The overall goal of this project is 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 appears to be influenced by a single major genetic locus with a dominant mode of inheritance and a common allele frequency.
The specific aims of this study are: 1) To identify, collect and construct a repository of immortalized cell lines and lipid and apo measurements from members of families informative for. ALP. 2) To test genes implicated in lipoprotein metabolism as possible candidate ALP genes and to use highly informative DNA probes to search the genome for linkage to the ALP gene. 3) To refine the model for the inheritance of ALP phenotypes and to test for genetic-environmental interactions. Forty informative families will be recruited for the repository. These families will be 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 will complete a medical history questionnaire and will provide a blood sample for ALP phenotype determination, for DNA studies, and for lipid and apo measurements. Linkage studies and LOD score analyses will begin with a candidate gene approach, and will continue by using DNA probes that reveal restriction fragment length polymorphisms (RFLPs) to search the genome for linkage to the ALP gene. When a linkage is found, ALP genotype information will be 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. This project is designed to identify a new gene involved in susceptibility to coronary heart disease. These studies could eventually lead to an understanding of how to modify the expression of the ALP gene and is associated risk for atherosclerosis in genetically susceptible individuals, through specific intervention strategies.
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