DESCRIPTION:This is an application to continue work initiated in 1987 in the RFHS to address whether knowledge about genomic variability may provide information for the prediction of CAD beyond that provided by the quantitative intermediate risk factors that link the effects of genetic and environmental variation to variation in risk of disease. This competing continuation application proposes five Specific Aims that take advantage of three major developments over the past five years: expanded theory for linkage and association studies, a human transcript map of over 8,000 genes, and the establishment of the RFHS resource of 575 pedigrees for which DNA samples measures of intermediate biological risk factors (plasma levels of apolipoprotein (apo) Al, apo All, apo B, apo Cll, apo Clll apo E, total cholesterol, high density lipoprotein (HDL) cholesterol, triglycerides, insulin, and glucose), body mass index smoking, and disease endpoints are available on the 3941 persons at no cost to this project. Specific Aims 1 and 2 will identify genomic regions containing new CAD susceptibility genes, using 234 tandem repeat marker loci at a 10 centimorgan (cM) density and the variance component method of linkage in 274 multigeneration pedigrees, both globally and in particular contexts defined by gender, age, (body mass index) BMI, and smoking. For those regions that show linkage, confirmatory linkage analysis will be conducted in a second independent sample of 301 multigeneration pedigrees. In regions where linkage is replicated, fine structure linkage analyses will be conducted, using additional marker loci, located approximately every 1 cM. Specific Aims 3 and 4 will identify functional DNA variations in the new candidate CAD susceptibility genes. Direct DNA sequencing and cladistic analyses will be used to estimate the average, context dependent, dominant, and epistatic effects associated with these functional DNA variations. Specific Aim 5 will estimate the association between the risk of CAD and functional genotypes identified by the cladistic analyses carried out in Specific Aims 3 and 4 before and after considering the intermediate biological risk factors that link the effects of genetic and environmental variation to variation in risk of disease.