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To map the major gene influencing low-density lipoprotein subclass phenotypes, denoted atherogenic lipoprotein (ALP) phenotypes, with a long term goal of cloning the ALP gene and understanding its role in genetic susceptibility to atherosclerosis.
ALP phenotype B (ALP-B), characterized by a predominance of small, dense LDL particles as determined by gradient gel electrophoresis, has been associated with increased risk of myocardial infarction and a constellation of atherogenic lipid and apolipoprotein (apo) changes. Based on complex segregation analysis, ALP-B appeared to be influenced by a single major genetic locus with a dominant mode of inheritance and a common allele frequency. This project was designed to identify a new gene involved in susceptibility to coronary heart disease.
The investigators identified, collected and constructed a repository of immortalized cell lines and lipid and apo measurements from members of families informative for ALP. They tested genes implicated in lipoprotein metabolism as possible candidate ALP genes and used highly informative DNA probes to search the genome for linkage to the ALP gene. They also refined the model for the inheritance of ALP phenotypes and tested for genetic-environmental interactions. Forty informative families were recruited for the repository. The families were identified through two sources of probands: former participants in a cholesterol-lowering diet study and patients seen at the lipid clinics at the University of Washington. Each participating family member completed a medical history questionnaire and provided a blood sample for ALP phenotype determination, for DNA studies, and for lipid and apo measurements. Linkage studies and LOD score analyses began with a candidate gene approach, and continued by using DNA probes that revealed restriction fragment length polymorphisms (RFLPs) to search the genome for linkage to the ALP gene. When a linkage was found, ALP genotype information was used to refine the statistical model describing the inheritance of ALP phenotypes, and to evaluate genetic-environmental interactions involving lipid and apo levels and environmental and behavioral factors.
Observational Model: Natural History
National Heart, Lung, and Blood Institute (NHLBI)
Published on BioPortfolio: 2014-08-27T03:57:50-0400
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Lack of perfusion in the EXTREMITIES resulting from atherosclerosis. It is characterized by INTERMITTENT CLAUDICATION, and an ANKLE BRACHIAL INDEX of 0.9 or less.
Complete blockage of blood flow through one of the CORONARY ARTERIES, usually from CORONARY ATHEROSCLEROSIS.
A drug that has been given by mouth in the treatment of atherosclerosis and other vascular disorders, hyperlipidemias, and thrombo-embolic disorders. (From Martindale, The Extra Pharmacopoeia, 30th ed, p1408)
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A measurement of the thickness of the carotid artery walls. It is measured by B-mode ULTRASONOGRAPHY and is used as a surrogate marker for ATHEROSCLEROSIS.
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Cloning in biology is the process of producing similar populations of genetically identical individuals that occurs in nature when organisms such as bacteria, insects or plants reproduce asexually. Cloning in biotechnology refers to processes used to cre...