The most important cause of death and disability in the Western world is atherosclerotic coronary artery disease (CAD) and its primary complication-acute myocardial infarction (MI). The long-term objective of this project is to define genetic pathways and molecular mechanisms for CAD and MI. The central hypothesis of this proposal is that the pathogenesis of CAD/MI involves functional mutations in key genes that perturb the complex molecular processes involved in CAD/MI. To this end, recently, in a large pedigree with autosomal dominant CAD/MI, we identified a specific MEF2A mutation (21-bp deletion) that appears to be responsible for this family's CAD/MI (Science, in press). Furthermore, we have completed a genomewide scan for susceptibility genes for CAD/MI in a well characterized U.S. cohort consisting of 1,163 affected persons in 428 multiplex families with premature CAD and MI (average age at onset: 44.4 + 9.7 years). Of eight novel significant susceptibility loci detected for MI linkage to the chromosomal region lp34-36 showed multipoint allelesharing P values of <10 -12 (LOD = 11.68). The present proposal is driven by these exciting results. The specific aims are: Specific Aim 1: To map and identify a novel CAD/MI gene using single large families and model-based linkage analysis, and positional cloning. First, we will continue to validate our finding that mutations in MEF2A cause familial CAD/MI by characterizing the MEF2A knockout mice and transgenic mice for phenotype related to CAD/MI. A series of molecular and cell biological experiments are designed to explore the molecular mechanisms of the MEF2A deletion. We will also identify SNPs in MEF2A and determine whether some of the SNPs increase or decrease the risk of common complex CAD/MI by association studies. Secondly, we plan to continue to use model-based linkage analysis and positional cloning to map and identify at least one new CAD/MI gene. We have recruited three large and extended CAD/MI pedigrees that are not linked toMEF2A, and each family has statistically sufficient power (simulated LOD scores of 3.53, 7.22, and 6.62, respectively) to conduct a genomewide scan of significant linkage to CAD and MI. Furthermore, 16 families of more than four affected individuals have been identified with an average of 27 living siblings and parents per family for this study. Specific Aim 2: To identify the susceptibility gene for MI on the chromosomal region lp34-36, We will focus on the chromosome lp34-36 MI locus for our follow-up gene discovery effort because this is the most significant linkage identified for MI to date (LOD score of 11.68). We will perform fine mapping, identification of candidate genes, SNP identification and genotyping_ family-TDT analysis (Sibship Disequilibrium Test) as well as population-based case-control studies to determine whether a specific SNP or SNP haplotype in a candidate gene is associated with MI. The accomplishment of research objectives in this proposal has the potential to have a substantial impact on the understanding of the molecular mechanism of CAD and MI, thereby facilitating better prevention, diagnosis and therapy.