Cardiovascular disease (CVD) is the largest cause of morbidity and mortality in the Western world. New risk factors for CVD include insulin resistance (IR) and chronic inflammation. The hypothesis of this proposal and its linked Progression R01 is that genetic factors are in significant measure responsible for the interrelationship between CVD, IR and inflammation, and that these can be identified by family studies utilizing high definition phenotyping of subclinical pathophysiologic processes, such as euglycemic clamp for IR and carotid intima-medial thickness (CIMT) by ultrasound for CVD, in a Mexican-American population at high risk for these disorders. In our prior work, we studied a large Mexican-American cohort, ascertained through an index case with coronary artery disease (CAD). Genome scans in the first half of this sample (Set 1) identified evidence for chromosomal loci for CIMT, for fasting insulin, and for IR. Aim 1 will confirm these loci by analysis of a genome wide scan in the second half of the sample (Set 2); followed by fine mapping with the goal of prioritizing the best peaks, between two and three, for use in Aim 2. Aim 2 will test all the genes under the "best" linkage peaks from Aim 1, taking advantage of growing resources that allow identification of tagged SNPs. This approach simultaneously avoids the limitation of trying to a priori decide what genes are true positional candidates, and yet by focusing on genes, is more efficient than a chromosomal marker approach. All genes under each peak will be tested in Set 1. Positive results will be confirmed using Set 2 and only those genes still positive will be evaluated further in Aim 4. This two-stage design provides the power to identify the relevant genes while minimizing false positives. In Aim 3, 20 biologic candidate genes identified as associated with IR, fasting insulin, or CIMT in Set 1, either during the first cycle of the Program (n=13) or suggested by the linked Progression R01 (n=7) (and tested in Set 1), will be tested in Set 2 to confirm the associations and prioritize the genes for study in Aim 4. These genes will have their haplotypes characterized in detail for testing in Set 2. In Aim 4, genes (from Aims 2 and 3) associated with CIMT, fasting insulin, and/or IR in Set 1 and confirmed in Set 2, will be sequenced in individuals with divergent haplotypes and phenotypes. New variants discovered by sequencing will be genotyped in the entire study population to assess the minimum variant(s) within each gene that appear responsible for the genetic effect. Gene-gene interactions will also be evaluated. A key strength of this proposal is that the size of the sample allows replication (Set 1 and Set 2) of both linkage and association results in the same population, with the same ethnicity, same ascertainment, and the same phenotyping. Identifying the genes for CIMT and IR in this understudied population will provide new tools for risk assessment and prevention. [unreadable] [unreadable] [unreadable]