Our overall objective is to understand the role of apolipoprotein B and apolipoprotein A1 in the etiology of coronary artery disease (CAD).
Our specific aims are: 1) Using our previously characterized population of 200 index cases (100 men, 100 women) who underwent elective coronary arteriography at the Johns Hopkins Hospital, we propose to determine if the apolipoprotein B gene and apolipoprotein A1-C3-A4 gene cluster are independent predictors of CAD. Using cloned DNA fragments as molecular probes, the relation between DNA polymorphic sites within these two genes and CAD will be determined after other risk factors have been considered. Based on studies in first degree relatives of the index cases, haplotypes of DNA polymorphisms will be assigned and their association with CAD studied. 2) To determine if apolipoprotein B and apolipoprotein A1 levels aggregate in families and explain a significant proportion of the positive family history of CAD and to determine if hyperapo B and hypoalphalipoproteinemia segregate as Mendelian traits. Age adjusted and sex specific cut points derived from the Columbia population (100 males, 100 females) will be used to define hyperapoB and hypoalphalipoproteinemia in the 200 index cases and their first degree relatives (N = 900). Through genetic analysis of both apolipoprotein levels and lipoprotein phenotypes, we will test for genetic control of apolipoprotein B and apolipoprotein A1 levels. 3) To determine if there is linkage between a) hyperapoB and haplotypes of the apolipoprotein B gene; b) hyperapoB and the Ag polymorphisms; c) hypoalphalipoproteinemia and haplotypes of the apolipoprotein A1-C3-A4 gene cluster; and to study genetic defects in the apolipoprotein B gene and the apolipoprotein A1-C3-A4 gene cluster. These studies may improve our understanding of the pathophysiology of CAD, of the genetic and biochemical defects of hyperapoB and hypoalphalipoproteinemia and may explain a significant proportion of the risk of developing CAD that is currently poorly understood.
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