APOLIPOPROTEIN POLYMORPHISMS AND RISK OF CHD

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Coronary Heart Disease (CHD) is a major cause of early death in the U.S. Numerous epidemiological studies have shown that the risk of CHD is strongly influenced by plasma lipid levels, especially HDL and LDL cholesterol, and their specific apolipoprotein constituents. Genetic studies have established significant heritability of these lipid components, and have also identified relatively rare major genes that result in extreme lipid values and increased risk of CHD. Recently, geneticist have identified a number of segregating polymorphisms at the four major apolipoprotein genomic regions, using a combination of protein and DNA assays. However, the relationship between these polymorphisms and risk of CHD has not yet been properly defined. This study aims to determine the relative risk of angiographically defined coronary artery disease (CAD) in a defined population (Washach Front and southern Idaho), due to genetic polymorphism at the four apolipoprotein genomic regions. We will use a case- control approach to identify the specific polymorphisms (both single sites, and haplotypes) that confer elevated risk of CAD, and determine whether these polymorphisms are associated with distinct lipid profiles, or interact with known environmental risk factors. This will be achieved by evaluating DNA polymorphisms, protein polymorphisms, lipid profiles, and epidemiological risk factors in 400 cases with angiographically defined disease, 400 age-sex matched controls with angiographically proven normal coronary arteris, and 400 age-sex matched controls with angiographically proven normal coronary arteris, and 400 age-sex matched random controls. Also, 800 first degree relatives will be typed for DNA polymorphisms, to define complex haplotypes for each of these genomic regions, as combinations of several segregating polymorphisms. The contribution of these four apolipoprotein genomic regions to risk of CAD will be estimated in a number of ways. First, the direct association of CAD risk with the presence of specific alleles, or genotypes, will be estimated be calculating odds ratios. Second, the influence of genetic segregation at these four apolipoprotein regions on lipid profiles will be estimated to evaluate the indirect influence of these loci on CAD risk. Third, interactions between the polymorphisms at these loci and specific environmental risk factors will be evaluated to determine to what extent risk of CAD is due to interaction between deleterious environments and susceptible genotypes.