The study was renewed again in 1997 with five specific aims. Aims 1 and 2 identified genomic regions containing new coronary artery disease 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 and smoking. For those regions that showed linkage, confirmatory linkage analysis was conducted in a second independent sample of 301 multigeneration pedigrees. In regions where linkage was replicated, fine structure linkage analyses was conducted, using additional marker loci, located approximately every 1 cM. Specific aims 3 and 4 identified functional DNA variations in the new candidate coronary artery disease susceptibility genes. Direct DNA sequencing and cladistic analyses were used to estimate the average, context dependent, dominant, and epistatic effects associated with these functional DNA variations. Specific aim 5 estimated the association between the risk of coronary artery disease 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.