Cardiovascular disease (CVD) remains the leading cause of death in the U.S.A., and lipid and lipoprotein phenotypes are important risk factors for susceptibility to CVD. However, with a few exceptions, the identification of genes that affect lipid and lipoprotein phenotypes and the interactions of such genes with environment remain unclear.
The aims of this project are to locate and define effects of genes affecting lipid and lipoprotein phenotypes. These phenotypes include serum levels of lipids, apolipoproteins and Lp(a); distributions of cholesterol and apoliproteins within lipoprotein size classes; LDL size; and levels of activities of enzymes involved in lipoprotein metabolism [e.g., lecithin:cholesterol acyltransferase (LCAT) activity]. Given the relationship between dietary fat and cholesterol and increased risk of atherosclerosis, as well as the unique strengths of the baboon colony, we are particularly interested in locating and characterizing genes that influence lipemic response to components of an atherogenic diet. To locate and define effects of these genes, we will exploit several unique strengths of our baboon colony including (1) lipoprotein phenotype data on 750 non-inbred pedigreed baboons phenotyped on each of three diets differing in level of fat and cholesterol, (2) lipoprotein phenotype data on 541 selectively inbred progeny and their parents phenotyped on each of the three diets, and (3) genotypic data on candidate gene polymorphisms and 350 highly polymorphic short tandem repeat (STR) markers (a 10 cM map) on each of the 750 non-inbred baboons and 175 STR markers (a 20 cM map) on each of each of the 541 inbred progeny and their parents. We will perform segregation and linkage analyses in a genomic search to locate and define effects of genes that account for a relatively large proportion (10% or more) of the variation of these lipid and lipoprotein phenotypes. This information also will enable us to detect recessive alleles and less frequent alleles that may influence susceptibility to CVD.
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