first application of CRISPR-Cpf1 in rats and investigate whether Apoe knockout rat can be used as an atherosclerosis model. We generated Apoe- and/or Ldlr-deficient rats via CRISPR-Cpf1 system, characterized by high efficiency, successful germline transmission, multiple gene targeting capacity, and minimal off-target effect. The resulting Apoe knockout rats displayed hyperlipidemia and aortic lesions. In partially ligated carotid arteries of rats and mice fed with high-fat diet, in contrast to Apoe knockout mice showing atherosclerotic lesions, Apoe knockout rats showed only adventitial immune infiltrates comprising T lymphocytes and mainly macrophages with no plaque. In addition, adventitial macrophage progenitor cells (AMPCs) were more abundant in Apoe knockout rats than in mice. Our data suggest that the Cpf1 system can target single or multiple genes efficiently and specifically in rats with genetic heritability and that Apoe knockout rats may help understand initial-stage atherosclerosis.
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PMID:Knockout rat models mimicking human atherosclerosis created by Cpf1-mediated gene targeting. 3079 31