Because advanced atherosclerosis is usually present by the time of presentation with symptoms of coronary heart disease (CHD), it would be optimal to identify early reliable markers for the disease, targeting the high risk population for preventive therapy. Disorders of the plasma lipid transport system represent one significant class of identifiable risk factors for the development of premature CHD. Such disorders can result from defects in the structure or biosynthesis of apolipoproteins, the lipid binding proteins involved in transport of cholesterol, triglycerides and phospholipids in the plasma. The genes coding for three of these apolipoproteins, namely apoAI, apoCIII and apoAIV, are clustered within a 15 kilobase DNA segment in the long arm of chromosome 11. It has recently been shown that the patterns of eleven restriction site polymorphisms (haplotypes) identified within this gene cluster represent a highly informative marker for genetic and epidemiologic studies. In this proposal, the possible association and genetic linkage of these haplotypes with high density lipoprotein (HDL) deficiency (hypoalphalipoproteinemia) in children will be studied. These studies will lend insight to the mode of inheritance of this trait and will permit estimation of its heterogeneity. Subsequently, ApoAI, apoCIII and apoAIV genes representing those haplotypes which cosegregate and are associated with HDL deficiency will be cloned into gene expression systems in which transcription, pre- mRNA splicing, translation and regulating cis-elements and trans- acting factors can be evaluated. The discovery and detailed characterization of mutations within or near the apoAI, apoCIII and apoAIV genes may elucidate mechanisms by which hypoalpholipoproteinemia predisposes to premature CHD, furthering our understanding of atherogenesis and of gene function, and offering a means by which definitive early diagnosis and preventive treatment of this disorder might be accomplished.
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| Dejager, S; Mietus-Synder, M; Pitas, R E (1993) Oxidized low density lipoproteins bind to the scavenger receptor expressed by rabbit smooth muscle cells and macrophages. Arterioscler Thromb 13:371-8 |
| Mietus-Snyder, M; Sladek, F M; Ginsburg, G S et al. (1992) Antagonism between apolipoprotein AI regulatory protein 1, Ear3/COUP-TF, and hepatocyte nuclear factor 4 modulates apolipoprotein CIII gene expression in liver and intestinal cells. Mol Cell Biol 12:1708-18 |
| Mietus-Snyder, M; Charmley, P; Korf, B et al. (1990) Genetic linkage of the human apolipoprotein AI-CIII-AIV gene cluster and the neural cell adhesion molecule (NCAM) gene. Genomics 7:633-7 |
